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  • 101. Kouyoumdjian, Joao Aris
    et al.
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Stimulated jitter with concentric needle in 42 myasthenia gravis patients2013In: Arquivos de Neuro-Psiquiatria, ISSN 0004-282X, E-ISSN 1678-4227, Vol. 71, no 4, p. 237-243Article in journal (Refereed)
    Abstract [en]

    Objective: To estimate jitter parameters in myasthenia gravis in stimulated frontalis and extensor digitorum muscles using the concentric needle electrode. Methods: Forty-two confirmed myasthenia gravis patients, being 22 males (aged 45.6 +/- 17.2 years-old) were studied. Jitter was expressed as the mean consecutive difference (MCD). Results: MCD in extensor digitorum was 61.6 mu s (abnormal in 85.7%) and in frontalis 57.3 mu s (abnormal in 88.1%). Outliers represented 90.5% for extensor digitorum and 88.1% for frontalis. At least one jitter parameter was abnormal in 90.5% of the combined studies. Acetylcholine receptor antibody was abnormal in 85.7% of the cases. Conclusions: Stimulated jitter recordings measured from muscles using concentric needle electrode can be used for myasthenia gravis diagnosis with high sensitivity. Extensive normative studies are still lacking and, therefore, borderline findings should be judged with great caution.

  • 102. Kouyoumdjian, Joao Aris
    et al.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Concentric needle jitter on stimulated Orbicularis Oculi in 50 healthy subjects2011In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 122, no 3, p. 617-622Article in journal (Refereed)
    Abstract [en]

    Objectives: The aim of this study was to estimate the jitter parameters in healthy controls in stimulated Orbicularis Oculi (OOc) muscle using concentric needle electrode (CNE). Methods: Fifty healthy subjects, 13 males and 37 females (21-56 years, mean age of 38 +/- 9.2 years) were studied. The zygomatic branch of facial nerve was stimulated with a bar electrode. Jitter was expressed as the mean consecutive difference (MCD). Filter settings 1000 Hz-10 kHz. Results: The mean MCD from individual studies (n = 50, Gaussian distribution) was 21.5 +/- 1.99 mu s (median = 21 mu s), ranging from 17.8 to 26 mu s (upper limit, 97.5%, 25.5 mu s). The mean and median MCD from all potentials (n = 1500, non-Gaussian distribution) were 21.6 and 21 mu s, ranging from 7.1 to 39 mu s (upper limit, 97.5%, 33.4 mu s). Conclusions: Suggested practical limits in the OOc for mean MCD was 26 mu s and for outliers 34 mu s. Significance: Stimulation jitter recordings with CNE could be used in practice but borderline findings should be judged with great caution until larger database obtained with uniform setting available.

  • 103. Kouyoumdjian, João Aris
    et al.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Reference jitter values for concentric needle electrodes in voluntarily activated extensor digitorum communis and orbicularis oculi muscles.2008In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 37, no 6, p. 694-699Article in journal (Refereed)
    Abstract [en]

    The aim of this study was to estimate normal jitter in voluntarily activated extensor digitorum communis (EDC) and orbicularis oculi (OOc) muscles using a disposable concentric needle electrode (CNE). The EDC of 67 normal subjects (22 males and 45 females, mean age 35.5 ± 10.2 years) and the OOc of 50 normal subjects (13 males and 37 females, mean age 37.9 ± 9.6 years) were studied. Jitter values were expressed as the mean consecutive difference (MCD) of 20 potential pairs. The mean MCD for EDC was 23.6 ± 3.1 µs (upper 95% confidence limit [CL]: 29.7 µs). The mean MCD of all potential pairs (n = 1340) was 23.5  ± 7.3 µs (95% CL: 38.2 µs). The mean MCD for the 18th highest value was 31.4 ± 4.9 µs (95% CL: 41.2 µs). The mean MCD for OOc was 24.7 ± 3.1 µs (95% CL: 31.0 µs). The mean MCD of all potential pairs (n = 1000) was 24.7 ± 7.1 µs (95% CL: 39.0 µs). The mean MCD for the 18th highest value was 32.7 ± 4.1 µs (95% CL: 40.9 µs). Our reported CNE jitter values obtained during voluntary activation represent the largest series currently available. The suggested practical limit in the EDC for mean MCD was 30 µs and for outliers was 42 µs, and in the OOc for mean MCD was 31 µs and 41 µs for outliers. The present study confirms that CNE can be used to assess jitter values, although certain precautions must be taken.

  • 104. Krivickas, Lisa S.
    et al.
    Dorer, David J.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Frontera, Walter R.
    Relationship between force and size in human single muscle fibres2011In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 96, no 5, p. 539-547Article in journal (Refereed)
    Abstract [en]

    When the contractile properties of single muscle fibres are studied, force is typically normalized by fibre cross-sectional area and expressed as specific force. We studied a set of 2725 chemically skinned human single muscle fibres from 119 healthy adults to determine whether specific force is the optimal way to express the relationship between single-fibre force and size. A linear mixed effects model was used to estimate the slope and slope variability among individuals of log-log plots of force and diameter. For type I fibres, the slope estimate was 0.99 (95% confidence interval 0.36-1.62), and for type IIa fibres it was 0.94 (95% confidence interval 0.77-1.11), indicating that force is proportional to fibre diameter, rather than to cross-sectional area. If force were proportional to cross-sectional area, the slope estimate would be 2.0. In future studies using the chemically skinned single fibre preparation, force may be normalized to fibre diameter rather than cross-sectional area. We propose that a new term, 'normalized force', be used for this variable, with units of newtons per metre. We demonstrate using our data set that when populations of single fibres are compared with one another, the determination of whether the size and force relationship is the same or different is dependent upon the method used to account for fibre size (i.e. specific force versus 'normalized force').

  • 105. Kurapati, Ramakrishna
    et al.
    McKenna, Caoimhe
    Lindqvist, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Williams, Debbie
    Simon, Michelle
    LeProust, Emily
    Baker, Jane
    Cheeseman, Michael
    Carroll, Natalie
    Denny, Paul
    Laval, Steve
    Lochmueller, Hanns
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Blanco, Gonzalo
    Myofibrillar myopathy caused by a mutation in the motor domain of mouse MyHC IIb2012In: Human Molecular Genetics, ISSN 0964-6906, E-ISSN 1460-2083, Vol. 21, no 8, p. 1706-1724Article in journal (Refereed)
    Abstract [en]

    Ariel is a mouse mutant that suffers from skeletal muscle myofibrillar degeneration due to the rapid accumulation of large intracellular protein aggregates. This fulminant disease is caused by an ENU-induced recessive mutation resulting in an L342Q change within the motor domain of the skeletal muscle myosin protein MYH4 (MyHC IIb). Although normal at birth, homozygous mice develop hindlimb paralysis from Day 13, consistent with the timing of the switch from developmental to adult myosin isoforms in mice. The mutated myosin (MYH4(L342Q)) is an aggregate-prone protein. Notwithstanding the speed of the process, biochemical analysis of purified aggregates showed the presence of proteins typically found in human myofibrillar myopathies, suggesting that the genesis of ariel aggregates follows a pathogenic pathway shared with other conformational protein diseases of skeletal muscle. In contrast, heterozygous mice are overtly and histologically indistinguishable from control mice. MYH4(L342Q) is present in muscles from heterozygous mice at only 7% of the levels of the wild-type protein, resulting in a small but significant increase in force production in isolated single fibres and indicating that elimination of the mutant protein in heterozygotes prevents the pathological changes observed in homozygotes. Recapitulation of the L342Q change in the functional equivalent of mouse MYH4 in human muscles, MYH1, results in a more aggregate-prone protein.

  • 106. Lang, Dean H.
    et al.
    Conroy, E
    Lionikas, Arimantas
    Mack, A
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Vogler, P
    Vandenbergh, J
    Blizard, A
    McClearn, E
    Sharkey, Neil A.
    Bone, Muscle, and Physical Activity: Structural Equation Modeling of Relationships and Genetic Influence With Age2009In: Journal of Bone and Mineral Research, ISSN 0884-0431, E-ISSN 1523-4681, Vol. 24, no 9, p. 1608-1617Article in journal (Refereed)
    Abstract [en]

    Correlations among bone strength, muscle mass, and physical activity suggest that these traits may be modulated by each other and/or by common genetic and/or environmental mechanisms. This study used structural equation modeling (SEM) to explore the extent to which select genetic loci manifest their pleiotropic effects through functional adaptations commonly referred to as Wolff's law. Quantitative trait locus (QTL) analysis was used to identify regions of chromosomes that simultaneously influenced skeletal mechanics, muscle mass, and/or activity-related behaviors in young and aged B6xD2 second-generation (F-2) mice of both sexes. SEM was used to further study relationships among select QTLs, bone mechanics, muscle mass, and measures of activity. The SEM approach provided the means to numerically decouple the musculoskeletal effects of mechanical loading from the effects of other physiological processes involved in locomotion and physical activity. It was found that muscle mass was a better predictor of bone mechanics in young females, whereas mechanical loading was a better predictor of bone mechanics in older females. An activity-induced loading factor positively predicted the mechanical behavior of hindlimb bones in older males; contrarily, load-free locomotion (i.e., the remaining effects after removing the effects of loading) negatively predicted bone performance. QTLs on chromosomes 4, 7, and 9 seem to exert some of their influence on bone through actions consistent with Wolff's Law. Further exploration of these and other mechanisms through which genes function will aid in development of individualized interventions able to exploit the numerous complex pathways contributing to skeletal health. J Bone Miner Res 2009;24:1608-1617. Published online on April 27, 2009; doi: 10.1359/JBMR.090418

  • 107.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Acute Quadriplegic Myopathy: An Acquired "Myosinopathy"2008In: Advances in Experimental Medicine and Biology, ISSN 0065-2598, E-ISSN 2214-8019, Vol. 642, p. 92-98Article in journal (Refereed)
    Abstract [en]

    Acquired neuromuscular disorders have been shown to be very common in critically ill patients receiving prolonged mechanical ventilation in the intensive care unit (ICU). Acute Quadriplegic Myopathy (AQM) is a specific acquired myopathy in ICU patients. Patients with AQM are characterized by severe muscle weakness and atrophy of spinal nerve innervated limb and trunk muscles, while cranial nerve innervated craniofacial muscles, sensory and cognitive functions are spared or less affected. The muscle weakness is associated with altered muscle membrane properties and a preferential loss of the motor protein myosin and myosin-associated thick filament proteins. Prolonged mechanical ventilation, muscle unloading, postsynaptic block of neuromuscular transmission, sepsis and systemic corticosteroid hormone treatment have been suggested as important triggering factors in AQM. However, the exact mechanisms underlying the loss of thick filament proteins are not known, though enhanced myofibrillar protein degradation in combination with a downregulation of protein synthesis at the transcriptional level play important roles.

  • 108.
    Larsson, Lars
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Wang, Xin
    Fushun, Yu
    Höök, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Borg, Kristian
    Chong, Stephen M
    Jin, J-P
    Adaptation by alternative RNA splicing of slow troponin T isoforms in type 1 but not type 2 Charcot-Marie-Tooth disease2008In: American Journal of Physiology - Cell Physiology, ISSN 0363-6143, E-ISSN 1522-1563, Vol. 295, no 3, p. 722-731Article in journal (Refereed)
    Abstract [en]

    Slow troponin T (TnT) plays an indispensable role in skeletal muscle function. Alternative RNA splicing in the NH2-terminal region produces high-molecular-weight (HMW) and low-molecular-weight (LMW) isoforms of slow TnT. Normal adult slow muscle fibers express mainly HMW slow TnT. Charcot-Marie-Tooth disease (CMT) is a group of inherited peripheral polyneuropathies caused by various neuronal defects. We found in the present study that LMW slow TnT was significantly upregulated in demyelination form type 1 CMT (CMT1) but not axonal form type 2 CMT (CMT2) muscles. Contractility analysis showed an increased specific force in single fibers isolated from CMT1 but not CMT2 muscles compared with control muscles. However, an in vitro motility assay showed normal velocity of the myosin motor isolated from CMT1 and CMT2 muscle biopsies, consistent with their unchanged myosin isoform contents. Supporting a role of slow TnT isoform regulation in contractility change, LMW and HMW slow TnT isoforms showed differences in the molecular conformation in conserved central and COOH-terminal regions with changed binding affinity for troponin I and tropomyosin. In addition to providing a biochemical marker for the differential diagnosis of CMT, the upregulation of LMW slow TnT isoforms under the distinct pathophysiology of CMT1 demonstrates an adaptation of muscle function to neurological disorders by alternative splicing modification of myofilament proteins.

  • 109.
    Lewandowska, Marta
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Bogatikov, Evgenii
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hierlemann, Andreas R.
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Basel, Switzerland.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Long-Term High-Density Extracellular Recordings Enable Studies of Muscle Cell Physiology2018In: Frontiers in Physiology, ISSN 1664-042X, E-ISSN 1664-042X, Vol. 9, article id 1424Article in journal (Refereed)
    Abstract [en]

    Skeletal (voluntary) muscle is the most abundant tissue in the body, thus making it an important biomedical research subject. Studies of neuromuscular transmission, including disorders of ion channels or receptors in autoimmune or genetic neuromuscular disorders, require high-spatial-resolution measurement techniques and an ability to acquire repeated recordings over time in order to track pharmacological interventions. Preclinical techniques for studying diseases of neuromuscular transmission can be enhanced by physiologic ex vivo models of tissue-tissue and cell-cell interactions. Here, we present a method, which allows tracking the development of primary skeletal muscle cells from myoblasts into mature contracting myotubes over more than 2 months. In contrast to most previous studies, the myotubes did not detach from the surface but instead formed functional networks between the myotubes, whose electrical signals were observed over the entire culturing period. Primary cultures of mouse myoblasts differentiated into contracting myotubes on a chip that contained an array of 26,400 platinum electrodes at a density of 3,265 electrodes per mm(2). Our ability to track extracellular action potentials at subcellular resolution enabled study of skeletal muscle development and kinetics, modes of spiking and spatio-temporal relationships between muscles. The developed system in turn enables creation of a novel electrophysiological platform for establishing ex vivo disease models.

  • 110.
    Lewandowska, Marta K.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Basel, Switzerland..
    Radivojevic, Milos
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Basel, Switzerland..
    Jaeckel, David
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Basel, Switzerland..
    Mueller, Jan
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Basel, Switzerland..
    Hierlemann, Andreas R.
    Swiss Fed Inst Technol, Dept Biosyst Sci & Engn, Bio Engn Lab, Basel, Switzerland..
    Cortical Axons, Isolated in Channels, Display Activity-Dependent Signal Modulation as a Result of Targeted Stimulation2016In: Frontiers in Neuroscience, ISSN 1662-4548, E-ISSN 1662-453X, Vol. 10, article id 83Article in journal (Refereed)
    Abstract [en]

    Mammalian cortical axons are extremely thin processes that are difficult to study as a result of their small diameter: they are too narrow to patch while intact, and super-resolution microscopy is needed to resolve single axons. We present a method for studying axonal physiology by pairing a high-density microelectrode array with a microfluidic axonal isolation device, and use it to study activity-dependent modulation of axonal signal propagation evoked by stimulation near the soma. Up to three axonal branches from a single neuron, isolated in different channels, were recorded from simultaneously using 10-20 electrodes per channel. The axonal channels amplified spikes such that propagations of individual signals along tens of electrodes could easily be discerned with high signal to noise. Stimulation from 10 up to 160 Hz demonstrated similar qualitative results from all of the cells studied: extracellular action potential characteristics changed drastically in response to stimulation. Spike height decreased, spike width increased, and latency increased, as a result of reduced propagation velocity, as the number of stimulations and the stimulation frequencies increased. Quantitatively, the strength of these changes manifested itself differently in cells at different frequencies of stimulation. Some cells' signal fidelity fell to 80% already at 10 Hz, while others maintained 80% signal fidelity at 80 Hz. Differences in modulation by axonal branches of the same cell were also seen for different stimulation frequencies, starting at 10 Hz. Potassium ion concentration changes altered the behavior of the cells causing propagation failures at lower concentrations and improving signal fidelity at higher concentrations.

  • 111.
    Li, M
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, M
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, J
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Scaling of motility speed and its temperature sensitivity in mammals representing a 5,500-fold difference in body size2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 4, p. 671-681Article in journal (Refereed)
    Abstract [en]

    Aim: 

    The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures.

    Methods: 

    A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C.

    Results: 

    The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature.

    Conclusion: 

    The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 112.
    Li, Meishan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Force-generating capacity of human myosin isoforms extracted from single muscle fibre segments2010In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 588, no 24, p. 5105-5114Article in journal (Refereed)
    Abstract [en]

    Muscle, motor unit and muscle fibre type-specific differences in force-generating capacity have been investigated for many years, but there is still no consensus regarding specific differences between slow- and fast-twitch muscles, motor units or muscle fibres. This is probably related to a number of different confounding factors disguising the function of the molecular motor protein myosin. We have therefore studied the force-generating capacity of specific myosin isoforms or combination of isoforms extracted from short single human muscle fibre segments in a modified single fibre myosin in vitro motility assay, in which an internal load (actin-binding protein) was added in different concentrations to evaluate the force-generating capacity. The force indices were the x-axis intercept and the slope of the relationship between the fraction of moving filaments and the α-actinin concentration. The force-generating capacity of the β/slow myosin isoform (type I) was weaker (P < 0.05) than the fast myosin isoform (type II), but the force-generating capacity of the different human fast myosin isoforms types IIa and IIx or a combination of both (IIax) were indistinguishable. A single fibre in vitro motility assay for both speed and force of specific myosin isoforms is described and used to measure the difference in force-generating capacity between fast and slow human myosin isoforms. The assay is proposed as a useful tool for clinical studies on the effects on muscle function of specific mutations or post-translational modifications of myosin.Myosin is the molecular motor protein in skeletal muscle that generates force and movement. It is expressed in multiple isoforms that have different enzymatic properties. There are isoform specific differences in contractile speed, but there is no consensus if the force generating capacity differs between isoforms. In this study we have modified a single fibre in vitro motility assay to measure both force and speed generated by specific myosin isoforms extracted from short single human muscle fibre segments. It is shown that human slow myosin is weaker and slower than fast myosin. This assay is put forward as a useful tool for future investigations on myosin function in response to modifications associated with muscle disease or ageing.

  • 113.
    Li, Meishan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, Mingxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, J O
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    There is no slowing of motility speed with increased body size in rat, human, horse and rhinoceros independent on temperature and skeletal muscle myosin isoform2011In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 202, no 4, p. 671-681Article in journal (Refereed)
    Abstract [en]

    Aim:  The predictions of scaling of skeletal muscle shortening velocity made by A.V. Hill 60-years ago have proven to be remarkably accurate at the cellular level. The current investigation looks to extend the study of scaling of contractile speed to the level of the molecular motor protein myosin at both physiological and unphysiological low temperatures. Methods:  A single muscle cell in vitro motility assay to test myosin function, i.e. myosin extracted from short single muscle fibre segments, was used in four species representing a 5 500-fold difference in body mass (rat, man, horse and rhinoceros) at temperatures ranging from 15 to 35 °C. Results:  The in vitro motility speed increased as the temperature of the assay increased, but a more profound effect was observed on the slower isoforms, narrowing the relative differences between fast and slow myosin heavy chain (MyHC) isoforms at physiological temperature in all species. The in vitro motility speed varied according to MyHC isoform within each species: I < IIa < IIx < IIb, but the expected scaling relationship within orthologous myosin isoforms was not observed at any temperature. Conclusion:  The scaling effect of body size and limb length on shortening velocity at the muscle fibre level, i.e. the decreasing shortening velocity associated with increasing body weight and limb length, was not confirmed at the motor protein level when including mammals of very large size. Thus, other factors than myosin structure and function appear to cause this scaling effect and thin filament isoform expression or myofilament lattice spacing are forwarded as alternative underlying factors.

  • 114.
    Li, Mingxin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Celluar and Molecular Mechanisms Underlying Regulation of Skeletal Muscle Contraction in Health and Disease2010Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Morphological changes, genetic modifications, and cell functional alterations are not always parallel. Therefore, assessment of skeletal muscle function is an integral part of the etiological approach. The general objective of this thesis was to look into the cellular and molecular events occurring in skeletal muscle contraction in healthy and diseased condition, using a single fiber preparation and a single fiber in vitro motility assay, in an attempt to approach the underlying mechanisms from different physiological angles. In a body size related muscle contractility study, scaling of actin filament sliding speed and its temperature sensitivity has been investigated in mammals covering a 5,500-fold difference in body mass. A profound temperature dependence of actin filament sliding speed over myosin head was demonstrated irrespective of MyHC isoform expression and species. However, the expected body size related scaling within orthologus myosin isoforms between species failed to be maintained at any temperature over 5,500-fold range in body mass, with the larger species frequently having faster in vitro motility speeds than the smaller species. This suggest that apart from the MyHC iso-form expression, other factors such as thin filament proteins and myofilament lattice spacing, may contribute to the scaling related regulation of skeletal muscle contractility. A study of a novel R133W β-tropomyosin mutation on regulation of skeletal muscle contraction in the skinned single fiber prepration and single fiber in vitro motility assay suggested that the mutation induced alteration in myosin-actin kinetics causing a reduced number of myosin molecules in the strong actin binding state, resulting in overall muscle weakness in the absence of muscle wasting. A study on a type IIa MyHC isoform missense mutation at the motor protein level demonstrated a significant negative effect on the function of the IIa MyHC isoform while other myosin isoforms had normal function. This provides evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle irrespective of MyHC isoform expression.

    List of papers
    1. Scaling of Motility Speed and Its Temperature Sensitivity in Mammals Representing a 5,500-fold Difference in Body Size
    Open this publication in new window or tab >>Scaling of Motility Speed and Its Temperature Sensitivity in Mammals Representing a 5,500-fold Difference in Body Size
    (English)Article in journal (Refereed) Submitted
    National Category
    Physiology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-123004 (URN)
    Note
    kommer att kompletterasAvailable from: 2010-04-22 Created: 2010-04-22 Last updated: 2018-01-12Bibliographically approved
    2. Human skeletal muscle myosin function at physiological and non-physiological temperatures
    Open this publication in new window or tab >>Human skeletal muscle myosin function at physiological and non-physiological temperatures
    2006 (English)In: Acta Physiol, Vol. 186, p. 151-158Article in journal (Refereed) Published
    Identifiers
    urn:nbn:se:uu:diva-78355 (URN)
    Available from: 2006-03-22 Created: 2006-03-22 Last updated: 2011-01-11
    3. Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
    Open this publication in new window or tab >>Effects of a R133W beta-tropomyosin mutation on regulation of muscle contraction in single human muscle fibres
    Show others...
    2007 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 581, no 3, p. 1283-1292Article in journal (Refereed) Published
    Abstract [en]

    A novel R133W β-tropomyosin (β-Tm) mutation, associated with muscle weakness and distal limb deformities, has recently been identified in a woman and her daughter. The muscle weakness was not accompanied by progressive muscle wasting or histopathological abnormalities in tibialis anterior muscle biopsy specimens. The aim of the present study was to explore the mechanisms underlying the impaired muscle function in patients with the β-Tm mutation. Maximum force normalized to fibre cross-sectional area (specific force, SF), maximum velocity of unloaded shortening (V0), apparent rate constant of force redevelopment (ktr) and force–pCa relationship were evaluated in single chemically skinned muscle fibres from the two patients carrying the β-Tm mutation and from healthy control subjects. Significant differences in regulation of muscle contraction were observed in the type I fibres: a lower SF (P < 0.05) and ktr (P < 0.01), and a faster V0 (P < 0.05). The force–pCa relationship did not differ between patient and control fibres, indicating an unaltered Ca2+ activation of contractile proteins. Collectively, these results indicate a slower cross-bridge attachment rate and a faster detachment rate caused by the R133W β-Tm mutation. It is suggested that the R133W β-Tm mutation induces alteration in myosin–actin kinetics causing a reduced number of myosin molecules in the strong actin-binding state, resulting in overall muscle weakness in the absence of muscle wasting.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-12417 (URN)10.1113/jphysiol.2007.129759 (DOI)000247174700035 ()
    Available from: 2007-12-17 Created: 2007-12-17 Last updated: 2017-12-11Bibliographically approved
    4. Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
    Open this publication in new window or tab >>Muscle cell and motor protein function in patients with a IIa myosin missense mutation (Glu-706 to Lys)
    Show others...
    2006 (English)In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 16, no 11, p. 782-791Article in journal (Refereed) Published
    Abstract [en]

    The pathogenic events leading to the progressive muscle weakness in patients with a E706K mutation in the head of the myosin heavy chain (MyHC) IIa were analyzed at the muscle cell and motor protein levels. Contractile properties were measured in single muscle fiber segments using the skinned fiber preparation and a single muscle fiber in vitro motility assay. A dramatic impairment in the function of the IIa MyHC isoform was observed at the motor protein level. At the single muscle fiber level, on the other hand, a general decrease was observed in the number of preparations where the specific criteria for acceptance were fulfilled irrespective of MyHC isoform expression. Our results provide evidence that the pathogenesis of the MyHC IIa E706K myopathy involves defective function of the mutated myosin as well as alterations in the structural integrity of all muscle cells irrespective of MyHC isoform expression.

    Keywords
    myosin heavy chain mutation, skinned muscle fibers, in vitro motility, shortening velocity, specific tension
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-82938 (URN)10.1016/j.nmd.2006.07.023 (DOI)000242494400009 ()17005402 (PubMedID)
    Available from: 2006-11-29 Created: 2006-11-29 Last updated: 2017-12-14Bibliographically approved
  • 115.
    Li, Mingxin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Marx, James O
    Univ of Pennsylvania USA, Dpt of Pathobiology, School of Veterrinary Medicin..
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Scaling of Motility Speed and Its Temperature Sensitivity in Mammals Representing a 5,500-fold Difference in Body SizeArticle in journal (Refereed)
  • 116.
    Liik, Maarika
    et al.
    Tartu Univ Hosp, Dept Neurol, Tartu, Estonia..
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Repetitive nerve stimulation often fails to detect abnormal decrement in acute severe generalized Myasthenia Gravis2016In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 127, no 11, p. 3480-3484Article in journal (Refereed)
    Abstract [en]

    Objective: We assessed the diagnostic pattern of repetitive nerve stimulation (RNS) test and concentric electrode (CNE) jitter analysis between patients with generalized myasthenia gravis (GMG) with acute versus slow onset. Methods: All examinations that established the diagnosis of GMG at the department of Clinical Neurophysiology, Uppsala University Hospital, were retrospectively analyzed from January 2012 to December 2014. Patients were grouped according to disease duration at neurophysiological evaluation: acute onset (< 4 weeks) or slow onset (>= 4 weeks). Results: We identified 41 patients diagnosed with GMG. Of the nine patients with acute onset GMG (5 women) only one patient had abnormal decrement, whereas of the 32 patients with slow onset (13 women) 26 patients (84%) had abnormal decrement. CNE jitter was abnormal in all. AChR antibody status was comparable (78% versus 84%) whereas the MGFA class was higher in the acute onset group (range: 3A-5) compared to the slow onset group (range: 2A-3B). Conclusions: RNS test is frequently normal in cases of acute severe GMG, including myasthenic crisis. Performing CNE jitter analysis is therefore of crucial importance for a correct early diagnosis. Significance: MG patients with acute severe onset of bulbar or generalized fatigue often have normal findings on RNS test in proximal muscles. (C) 2016 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

  • 117. Lindberg, Uno
    et al.
    Karlsson, Roger
    Lassing, Ingrid
    Schutt, Clarence E.
    Höglund, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The microfilament system and malignancy2008In: Seminars in Cancer Biology, ISSN 1044-579X, E-ISSN 1096-3650, Vol. 18, no 1, p. 2-11Article, review/survey (Refereed)
    Abstract [en]

    Increased motile activity, increased rate of cell proliferation and removal of growth inhibiting cell-cell contacts are hallmarks of tumorigenesis. Activation of cell motility and migration is caused by activation of receptors, turning on the growth cycle. Increased expression of metalloproteinases, breaking cell:cell contacts and organ confines, allows the spread of malignant cancer cells to other sites in the organism. It has become increasingly clear that most transmembrane proteins (growth factor receptors, adhesion proteins and ion channels) are either permanently or transiently associated with the sub-membraneous system of actin microfilaments (MF), whose force generating capacity they control. Although there has been great progress in our understanding of the physiological importance of the MF-system, as will be exemplified in this issue of SCB, many aspects of actin microfilament formation and its regulation are still unclear. Redox control of the actin (MF)-system in cell motility and migration and its perturbations in pathophysiology, including cancer, is an emerging field of research.

  • 118.
    Lindqvist, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cellular and Molecular Mechanisms Underlying Congenital Myopathy-related Weakness2014Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Congenital myopathies are a rare and heterogeneous group of diseases. They are primarily characterised by skeletal muscle weakness and disease-specific pathological features. They harshly limit ordinary life and in severe cases, these myopathies are associated with early death of the affected individuals. The congenital myopathies investigated in this thesis are nemaline myopathy and myofibrillar myopathy. These diseases are usually caused by missense mutations in genes encoding myofibrillar proteins, but the exact mechanisms by which the point mutations in these proteins cause the overall weakness remain mysterious. Hence, in this thesis two different nemaline myopathy-causing actin mutations and one myofibrillar myopathy-causing myosin-mutation found in both human patients and mouse models were used to investigate the cascades of molecular and cellular events leading to weakness.

    I performed a broad range of functional and structural experiments including skinned muscle fibre mechanics, small-angle X-ray scattering as well as immunoblotting and histochemical techniques. Interestingly, according to my results, point mutations in myosin and actin differently modify myosin binding to actin, cross-bridge formation and muscle fibre force production revealing divergent mechanisms, that is, gain versus loss of function (papers I, II and IV). In addition, one point mutation in actin appears to have muscle-specific effects.  The presence of that mutant protein in respiratory muscles, i.e. diaphragm, has indeed more damaging consequences on myofibrillar structure than in limb muscles complexifying the pathophysiological mechanisms (paper II).

    As numerous atrophic muscle fibres can be seen in congenital myopathies, I also considered this phenomenon as a contributing factor to weakness and characterised the underlying causes in presence of one actin mutation. My results highlighted a direct muscle-specific up-regulation of the ubiquitin-proteasome system (paper III).

    All together, my research work demonstrates that mutation- and muscle-specific mechanisms trigger the muscle weakness in congenital myopathies. This gives important insights into the pathophysiology of congenital myopathies and will undoubtedly help in designing future therapies.

    List of papers
    1. A myopathy-related actin mutation increases contractile function
    Open this publication in new window or tab >>A myopathy-related actin mutation increases contractile function
    Show others...
    2012 (English)In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 5, p. 739-746Article in journal (Refereed) Published
    Abstract [en]

    Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

    Keywords
    Nemaline myopathy, ACTA1 mutation, Skeletal muscle, Force, Actin, Myosin cross-bridge
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-173318 (URN)10.1007/s00401-012-0962-z (DOI)000302255000009 ()
    Available from: 2012-04-25 Created: 2012-04-23 Last updated: 2017-12-07Bibliographically approved
    2. Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
    Open this publication in new window or tab >>Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy
    Show others...
    2013 (English)In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 72, no 6, p. 472-481Article in journal (Refereed) Published
    Abstract [en]

    Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.

    Keywords
    Actin, Contractile dysfunction, Limb muscle, Nemaline myopathy, Respiratory muscle, Weakness
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-204291 (URN)10.1097/NEN.0b013e318293b1cc (DOI)000319454400003 ()
    Available from: 2013-07-30 Created: 2013-07-29 Last updated: 2017-12-06Bibliographically approved
    3. Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
    Open this publication in new window or tab >>Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathy
    (English)Manuscript (preprint) (Other academic)
    Abstract [en]

    Nemaline myopathy, the most common congenital myopathy, is characterized by muscle fibre atrophy.  This compromises contractile performance and ultimately contributes to muscle weakness.  The pathogenic mechanisms remain obscure but may be related to an aberrant protein turnover rate due to an increased activation of the ubiquitin-proteasome pathway.  To verify, this hypothesis, in the present study, we used skeletal muscles from a transgenic mouse model of nemaline myopathy.  We then evaluated the expression of key proteins such as MuRF1 and atrogin-1.  In the slow-twitch soleus muscle, we observed a trend towards a higher level of atrogin-1 whereas in the fast-twitch tibialis anterior muscle, we revealed a greater expression of MuRF1.  These led to divergent effects on protein content and muscle fibre size.  Indeed, in the soleus, a general protein loss and atrophy was found whilst in tibialis anterior, a preferential myosin loss without any clear reduction in the mean muscle fibre size was noticed.  Overall these findings prove for the first time that in nemaline myopathy, the ubiquitin-proteasome pathway (i) is involved in the process of muscle wasting; (ii) is differentially activated in slow- and fast-twitch muscles; (iii) may be targeted as a future therapy to alleviate muscle wasting.

    Keywords
    myopathy, muscle wasting, atrophy, Murf1, atrogin-1
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-219403 (URN)
    Available from: 2014-02-28 Created: 2014-02-28 Last updated: 2014-04-29
    4. The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)
    Open this publication in new window or tab >>The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)
    2013 (English)In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 3, p. 834-840Article in journal (Refereed) Published
    Abstract [en]

    Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4(arl) mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4(arl)/+). Myh4(arl)/+ mice contain MYH4(L342Q) expressed at 7% of the levels of the wild-type (WT) protein, and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4(arl)/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4(arl)/+ and WT mice. Altogether, these findings prove that, in adult MYH4(L342Q) heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4(L342Q), leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-202382 (URN)10.1242/dmm.011155 (DOI)000318847400029 ()
    Available from: 2013-06-24 Created: 2013-06-24 Last updated: 2017-12-06Bibliographically approved
  • 119.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cheng, Arthur J.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hardeman, Edna C.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Distinct Underlying Mechanisms of Limb and Respiratory Muscle Fiber Weaknesses in Nemaline Myopathy2013In: Journal of Neuropathology and Experimental Neurology, ISSN 0022-3069, E-ISSN 1554-6578, Vol. 72, no 6, p. 472-481Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy is the most common congenital myopathy and is caused by mutations in various genes such as ACTA1 (encoding skeletal alpha-actin). It is associated with limb and respiratory muscle weakness. Despite increasing clinical and scientific interest, the molecular and cellular events leading to such weakness remain unknown, which prevents the development of specific therapeutic interventions. To unravel the potential mechanisms involved, we dissected lower limb and diaphragm muscles from a knock-in mouse model of severe nemaline myopathy expressing the ACTA1 His40Tyr actin mutation found in human patients. We then studied a broad range of structural and functional characteristics assessing single-myofiber contraction, protein expression, and electron microscopy. One of the major findings in the diaphragm was the presence of numerous noncontractile areas (including disrupted sarcomeric structures and nemaline bodies). This greatly reduced the number of functional sarcomeres, decreased the force generation capacity at the muscle fiber level, and likely would contribute to respiratory weakness. In limb muscle, by contrast, there were fewer noncontractile areas and they did not seem to have a major role in the pathogenesis of weakness. These divergent muscle-specific results provide new important insights into the pathophysiology of severe nemaline myopathy and crucial information for future development of therapeutic strategies.

  • 120.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hardeman, E
    Ochala, J
    Muscle-specific up-regulation of the ubiquitin-proteasome pathway in a mouse model of nemaline myopathyManuscript (preprint) (Other academic)
    Abstract [en]

    Nemaline myopathy, the most common congenital myopathy, is characterized by muscle fibre atrophy.  This compromises contractile performance and ultimately contributes to muscle weakness.  The pathogenic mechanisms remain obscure but may be related to an aberrant protein turnover rate due to an increased activation of the ubiquitin-proteasome pathway.  To verify, this hypothesis, in the present study, we used skeletal muscles from a transgenic mouse model of nemaline myopathy.  We then evaluated the expression of key proteins such as MuRF1 and atrogin-1.  In the slow-twitch soleus muscle, we observed a trend towards a higher level of atrogin-1 whereas in the fast-twitch tibialis anterior muscle, we revealed a greater expression of MuRF1.  These led to divergent effects on protein content and muscle fibre size.  Indeed, in the soleus, a general protein loss and atrophy was found whilst in tibialis anterior, a preferential myosin loss without any clear reduction in the mean muscle fibre size was noticed.  Overall these findings prove for the first time that in nemaline myopathy, the ubiquitin-proteasome pathway (i) is involved in the process of muscle wasting; (ii) is differentially activated in slow- and fast-twitch muscles; (iii) may be targeted as a future therapy to alleviate muscle wasting.

  • 121.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Hardeman, Edna C
    Ochala, Julien
    Sexually dimorphic myofilament function in a mouse model of nemaline myopathy2014In: Archives of Biochemistry and Biophysics, ISSN 0003-9861, E-ISSN 1096-0384, Vol. 564, p. 37-42Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy, the most common congenital myopathy, is characterized by mutations in genes encoding myofilament proteins such as skeletal alpha-actin. These mutations are thought to ultimately lead to skeletal muscle weakness. Interestingly, some of the mutations appear to be more potent in males than in females. The underlying mechanisms remain obscure but may be related to sex-specific differences in the myofilament function of both limb and respiratory muscles. To verify this, in the present study, we used skeletal muscles (tibialis anterior and diaphragm) from a transgenic mouse model harbouring the His40Tyr amino acid substitution in skeletal alpha-actin. In this animal model, 60% of males die by 13weeks of age (the underlying causes of death are obscure but probably due to respiratory insufficiency) whereas females have a normal lifespan. By recording and analysing the mechanics of membrane-permeabilized myofibres, we only observed sex-related differences in the tibialis anterior muscles. Indeed, the concomitant deficits in maximal steady-state isometric force and stiffness of myofibres were less exacerbated in transgenic females than in males, potentially explaining the lower potency in limb muscles. However, the absence of sex-difference in the diaphragm muscles was rather unexpected and suggests that myofilament dysfunction does not solely underlie the sexually dimorphic phenotypes.

  • 122.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Iwamoto, Hiroyuki
    Blanco, Gonzalo
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The fraction of strongly bound cross-bridges is increased in mice that carry the myopathy-linked myosin heavy chain mutation MYH4(L342Q)2013In: Disease Models and Mechanisms, ISSN 1754-8403, E-ISSN 1754-8411, Vol. 6, no 3, p. 834-840Article in journal (Refereed)
    Abstract [en]

    Myosinopathies have emerged as a new group of diseases and are caused by mutations in genes encoding myosin heavy chain (MyHC) isoforms. One major hallmark of these diseases is skeletal muscle weakness or paralysis, but the underlying molecular mechanisms remain unclear. Here, we have undertaken a detailed functional study of muscle fibers from Myh4(arl) mice, which carry a mutation that provokes an L342Q change within the catalytic domain of the type IIb skeletal muscle myosin protein MYH4. Because homozygous animals develop rapid muscle-structure disruption and lower-limb paralysis, they must be killed by postnatal day 13, so all experiments were performed using skeletal muscles from adult heterozygous animals (Myh4(arl)/+). Myh4(arl)/+ mice contain MYH4(L342Q) expressed at 7% of the levels of the wild-type (WT) protein, and are overtly and histologically normal. However, mechanical and X-ray diffraction pattern analyses of single membrane-permeabilized fibers revealed, upon maximal Ca2+ activation, higher stiffness as well as altered meridional and equatorial reflections in Myh4(arl)/+ mice when compared with age-matched WT animals. Under rigor conditions, by contrast, no difference was observed between Myh4(arl)/+ and WT mice. Altogether, these findings prove that, in adult MYH4(L342Q) heterozygous mice, the transition from weak to strong myosin cross-bridge binding is facilitated, increasing the number of strongly attached myosin heads, thus enhancing force production. These changes are predictably exacerbated in the type IIb fibers of homozygous mice, in which the embryonic myosin isoform is fully replaced by MYH4(L342Q), leading to a hypercontraction, muscle-structure disruption and lower-limb paralysis. Overall, these findings provide important insights into the molecular pathogenesis of skeletal myosinopathies.

  • 123.
    Lindqvist, Johan M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The Cardiac Alkali Myosin Light Chain Can Restore Skeletal Muscle Function in a Mouse Model of Nemaline Myopathy2013In: Molecular Therapy, ISSN 1525-0016, E-ISSN 1525-0024, Vol. 21, p. S68-S68Article in journal (Other academic)
  • 124.
    Lindqvist, Johan M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The H40Y alpha-actin mutation differently affects limb and respiratory muscle contraction2012In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 22, no 9-10, p. 844-844Article in journal (Other academic)
    Abstract [en]

    Nemaline myopathy is the most common of the congenital non-dystrophic myopathies, with an estimated incidence of 1:50,000. The severe form of this disease is characterized by generalized weakness especially affecting limb and respiratory muscles. Questions that remain unanswered are (i) whether limb and respiratory muscles are affected to the same extent, and (ii) whether the underlying mechanisms are similar. The aim of the present study was to address these questions in a novel transgenic mouse model of severe nemaline myopathy. This model expresses the heterozygous amino acid substitution, H40Y, in skeletal α-actin. Hence, we dissected EDL and diaphragm muscles and evaluated the contraction mechanism. To our surprise, we observed muscle-specific defects that will be presented during the conference. These findings give valuable information for future potential therapeutic interventions.

  • 125.
    Lindqvist, Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Penisson-Besnier, Isabelle
    Iwamoto, Hiroyuki
    Li, Meishan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Yagi, Naoto
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    A myopathy-related actin mutation increases contractile function2012In: Acta Neuropathologica, ISSN 0001-6322, E-ISSN 1432-0533, Vol. 123, no 5, p. 739-746Article in journal (Refereed)
    Abstract [en]

    Nemaline myopathy (NM) is the most common congenital myopathy and is caused by mutations in various genes including NEB (nebulin), TPM2 (beta-tropomyosin), TPM3 (gamma-tropomyosin), and ACTA1 (skeletal alpha-actin). 20-25% of NM cases carry ACTA1 defects and these particular mutations usually induce substitutions of single residues in the actin protein. Despite increasing clinical and scientific interest, the contractile consequences of these subtle amino acid substitutions remain obscure. To decipher them, in the present study, we originally recorded and analysed the mechanics as well as the X-ray diffraction patterns of human membrane-permeabilized single muscle fibres with a particular peptide substitution in actin, i.e. p.Phe352Ser. Results unravelled an unexpected cascade of molecular and cellular events. During contraction, p.Phe352Ser greatly enhances the strain of individual cross-bridges. Paradoxically, p.Phe352Ser also slightly lowers the number of cross-bridges by altering the rate of myosin head attachment to actin monomers. Overall, at the cell level, these divergent mechanisms conduct to an improved steady-state force production. Such results provide new surprising scientific insights and crucial information for future therapeutic strategies.

  • 126.
    Lionikas, A.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Blizard, D A
    Gerhard, G S
    Vandenbergh, D J
    Stout, J T
    Vogler, G P
    McClearn, G E
    Larsson, L.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Genetic determinants of weight of fast- and slow-twitch skeletal muscle in 500-day-old mice of the C57BL/6J and DBA/2J lineage.2005In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 21, no 2, p. 184-192Article in journal (Refereed)
    Abstract [en]

    C57BL/6J (B6) and DBA/2J (D2) strains and two derivative populations, BXD recombinant inbred strains (BXD RIs) and B6D2F2, were used to explore genetic basis for variation in muscle weight at 500 days of age. In parallel with findings in 200-day-old mice (Lionikas A, Blizard DA, Vandenbergh DJ, Glover MG, Stout JT, Vogler GP, McClearn GE, and Larsson L. Physiol Genomics 16: 141-152, 2003), weight of slow-twitch soleus, mixed gastrocnemius, and fast-twitch tibialis anterior (TA) and extensor digitorum longus (EDL) muscles was 13-22% greater (P < 0.001) in B6 than in D2. Distribution of BXD RI strain means indicated that genetic influence on muscle weight (strain effect P < 0.001, all muscles) was of polygenic origin, and effect of genetic factors differed between males and females (strain-by-sex interaction: P < 0.01 for soleus, EDL; P < 0.05 for TA, gastrocnemius). Linkage analyses in B6D2F2 population identified QTL affecting muscle weight on Chr 1, 2, 6, and 9. Pleiotropic influences were observed for QTL on Chr 1 (soleus, TA), 2 (TA, EDL, gastrocnemius), and 9 (soleus, TA, EDL) and were not related to muscle type (fast/slow-twitch) or function (flexor/extensor). Effect of QTL on Chr 9 on soleus muscle was male specific. QTL on Chr 2 and 6 were previously observed at 200 days of age, whereas QTL on Chr 1 and 9 are novel muscle weight QTL. In summary, muscle weight in B6/D2 lineage is affected by a polygenic system that has variable influences at different ages, between males and females, and across muscles in a manner independent of muscle type.

  • 127.
    Liu, Jing-Xia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Höglund, Anna-Stina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Karlsson, Patrick
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Lindblad, Joakim
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Qaisar, Rizwan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Aare, Sudhakar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Bengtsson, Ewert
    Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Centre for Image Analysis. Uppsala University, Disciplinary Domain of Science and Technology, Mathematics and Computer Science, Department of Information Technology, Computerized Image Analysis.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Myonuclear domain size and myosin isoform expression in muscle fibres from mammals representing a 100 000-fold difference in body size2009In: Experimental Physiology, ISSN 0958-0670, E-ISSN 1469-445X, Vol. 94, no 1, p. 117-129Article in journal (Refereed)
    Abstract [en]

    This comparative study of myonuclear domain (MND) size in mammalian species representing a 100 000-fold difference in body mass, ranging from 25 g to 2500 kg, was undertaken to improve our understanding of myonuclear organization in skeletal muscle fibres. Myonuclear domain size was calculated from three-dimensional reconstructions in a total of 235 single muscle fibre segments at a fixed sarcomere length. Irrespective of species, the largest MND size was observed in muscle fibres expressing fast myosin heavy chain (MyHC) isoforms, but in the two smallest mammalian species studied (mouse and rat), MND size was not larger in the fast-twitch fibres expressing the IIA MyHC isofom than in the slow-twitch type I fibres. In the larger mammals, the type I fibres always had the smallest average MND size, but contrary to mouse and rat muscles, type IIA fibres had lower mitochondrial enzyme activities than type I fibres. Myonuclear domain size was highly dependent on body mass in the two muscle fibre types expressed in all species, i.e. types I and IIA. Myonuclear domain size increased in muscle fibres expressing both the β/slow (type I; r= 0.84, P < 0.001) and the fast IIA MyHC isoform (r= 0.90; P < 0.001). Thus, MND size scales with body size and is highly dependent on muscle fibre type, independent of species. However, myosin isoform expression is not the sole protein determining MND size, and other protein systems, such as mitochondrial proteins, may be equally or more important determinants of MND size.

  • 128.
    Llano-Diez, Monica
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mechanisms Underlying Intensive Care Unit Muscle Wasting: Intervention Strategies in an Experimental Animal Model and in Intensive Care Unit Patients2012Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Critically ill patients admitted to the intensive care unit (ICU) commonly develop severe muscle wasting and weakness and consequently impaired muscle function. This not only delays respirator weaning and ICU discharge, but has deleterious effects on morbidity, mortality, financial costs, and quality of life of survivors. Acute Quadriplegic Myopathy (AQM) is one of the most common neuromuscular disorders underlying ICU muscle wasting and paralysis, and is a consequence of modern intensive care interventions, although the exact causes remain unclear. Muscle gene/protein expression, intracellular signalling, post-translational modifications, muscle membrane excitability, and contractile properties at the single muscle fibre level were explored in order to unravel the mechanisms underlying the muscle wasting and weakness associated with AQM and how this can be counteracted by specific intervention strategies. A unique experimental rat ICU model was used to address the mechanistic and therapeutic aspects of this condition, allowing time-resolved studies for a period of two weeks. Subsequently, the findings obtained from this model were translated into a clinical study. The obtained results showed that the mechanical silencing of skeletal muscle, i.e., absence of external strain (weight bearing) and internal strain (myosin-actin activation) due to the pharmacological paralysis or sedation associated with the ICU intervention, is likely to be the primary mechanism triggering the preferential myosin loss and muscle wasting, features specifically characteristic of AQM. Moreover, mechanical silencing induces a specific gene expression pattern as well as post-translational modifications in the motor domain of myosin that may be critical for both function and for triggering proteolysis. The higher nNOS expression found in the ICU patients and its cytoplasmic dislocation are indicated as a probable mechanism underlying these highly specific modifications. This work also demonstrated that passive mechanical loading is able to attenuate the oxidative stress associated with the mechanical silencing and induces positive effects on muscle function, i.e., alleviates the loss of force-generating capacity that underlie the ICU intervention, supporting the importance of early physical therapy in immobilized, sedated, and mechanically ventilated ICU patients.

    List of papers
    1. Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
    Open this publication in new window or tab >>Preferential skeletal muscle myosin loss in response to mechanical silencing in a novel rat intensive care unit model: underlying mechanisms
    Show others...
    2011 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 589, no 8, p. 2007-2026Article in journal (Refereed) Published
    Abstract [en]

    Non-technical summary Wasting and severely impaired function of skeletal muscle is frequently observed in critically ill intensive care unit (ICU) patients, with negative consequences for recovery and quality of life. An experimental rat ICU model has been used to study the mechanisms underlying this unique wasting condition in neuromuscularly blocked and mechanically ventilated animals at durations varying between 6 h and 2 weeks. The complete 'mechanical silencing' of skeletal muscle (removal of both weight bearing and activation) resulted in a specific myopathy frequently observed in ICU patients and characterized by a preferential loss of the motor protein myosin. A highly complex and coordinated protein synthesis and degradation system was observed in the time-resolved analyses. It is suggested the 'mechanical silencing' of skeletal muscle is a dominating factor triggering the specific myopathy associated with the ICU intervention, and strongly supporting the importance of interventions counteracting the complete unloading in ICU patients.The muscle wasting and impaired muscle function in critically ill intensive care unit (ICU) patients delay recovery from the primary disease, and have debilitating consequences that can persist for years after hospital discharge. It is likely that, in addition to pernicious effects of the primary disease, the basic life support procedures of long-term ICU treatment contribute directly to the progressive impairment of muscle function. This study aims at improving our understanding of the mechanisms underlying muscle wasting in ICU patients by using a unique experimental rat ICU model where animals are mechanically ventilated, sedated and pharmacologically paralysed for duration varying between 6 h and 14 days. Results show that the ICU intervention induces a phenotype resembling the severe muscle wasting and paralysis associated with the acute quadriplegic myopathy (AQM) observed in ICU patients, i.e. a preferential loss of myosin, transcriptional down-regulation of myosin synthesis, muscle atrophy and a dramatic decrease in muscle fibre force generation capacity. Detailed analyses of protein degradation pathways show that the ubiquitin proteasome pathway is highly involved in this process. A sequential change in localisation of muscle-specific RING finger proteins 1/2 (MuRF1/2) observed during the experimental period is suggested to play an instrumental role in both transcriptional regulation and protein degradation. We propose that, for those critically ill patients who develop AQM, complete mechanical silencing, due to pharmacological paralysis or sedation, is a critical factor underlying the preferential loss of the molecular motor protein myosin that leads to impaired muscle function or persisting paralysis.

    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-152844 (URN)10.1113/jphysiol.2010.202044 (DOI)000289527200018 ()
    Available from: 2011-05-03 Created: 2011-05-02 Last updated: 2017-12-11Bibliographically approved
    2. Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model
    Open this publication in new window or tab >>Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model
    Show others...
    2011 (English)In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, p. 602-Article in journal (Refereed) Published
    Abstract [en]

    BACKGROUND:

    Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. To elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness associated with AQM, a gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.

    RESULTS:

    During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an upregulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of 3 myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days.

    CONCLUSIONS:

    Novel temporal patterns of gene expression have been uncovered, suggesting a unique, coordinated and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target genes and avenues for intervention studies.

    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-164314 (URN)10.1186/1471-2164-12-602 (DOI)000299899100001 ()22165895 (PubMedID)
    Available from: 2011-12-19 Created: 2011-12-19 Last updated: 2017-12-08Bibliographically approved
    3. Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
    Open this publication in new window or tab >>Sparing of muscle mass and function by passive loading in an experimental intensive care unit model
    Show others...
    2013 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 5, p. 1385-1402Article in journal (Refereed) Published
    Abstract [en]

    The response to mechanical stimuli, i.e., tensegrity, plays an important role in regulating cell physiological and pathophysiological function and the mechanical silencing observed in intensive care unit (ICU) patients leads to a severe and specific muscle wasting condition. This study aims at unravelling the underlying mechanisms and the effects of passive mechanical loading on skeletal muscle mass and function at the gene, protein and cellular levels. A unique experimental rat ICU model has been used allowing long-term (weeks) time-resolved analyses of the effects of standardized unilateral passive mechanical loading on skeletal muscle size and function and underlying mechanisms. Results show that passive mechanical loading alleviated the muscle wasting and the loss of force-generation associated with the ICU intervention, resulting in a doubling of the functional capacity of the loaded vs. the unloaded muscles after a 2-week ICU intervention. We demonstrated that the improved maintenance of muscle mass and function is likely a consequence of a reduced oxidative stress revealed by lower levels of carbonylated proteins, and a reduced loss of the molecular motor protein myosin. A complex temporal gene expression pattern, delineated by microarray analysis, was observed with loading-induced changes in transcript levels of sarcomeric proteins, muscle developmental processes, stress response, ECM/cell adhesion proteins and metabolism. Thus, the results from this study show that passive mechanical loading alleviates the severe negative consequences on muscle size and function associated with the mechanical silencing in ICU patients, strongly supporting early and intense physical therapy in immobilized ICU patients.

    National Category
    Clinical Laboratory Medicine
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-189247 (URN)10.1113/jphysiol.2012.248724 (DOI)000315514300018 ()23266938 (PubMedID)
    Available from: 2012-12-28 Created: 2012-12-28 Last updated: 2017-12-06Bibliographically approved
    4. Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
    Open this publication in new window or tab >>Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading
    Show others...
    2012 (English)In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, no 5, p. R209-Article in journal (Refereed) Published
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

    National Category
    Clinical Laboratory Medicine
    Research subject
    Clinical Neurophysiology
    Identifiers
    urn:nbn:se:uu:diva-183734 (URN)10.1186/cc11841 (DOI)000317499900046 ()23098317 (PubMedID)
    Note

    De två (2) första författarna delar förstaförfattarskapet.

    Available from: 2012-11-01 Created: 2012-11-01 Last updated: 2017-12-07Bibliographically approved
  • 129.
    Llano-Diez, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Gustafson, Ann-Marie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Olsson, Carl
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Muscle wasting and the temporal gene expression pattern in a novel rat intensive care unit model2011In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 12, p. 602-Article in journal (Refereed)
    Abstract [en]

    BACKGROUND:

    Acute quadriplegic myopathy (AQM) or critical illness myopathy (CIM) is frequently observed in intensive care unit (ICU) patients. To elucidate duration-dependent effects of the ICU intervention on molecular and functional networks that control the muscle wasting and weakness associated with AQM, a gene expression profile was analyzed at time points varying from 6 hours to 14 days in a unique experimental rat model mimicking ICU conditions, i.e., post-synaptically paralyzed, mechanically ventilated and extensively monitored animals.

    RESULTS:

    During the observation period, 1583 genes were significantly up- or down-regulated by factors of two or greater. A significant temporal gene expression pattern was constructed at short (6h-4 days), intermediate (5-8 days) and long (9-14 days) durations. A striking early and maintained up-regulation (6h-14d) of muscle atrogenes (muscle ring-finger 1/tripartite motif-containing 63 and F-box protein 32/atrogin-1) was observed, followed by an upregulation of the proteolytic systems at intermediate and long durations (5-14d). Oxidative stress response genes and genes that take part in amino acid catabolism, cell cycle arrest, apoptosis, muscle development, and protein synthesis together with myogenic factors were significantly up-regulated from 5 to 14 days. At 9-14 d, genes involved in immune response and the caspase cascade were up-regulated. At 5-14d, genes related to contractile (myosin heavy chain and myosin binding protein C), regulatory (troponin, tropomyosin), developmental, caveolin-3, extracellular matrix, glycolysis/gluconeogenesis, cytoskeleton/sarcomere regulation and mitochondrial proteins were down-regulated. An activation of genes related to muscle growth and new muscle fiber formation (increase of 3 myogenic factors and JunB and down-regulation of myostatin) and up-regulation of genes that code protein synthesis and translation factors were found from 5 to 14 days.

    CONCLUSIONS:

    Novel temporal patterns of gene expression have been uncovered, suggesting a unique, coordinated and highly complex mechanism underlying the muscle wasting associated with AQM in ICU patients and providing new target genes and avenues for intervention studies.

  • 130.
    Llano-Diez, Monica
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Renaud, Guillaume
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Andersson, Magnus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Gonzales Marrero, Humberto
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Cacciani, Nicola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Engquist, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Corpeno, Rebeca
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Artemenko, Konstantin
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Bergquist, Jonas
    Uppsala University, Disciplinary Domain of Science and Technology, Chemistry, Department of Chemistry - BMC, Analytical Chemistry.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mechanisms underlying intensive care unit muscle wasting and effects of passive mechanical loading2012In: Critical Care, ISSN 1364-8535, E-ISSN 1466-609X, Vol. 16, no 5, p. R209-Article in journal (Refereed)
    Abstract [en]

    ABSTRACT: INTRODUCTION: Critical ill intensive care unit (ICU) patients commonly develop severe muscle wasting and impaired muscle function, leading to delayed recovery, with subsequent increased morbidity and financial costs, and decreased quality of life of survivors. Critical illness myopathy (CIM) is a frequently observed neuromuscular disorder in ICU patients. Sepsis, systemic corticosteroid hormone treatment and post-synaptic neuromuscular blockade have been forwarded as the dominating triggering factors. Recent experimental results from our group using a unique experimental rat ICU model have shown that the "mechanical silencing" associated with the ICU condition is the primary triggering factor. This study aims at (1) unraveling the mechanisms underlying CIM, and (2) evaluating the effects of a specific intervention aiming at reducing the mechanical silencing in sedated and mechanically ventilated ICU patients. METHODS: Muscle gene/protein expression, post-translational modifications (PTMs), muscle membrane excitability, muscle mass measurements, and contractile properties at the single muscle fiber level were explored in seven deeply sedated and mechanically ventilated ICU patients (not exposed to systemic corticosteroid hormone treatment, post-synaptic neuromuscular blockade or sepsis) subjected to unilateral passive mechanical loading 10 hours per day (2.5 hours, 4 times) for 9 +/- 1 days. RESULTS: These patients developed a phenotype considered pathognomonic of CIM, i.e., severe muscle wasting and a preferential myosin loss (P<0.001). In addition, myosin PTMs specific to the ICU condition were observed in parallel with an increased sarcolemmal expression and cytoplasmic translocation of nNOS. Passive mechanical loading for 9 +/- 1 resulted in a 35% higher specific force (P<0.001) compared with the unloaded leg, although it was not sufficient to prevent the loss of muscle mass. CONCLUSIONS: Mechanical silencing is suggested to be a primary mechanism underlying CIM, i.e., triggering the myosin loss, muscle wasting and myosin PTMs. The higher nNOS expression found in the ICU patients and its cytoplasmic translocation are forwarded as a probable mechanism underlying these modifications. The positive effect of passive loading on muscle fiber function strongly supports the importance of early physical therapy and mobilization in deeply sedated and mechanically ventilated ICU patients.

  • 131. Loseth, S.
    et al.
    Bagenholm, A.
    Torbergsen, T.
    Stalberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Peripheral neuropathy caused by severe hypothermia2013In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 124, no 5, p. 1019-1024Article in journal (Refereed)
    Abstract [en]

    Objective: To report follow-up data in the evaluation of peripheral neuropathy in a 29-year old female after accidental deep hypothermia (13.7 degrees C) in 1999. Methods: Nerve conduction studies (NCS) and electromyography (EMG) were performed 20 days after the accident and again after 5 months and 1, 3, 5 and 11 years. Macro EMG was performed after 3, 5 and 11 years. To evaluate small fiber function, RR-interval, sympathetic skin response, quantitative sensory testing and skin biopsy for quantification of intra-epidermal nerve fiber density were performed in 2009. Results: In the intensive care unit sensory and motor responses were absent except for the tibial nerves, and EMG showed profuse denervation. Improvement of amplitudes and conduction velocities was seen during the first 5 years. Muscular atrophy of hand muscles persisted. Large fibers were involved more extensively than small fibers. Conclusions: A severe axonal sensorimotor polyneuropathy developed in the intensive care unit following severe hypothermia. The mechanism was most likely cold injury to peripheral nerves. Significance: The clinical picture and the laboratory findings indicate that even multi-organ dysfunction and, of specific interest in this study, a severe axonal degeneration may come to a good restitution after long time.

  • 132. Loseth, Sissel
    et al.
    Mellgren, Svein I.
    Jorde, Rolf
    Lindal, Sigurd
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Polyneuropathy in type 1 and type 2 diabetes: comparison of nerve conduction studies, thermal perception thresholds and intraepidermal nerve fibre densities2010In: Diabetes/Metabolism Research Reviews, ISSN 1520-7552, E-ISSN 1520-7560, Vol. 26, no 2, p. 100-106Article in journal (Refereed)
    Abstract [en]

    Background To evaluate possible differences in distal polyneuropathy (PN) characteristics and degree of abnormalities for various small and large fibre parameters in diabetes type 1 (DM1) and type 2 (DM2). Methods Sixty-six DM1 and 57 DM2 patients with or without PN symptoms were included. Nerve conduction studies (NCS), quantitative sensory testing (QST) and quantification of intraepidermal nerve fibres (IENFs) were performed. Z-scores were calculated from reference materials. Results In both groups, 42% had abnormal NCS classification, 42% (DM1) and 39% (DM2) abnormal QST, as well as 40% (DM1) and 32% (DM2) abnormal IENF density. Seventy percent (DM1) and 65% (DM2) had one of the three tests abnormal (differences not significant). Correlations were found between most Z-score parameters and disease duration and HbAlc in DM1, but fewer in DM2. In multivariate analysis, some NCS and QST Z-scores were more abnormal in DM2. Symptom scoring correlated better with NCS and QST parameters in DM1. Conclusions The differences could be referred to disease duration, glycaemic control and possibly patient age. The various parameters from NCS, QST and IENF analysis contribute differently in the assessment of polyneuropathy. Copyright (C) 2009 John Wiley & Sons, Ltd.

  • 133. Loseth, Sissel
    et al.
    Nebuchennykh, Maria
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mellgren, Svein Ivar
    Medial plantar nerve conduction studies in healthy controls and diabetics2007In: Clinical Neurophysiology, ISSN 1388-2457, E-ISSN 1872-8952, Vol. 118, no 5, p. 1155-1161Article in journal (Refereed)
    Abstract [en]

    Objective: To collect a reference material of the medial plantar nerve action potential, to test intra/interobserver reliability in healthy controls and to apply the test to a group of patients with diabetes mellitus. Methods: 98 healthy controls and 50 patients with diabetes mellitus were included. The medial plantar nerve was stimulated orthodromically and recorded with a surface electrode. In the patient group, NCS of motor and sensory nerves and quantitative sensory testing were also performed. Results: Responses of the medial plantar nerve were obtained from all controls except from one aged 72. Amplitude decreased with age (r = -0.68, p < 0.0001). Intra/interobserver reliability was acceptable. 52% of the patients had abnormal overall NCS classification. Forty-eight percent had delayed tibial F-response latency. The medial plantar NCS were abnormal in 59% of the cases (47% abnormal NAP amplitude and 39% reduced CV), 59% of those with abnormal NCS had symptoms of sensory polyneuropathy. Only 24% had abnormal sural amplitude. Cold perception threshold was abnormal in more patients (30%) than warmth perception threshold (14%). Conclusions: Responses were easily obtained in controls under 70 years. In diabetics the amplitudes of the medial plantar nerve were abnormal more often than in the sural nerve. Significance: The medial plantar nerve response is reliable in patients under 70 years, and intra/interobserver reliability is acceptable.

  • 134.
    Lundqvist, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ågren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Wickstrom, R.
    Pediatric Neurology Unit, Department of Women′s and Children′s Health, Karolinska Institute, Stockholm, Sweden.
    Adverse effects following lidocaine treatment are limited with current dosing regimens2013In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 102, no 11, p. E485-E486Article in journal (Refereed)
  • 135.
    Lundqvist, M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Ågren, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Hellström-Westas, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Wickstrom, R.
    Pediatric Neurology Unit, Department of Women′s and Children′s Health, Karolinska Institutet, Stockholm, Sweden.
    Efficacy and safety of lidocaine for treatment of neonatal seizures2013In: Acta Paediatrica, ISSN 0803-5253, E-ISSN 1651-2227, Vol. 102, no 9, p. 863-867Article in journal (Refereed)
    Abstract [en]

    Aim: Treatment of neonatal seizures still relies primarily on phenobarbital, despite an estimated efficacy of less than 50% and concern over neurodegenerative side effects. The objective of this study was to evaluate the efficacy and safety of lidocaine as second-line treatment of neonatal seizures in infants following benzodiazepine treatment but without previous treatment with phenobarbital. Methods: In a 10-year cohort, a retrospective chart review was conducted for all infants (gestational age >= 37 w, age <= 28 days) who had received lidocaine as second-line treatment of neonatal seizures prior to treatment with phenobarbital between January 2000 and June 2010. Infants were included if they had electroencephalographic seizures. Results: Cessation of seizure activity was seen in 16 of 30 infants based on clinical and electroencephalographic features, and a probable response was seen in an additional 3 of 30 patients. Suspected adverse effects were seen in only one patient, who developed a transient bradycardia. Conclusion: Lidocaine has a moderate efficacy as second-line therapy following benzodiazepines for treating neonatal seizures and is not frequently associated with cardiovascular adverse effects. Lidocaine should therefore be considered in the treatment of seizures in the neonatal period to a higher extent than is the case today.

  • 136. Løseth, Sissel
    et al.
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Jorde, Rolf
    Mellgren, Svein Ivar
    Early diabetic neuropathy: thermal thresholds and intraepidermal nerve fibre density in patients with normal nerve conduction studies.2008In: Journal of Neurology, ISSN 0340-5354, E-ISSN 1432-1459, Vol. 255, no 8, p. 1197-1202Article in journal (Refereed)
    Abstract [en]

    OBJECTIVES

    To determine whether neuropathy in diabetic patients with normal nerve conduction studies could be detected by measurements of thermal thresholds and quantification of intraepidermal nerve fibre (IENF) density, and to evaluate differences in parameters between patients with and without neuropathic symptoms.

    METHODS

    A total of 22 patients with and 37 patients without sensory symptoms suggesting distal neuropathy were included. Measurements of warm and cold perception thresholds and skin biopsy for quantification of IENFs were performed distally on the leg. Reference data were used to normalize test results for age and height or gender of individual patients by calculating the Z-scores.

    RESULTS

    IENF density was significantly reduced in both symptomatic and asymptomatic patients compared to controls (p < 0.001), and in patients with symptoms compared to those without (p = 0.01). Thermal thresholds were significantly elevated (more abnormal) in patients with symptoms compared to controls (p < 0.01), but only for cold perception threshold (CPT) (p < 0.001) in the asymptomatic group. When comparing symptomatic and asymptomatic patients, there was no statistically significant difference in thermal thresholds. Depletion of IENFs in skin biopsy was the most frequent abnormal finding in the subgroup of patients with neuropathic symptoms (36 %) followed by abnormal CPT (27 %).

    CONCLUSION 

    Patients with diabetes and normal nerve conduction studies had significantly lower IENF density and higher CPT than controls, whether they had symptoms of polyneuropathy or not. In patients with neuropathic symptoms, abnormal IENF density predominated and seemed thus to be the most sensitive tool of detecting small diameter nerve fibre involvement.

  • 137.
    Løseth, Sissel
    et al.
    Univ Hosp North Norway, Dept Neurol & Neurophysiol, N-9038 Tromso, Norway.;Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Stålberg, Erik V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Lindal, Sigurd
    Univ Hosp North Norway, Dept Clin Pathol, N-9038 Tromso, Norway.;Arctic Univ Norway, Dept Med Biol, Tromso, Norway..
    Olsen, Edel
    Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Jorde, Rolf
    Arctic Univ Norway, Dept Clin Med, Tromso, Norway.;Univ Hosp North Norway, Dept Internal Med, N-9038 Tromso, Norway..
    Mellgren, Svein I.
    Univ Hosp North Norway, Dept Neurol & Neurophysiol, N-9038 Tromso, Norway.;Arctic Univ Norway, Dept Clin Med, Tromso, Norway..
    Small and large fiber neuropathy in those with type 1 and type 2 diabetes: a 5-year follow-up study2016In: Journal of the peripheral nervous system, ISSN 1085-9489, E-ISSN 1529-8027, Vol. 21, no 1, p. 15-21Article in journal (Refereed)
    Abstract [en]

    The purpose of this study was to evaluate progression of diabetic polyneuropathy and differences in the spectrum and evolution of large- and small-fiber involvement in patients with diabetes type 1 and 2 over 5 years. Fifty-nine patients (35 type 1 and 24 type 2) were included. Nerve conduction studies (NCS), quantitative sensory testing, skin biopsy for quantification of intraepidermal nerve fiber density (IENFD), symptom scoring and clinical evaluations were performed. Z-scores were calculated to adjust for the physiologic effects of age and height/gender. Neuropathic symptoms were not significantly more frequent in type 2 than in type 1 diabetic patients at follow-up (54% vs. 37%). The overall mean NCS Z-score remained within the normal range, but there was a small significant decline after 5 years in both groups: type 1 (p = 0.004) and type 2 (p = 0.02). Mean IENFD Z-scores changed from normal to abnormal in both groups, but only significantly in those with type 2 diabetes (reduction from 7.9 +/- 4.8 to 4.3 +/- 2.8 fibers/mm, p = 0.006). Cold perception threshold became more abnormal only in those with type 2 diabetes (p = 0.049). There was a minimal progression of large fiber neuropathy in both groups. Reduction of small fibers predominated and progressed more rapidly in those with type 2 diabetes.

  • 138. Malmgren, K.
    et al.
    Bialek, F.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rydenhag, B.
    Seizure outcome and complications after resective epilepsy surgery in patients over 50 years in Sweden 1990-20092013In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 54, no S3, p. 180-180Article in journal (Other academic)
  • 139.
    Malmgren, K.
    et al.
    Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden..
    Rydenhag, B.
    Gothenburg Univ, Sahlgrenska Acad, Inst Neurosci & Physiol, Dept Clin Neurosci & Rehabil, Gothenburg, Sweden..
    Olsson, I.
    Gothenburg Univ, Sahlgrenska Acad, Inst Clin Sci, Dept Paediat, Gothenburg, Sweden..
    Kumlien, Eva
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Mattsson, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Flink, Roland
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Epilepsy Surgery Trends In Sweden 1990-20132015In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 56, p. 145-145Article in journal (Other academic)
  • 140.
    Marrero, Humberto Gonzalez
    et al.
    Karolinska Inst, Dept Clin Neurosci, Clin Neurophysiol Sect, Stockholm, Sweden.
    Stålberg, Erik V
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Optimizing testing methods and collection of reference data for differentiating critical illness polyneuropathy from critical illness myopathy.2016In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 53, no 4, p. 555-563Article in journal (Refereed)
    Abstract [en]

    INTRODUCTION: In severe acute quadriplegic myopathy in intensive care unit (ICU) patients, muscle fibers are electrically inexcitable; in critical illness polyneuropathy the excitability remains normal. Conventional electrodiagnostic methods do not provide the means to adequately differentiate between them.

    OBJECTIVE: To further optimize methodology for the study of critically ill ICU patients and to create a reference database in healthy controls.

    METHODS: Different electrophysiologic protocols were tested to find sufficiently robust and reproducible techniques for clinical diagnostic applications.

    RESULTS: Many parameters show large test-retest variability within the same healthy subject. Reference values have been collected and described as a basis for studies of weakness in critical illness.

    DISCUSSION: Using the ratio of neCMAP/dmCMAP (response from nerve and direct muscle stimulation), refractory period, and stimulus-response curves may optimize the electrodiagnostic differentiation of patients with critical illness myopathy from those with critical illness polyneuropathy.

  • 141.
    Martinez-Aparicio, Carmen
    et al.
    Univ Granada, Doctoral Programme Med & Publ Hlth, Granada, Spain;Vithas Virgen Mar Hosp, Dept Clin Neurophysiol, Almeria, Spain.
    Jääskeläinen, Satu K.
    Turku Univ Hosp, Dept Clin Neurophysiol, Turku, Finland; Univ Turku, Turku, Finland.
    Muyor, José M.
    Univ Almeria, Res Cent Serv, Lab Kinesiol Biomech & Ergon KIBIOMER, Almeria, Spain.
    Falck, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nerve conduction study of the three supraclavicular nerve branches2018In: Muscle and Nerve, ISSN 0148-639X, E-ISSN 1097-4598, Vol. 58, no 2, p. 300-303Article in journal (Refereed)
    Abstract [en]

    Introduction: We describe a new nerve conduction study technique with reference values for the 3 branches of the supraclavicular nerve (SCN) in young healthy subjects and application of it in 2 patients.

    Methods: The recording electrode was placed on the posterior border of the sternocleidomastoid muscle, 6–7 cm from the sternoclavicular joint. SCN branches were stimulated below the clavicle, 2.5, 7, and 10.5 cm lateral to the sternoclavicular joint.

    Results: Twenty healthy volunteers (10 men), 19–38 years, mean 25.9 years (SD 6.3), and 2 patients with SCN lesions were studied. The mean conduction velocities of the SCN branches were 70–78 m/s (SD 8–10 m/s), and amplitudes 3–4 µV (SD 0.9–2.0 µV). There were no side‐to‐side or gender differences.

    Discussion: The 3 SCN branches could be studied in all subjects. We provide reference values for young subjects. This new method was useful in verifying SCN lesions in 2 patients.

  • 142.
    Mattsson, Peter
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Tomson, Torbjörn
    Edebol Eeg-Olofsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Brännström, Lars
    Ringbäck Weitoft, Gunilla
    Association between sociodemographic status and antiepileptic drug prescriptions in children with epilepsy2012In: Epilepsia, ISSN 0013-9580, E-ISSN 1528-1167, Vol. 53, no 12, p. 2149-2155Article in journal (Refereed)
    Abstract [en]

    Purpose: 

    We investigated whether in Sweden sociodemographic differences are associated with access to expert health care and antiepileptic drug (AED) prescriptions in children with epilepsy.

    Methods:

    Data on epilepsy, prescription of AEDs, and sociodemographic variables were obtained from several national administrative registers. We linked individual data to examine whether access by pediatric epilepsy patients to neuropediatricians and the prescription of individual AEDs differed according to gender, age, parental education, place of residence, parental region of birth, and household income. We also assessed whether AEDs are prescribed differently to patients with epilepsy by neuropediatricians as compared to other physicians.

    Key Findings: 

    Of 1,788,382 children aged 1-17 years in 2006, living in the country by the end of 2006, 9,935 had a diagnosis of epilepsy (0.56%). Patients with epilepsy on AED treatment (n = 3,631) comprised 0.24% of the total Swedish population aged 1-17 years. Out of 3631 patients with epilepsy on AED treatment, 2301 (63.4%) received prescriptions from a neuropediatrician. Children with epilepsy aged 1-5 years old-as opposed to older children and adolescents-and children with epilepsy residing in large cities-as opposed to children living in smaller cities and rural areas-were more likely to be treated by a neuropediatrician. Children living in large cities received oxcarbazepine to a greater extent than children living in rural areas. Levetiracetam was prescribed more extensively to children whose parents had higher incomes. Of the five most frequently used AEDs, three (lamotrigine, oxcarbazepine, and levetiracetam) were prescribed to a larger extent by a neuropediatrician rather than by other specialists, and one AED (carbamazepine) was prescribed to a lesser extent.

    Significance: 

    The results of this nationwide cross-sectional study of children with epilepsy are important because they show that universal coverage for medical care does not eliminate inequalities of access to health care services among children and adolescents. No data are available that can guide us as to whether the density of child neurologists is of importance to access to expert health care, but this seems likely. Prescription patterns of AEDs differ between child neurologists and other specialists.

  • 143. Meinen, S.
    et al.
    Lin, S.
    Ruegg, M. A.
    Punga, A. R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Dissociation of sarcolemmal nNOS: a novel fatigue mechanism in MG2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 847-847Article in journal (Other academic)
  • 144.
    Melberg, Atle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Kretz, Christine
    Kalimo, Hannu
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Genetics and Pathology.
    Wallgren-Pettersson, Carina
    Toussaint, Anne
    Böhm, Johann
    Stålberg, Erik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Laporte, Jocelyn
    Adult course in dynamin 2 dominant centronuclear myopathy with neonatal onset2010In: Neuromuscular Disorders, ISSN 0960-8966, E-ISSN 1873-2364, Vol. 20, no 1, p. 53-56Article in journal (Refereed)
    Abstract [en]

    We report a family with autosomal dominant centronuclear (myotubular) myopathy caused by a novel mutation, p.A618D, in dynamin 2 (DNM2). The 64-year-old mother and 26-year-old daughter had neonatal onset with hypotonia and weak suckling, followed by improvement, then slowly progressive muscle weakness and respiratory restriction. Muscle biopsy showed radial sarcoplasmic strands around the frequent central nuclei. Electrophysiology revealed predominantly myopathic patterns without peripheral nerve involvement. Centronuclear myopathy with neonatal onset caused by a DNM2 mutation in the C-terminal part of the pleckstrin homology domain may have a favorable prognosis and follow a course similar to adult-onset centronuclear myopathy. We advise respiratory follow-up in these patients.

  • 145.
    Molin, Carl Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    New Biomarkers for Neuromuscular Function and Myasthenia Gravis2018Doctoral thesis, comprehensive summary (Other academic)
    Abstract [en]

    Myasthenia gravis (MG) is an autoimmune disorder, which is caused by autoantibodies against the acetylcholine receptor (AChR). The cardinal symptom is muscle fatigue, which can range from slight weakness of the extraocular muscles (causing droopy eyelids or double vision), to paralysis of the respiratory muscles. Antibodies towards other muscle proteins have been discovered, and MG is now considered a very heterogeneous disease with several subgroups. The severity of symptoms in MG patients is often fluctuating, and the antibody titers do not correlate with disease severity or treatment response. Therefore, there is a great need for reliable biomarkers in MG, both for assessing neuromuscular function, but also for clinical aspects such as disease progression and subgrouping.

    In Study I, the use of compound motor action potential (CMAP) as a biomarker for muscle status was examined in trained and untrained individuals. We found that trained individuals have a higher CMAP in proximal muscles, and the CMAP value in the biceps correlate with muscle strength in these individuals, indicating that CMAP can be used as a biomarker for muscle function. In Study II, subjects from study I were examined with ultrasound to assess the effect of high-resistance strength training (HRST) on peripheral nerves, and to compare muscle thickness. We did not find a difference in nerve cross-sectional area between the two groups. Trained individuals had thicker biceps muscles. The results from study I and II has led to CMAP and ultrasound being used to evaluate the result of physical exercise as an intervention in MG patients.

    In Study III, the expression of inflammatory proteins in the sera of MG patients was compared to healthy controls, in search for possible biomarkers. We found eleven proteins to be elevated, which provide new insight to the inflammatory response in MG and have possible functions as new biomarkers of inflammatory activity.

    In Study IV, the effect of thymectomy on the potential microRNA MG biomarkers miR-150-5p and miR-21-5p was examined. A decrease in miR-150-5p was seen 24 months after thymectomy, which further validate the use of miR-150-5p as a disease-specific biomarker for clinical outcome in AChR positive MG patients.

    List of papers
    1. Compound Motor Action Potential: Electrophysiological Marker for Muscle Training
    Open this publication in new window or tab >>Compound Motor Action Potential: Electrophysiological Marker for Muscle Training
    2016 (English)In: Journal of clinical neurophysiology, ISSN 0736-0258, E-ISSN 1537-1603, Vol. 33, no 4, p. 340-345Article in journal (Refereed) Published
    Abstract [en]

    Purpose:The compound motor action potential (CMAP) represents the summated action potentials of all stimulated motor endplates and potentially reflects muscle hypertrophy and increased muscle contractions. Since electrophysiological biomarkers for high-resistance strength training are lacking, the authors evaluated whether the CMAP of distal and proximal muscles differs between healthy men and women who perform and do not perform high-resistance muscle training.Methods:Motor neurography was performed with stimulation of the median nerve (recording of abductor pollicis brevis muscle), peroneal nerve (recording of extensor digitorum brevis muscle), femoral nerve (recording of rectus femoris muscle) and musculocutaneous nerve (recording of biceps brachii muscle), and isometric muscle strength, measured with a hand-held dynamometer, were performed on 83 healthy subjects (52 women).Results:Trained women had 25% higher CMAP amplitude in the rectus femoris muscle than untrained women (P < 0.001), whereas CMAP amplitude in the trained male cohort was 25% higher in the biceps (P = 0.005) compared with untrained men. In the trained group, CMAP amplitude in the biceps correlated with isometric muscle strength (R = 0.30; P = 0.046).Conclusions:The authors' propose the CMAP as an objective neurophysiological parameter for proximal muscle status and training effects in future interventional studies of patients with neuromuscular disorders.

    Keywords
    Compound motor action potential, CMAP, Electrophysiological marker, Muscle training, Isometric muscle strength
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-304429 (URN)10.1097/WNP.0000000000000252 (DOI)000382523700013 ()26744834 (PubMedID)
    Funder
    Swedish Society of Medicine, SLS-330141Swedish Research Council, VR-523-2014-2048
    Available from: 2016-10-05 Created: 2016-10-05 Last updated: 2018-08-01Bibliographically approved
    2. High-resistance strength training does not affect nerve cross sectional area – An ultrasound study
    Open this publication in new window or tab >>High-resistance strength training does not affect nerve cross sectional area – An ultrasound study
    2017 (English)In: Clinical Neurophysiology Practice, ISSN 2467-981X, Vol. 2, p. 163-169Article in journal (Refereed) Published
    Abstract [en]

    ObjectiveThe aim was to study the effect of high-resistance strength training on peripheral nerve morphology, by examining properties of peripheral nerves as well as distal and proximal muscle thickness with ultrasound, comparing healthy individuals who perform and do not perform high-resistance strength training.

    MethodsNeuromuscular ultrasound was used to examine cross sectional area (CSA) of the median and musculocutaneous nerves, and muscle thickness of the abductor pollicis brevis muscle, biceps brachii muscle, quadriceps muscle and extensor digitorum brevis muscle, in 44 healthy individuals, of whom 22 performed regular high-resistance strength training.

    ResultsNo difference in nerve CSA was found between trained and untrained individuals although trained individuals had thicker biceps brachii muscles. The CSA of the median nerve in the forearm correlated with participants’ height and was significantly larger in men than women.

    ConclusionsIn this cohort, CSA of the median and musculocutaneous nerves was not affected by strength training, whereas gender had a prominent effect both on CSA and muscle thickness.

    SignificanceThis is the first study to examine the effect of high-resistance strength training on peripheral nerves with neuromuscular ultrasound.

    Keywords
    High-resistance strength training, Muscle thickness, Reference values, Nerve remodeling, Nerve cross sectional area
    National Category
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-356114 (URN)10.1016/j.cnp.2017.07.003 (DOI)
    Available from: 2018-07-14 Created: 2018-07-14 Last updated: 2018-10-04Bibliographically approved
    3. Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.
    Open this publication in new window or tab >>Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.
    2017 (English)In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 39716Article in journal (Refereed) Published
    Abstract [en]

    This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

    National Category
    Medical and Health Sciences Neurology
    Research subject
    Immunology; Neurology
    Identifiers
    urn:nbn:se:uu:diva-314679 (URN)10.1038/srep39716 (DOI)000391148300002 ()28045063 (PubMedID)
    Funder
    Swedish Research Council, 2014-02048Swedish Research Council, 2014-07603Swedish Society of Medicine, SLS-499271Futurum - Academy for Health and Care, Jönköping County Council, Sweden, 520281
    Available from: 2017-02-04 Created: 2017-02-04 Last updated: 2018-08-01Bibliographically approved
    4. Thymectomy lowers the myasthenia gravis biomarker miR-150-5p
    Open this publication in new window or tab >>Thymectomy lowers the myasthenia gravis biomarker miR-150-5p
    Show others...
    2018 (English)In: Neurology: Neuroimmunology and neuroinflammation, ISSN 0948-6259, E-ISSN 2332-7812, Vol. 5, no 3, article id e450Article in journal (Refereed) Published
    Abstract [en]

    Objective: The aim of the study was to analyze the effect of thymectomy on the proposed disease-specific microRNA (miRNA) biomarkers miR-150-5p and miR-21-5p in patients from the prospective randomized trial of thymectomy in myasthenia gravis (MGTX trial) and to evaluate the longitudinal changes in clinical patterns compared with these miRNA levels.

    Methods: Serum samples were obtained from 80 patients with MG who were included in the MGTX trial. Thirty-eight patients were randomized to thymectomy plus prednisone treatment, and 42 patients were randomized to prednisone treatment. Serum samples were analyzed for the expression of miR-150-5p and miR-21-5p, with quantitative reverse transcriptase PCR at baseline and at 12, 24, and 36 months after randomization. The inclusion criteria for participation in the MGTX trial were age 18-65 years, generalized myasthenia gravis (Myasthenia Gravis Foundation of America Class II-IV), disease duration of less than 5 years, and seropositivity for acetylcholine receptor antibodies (AChR+).

    Results: Patients treated with thymectomy had lower levels of miR-150-5p at 24 months, both compared with baseline values (p = 0.0011) and the prednisone group (p = 0.04). No change in miRNA levels was found in the prednisone group. Levels of miR-21-5p displayed a negative correlation with the prednisone dose within the prednisone-only group (p ≤ 0.001).

    Conclusions: Thymectomy lowers the levels of the proposed biomarker miR-150-5p, which strengthens its position as a potential disease-specific biomarker for AChR+ MG.

    National Category
    Neurology
    Research subject
    Neurology
    Identifiers
    urn:nbn:se:uu:diva-356113 (URN)10.1212/NXI.0000000000000450 (DOI)000437787600006 ()29511707 (PubMedID)
    Funder
    Swedish Research Council, VR-523-2014-2048NIH (National Institute of Health), U01 NS 42685
    Available from: 2018-07-14 Created: 2018-07-14 Last updated: 2018-09-20Bibliographically approved
  • 146.
    Molin, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Punga, Anna R.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Compound Motor Action Potential: Electrophysiological Marker for Muscle Training2016In: Journal of clinical neurophysiology, ISSN 0736-0258, E-ISSN 1537-1603, Vol. 33, no 4, p. 340-345Article in journal (Refereed)
    Abstract [en]

    Purpose:The compound motor action potential (CMAP) represents the summated action potentials of all stimulated motor endplates and potentially reflects muscle hypertrophy and increased muscle contractions. Since electrophysiological biomarkers for high-resistance strength training are lacking, the authors evaluated whether the CMAP of distal and proximal muscles differs between healthy men and women who perform and do not perform high-resistance muscle training.Methods:Motor neurography was performed with stimulation of the median nerve (recording of abductor pollicis brevis muscle), peroneal nerve (recording of extensor digitorum brevis muscle), femoral nerve (recording of rectus femoris muscle) and musculocutaneous nerve (recording of biceps brachii muscle), and isometric muscle strength, measured with a hand-held dynamometer, were performed on 83 healthy subjects (52 women).Results:Trained women had 25% higher CMAP amplitude in the rectus femoris muscle than untrained women (P < 0.001), whereas CMAP amplitude in the trained male cohort was 25% higher in the biceps (P = 0.005) compared with untrained men. In the trained group, CMAP amplitude in the biceps correlated with isometric muscle strength (R = 0.30; P = 0.046).Conclusions:The authors' propose the CMAP as an objective neurophysiological parameter for proximal muscle status and training effects in future interventional studies of patients with neuromuscular disorders.

  • 147.
    Molin, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Sabre, Liis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Weis, Cleo-Aron
    Punga, Tanel
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Thymectomy lowers the myasthenia gravis biomarker miR-150-5p2018In: Neurology: Neuroimmunology and neuroinflammation, ISSN 0948-6259, E-ISSN 2332-7812, Vol. 5, no 3, article id e450Article in journal (Refereed)
    Abstract [en]

    Objective: The aim of the study was to analyze the effect of thymectomy on the proposed disease-specific microRNA (miRNA) biomarkers miR-150-5p and miR-21-5p in patients from the prospective randomized trial of thymectomy in myasthenia gravis (MGTX trial) and to evaluate the longitudinal changes in clinical patterns compared with these miRNA levels.

    Methods: Serum samples were obtained from 80 patients with MG who were included in the MGTX trial. Thirty-eight patients were randomized to thymectomy plus prednisone treatment, and 42 patients were randomized to prednisone treatment. Serum samples were analyzed for the expression of miR-150-5p and miR-21-5p, with quantitative reverse transcriptase PCR at baseline and at 12, 24, and 36 months after randomization. The inclusion criteria for participation in the MGTX trial were age 18-65 years, generalized myasthenia gravis (Myasthenia Gravis Foundation of America Class II-IV), disease duration of less than 5 years, and seropositivity for acetylcholine receptor antibodies (AChR+).

    Results: Patients treated with thymectomy had lower levels of miR-150-5p at 24 months, both compared with baseline values (p = 0.0011) and the prednisone group (p = 0.04). No change in miRNA levels was found in the prednisone group. Levels of miR-21-5p displayed a negative correlation with the prednisone dose within the prednisone-only group (p ≤ 0.001).

    Conclusions: Thymectomy lowers the levels of the proposed biomarker miR-150-5p, which strengthens its position as a potential disease-specific biomarker for AChR+ MG.

  • 148.
    Molin, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Westerberg, Elisabet
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Profile of upregulated inflammatory proteins in sera of Myasthenia Gravis patients.2017In: Scientific Reports, ISSN 2045-2322, E-ISSN 2045-2322, Vol. 7, article id 39716Article in journal (Refereed)
    Abstract [en]

    This study describes specific patterns of elevated inflammatory proteins in clinical subtypes of myasthenia gravis (MG) patients. MG is a chronic, autoimmune neuromuscular disease with antibodies most commonly targeting the acetylcholine receptors (AChRab), which causes fluctuating skeletal muscle fatigue. MG pathophysiology includes a strong component of inflammation, and a large proportion of patients with early onset MG additionally present thymus hyperplasia. Due to the fluctuating nature and heterogeneity of the disease, there is a great need for objective biomarkers as well as novel potential inflammatory targets. We examined the sera of 45 MG patients (40 AChRab seropositive and 5 AChRab seronegative), investigating 92 proteins associated with inflammation. Eleven of the analysed proteins were significantly elevated compared to healthy controls, out of which the three most significant were: matrix metalloproteinase 10 (MMP-10; p = 0.0004), transforming growth factor alpha (TGF-α; p = 0.0017) and extracellular newly identified receptor for advanced glycation end-products binding protein (EN-RAGE) (also known as protein S100-A12; p = 0.0054). Further, levels of MMP-10, C-X-C motif ligand 1 (CXCL1) and brain derived neurotrophic factor (BDNF) differed between early and late onset MG. These novel targets provide valuable additional insight into the systemic inflammatory response in MG.

  • 149.
    Molin, Carl Johan
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Widenfalk, Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Rostedt Punga, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    High-resistance strength training does not affect nerve cross sectional area – An ultrasound study2017In: Clinical Neurophysiology Practice, ISSN 2467-981X, Vol. 2, p. 163-169Article in journal (Refereed)
    Abstract [en]

    ObjectiveThe aim was to study the effect of high-resistance strength training on peripheral nerve morphology, by examining properties of peripheral nerves as well as distal and proximal muscle thickness with ultrasound, comparing healthy individuals who perform and do not perform high-resistance strength training.

    MethodsNeuromuscular ultrasound was used to examine cross sectional area (CSA) of the median and musculocutaneous nerves, and muscle thickness of the abductor pollicis brevis muscle, biceps brachii muscle, quadriceps muscle and extensor digitorum brevis muscle, in 44 healthy individuals, of whom 22 performed regular high-resistance strength training.

    ResultsNo difference in nerve CSA was found between trained and untrained individuals although trained individuals had thicker biceps brachii muscles. The CSA of the median nerve in the forearm correlated with participants’ height and was significantly larger in men than women.

    ConclusionsIn this cohort, CSA of the median and musculocutaneous nerves was not affected by strength training, whereas gender had a prominent effect both on CSA and muscle thickness.

    SignificanceThis is the first study to examine the effect of high-resistance strength training on peripheral nerves with neuromuscular ultrasound.

  • 150. Muresanu, D. F.
    et al.
    Winkler, Tomas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Nozari, A.
    Menon, P. K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences.
    Sharma, Aruna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Sharma, Hari Shanker
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Cerebrolysin enhances spinal cord conduction and reduces blood-spinal cord barrier breakdown, oedema formation, immediate early gene expression and cord pathology after injury2012In: European Journal of Neurology, ISSN 1351-5101, E-ISSN 1468-1331, Vol. 19, no S1, p. 798-798Article in journal (Other academic)
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