uu.seUppsala University Publications
Change search
Link to record
Permanent link

Direct link
BETA
Larsson, Lars
Alternative names
Publications (10 of 61) Show all publications
Elf, K., Shevchenko, G., Nygren, I., Larsson, L., Bergquist, J., Askmark, H. & Artemenko, K. (2014). Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis. Journal of Proteomics, 108, 55-64
Open this publication in new window or tab >>Alterations in muscle proteome of patients diagnosed with amyotrophic lateral sclerosis
Show others...
2014 (English)In: Journal of Proteomics, ISSN 1874-3919, E-ISSN 1876-7737, Vol. 108, p. 55-64Article in journal (Refereed) Published
Abstract [en]

Amyotrophic lateral sclerosis (ALS) is a motor neuron disease characterized by progressive muscle paralysis. Currently clinical tools for ALS diagnostics do not perform well enough and their improvement is needed. The objective of this study was to identify specific protein alterations related to the development of ALS using tiny muscle biopsies. We applied a shotgun proteomics and quantitative dimethyl labeling in order to analyze the global changes in human skeletal muscle proteome of ALS versus healthy subjects for the first time. 235 proteins were quantified and 11 proteins were found significantly regulated in ALS muscles. These proteins are involved in muscle development and contraction, metabolic processes, enzyme activity, regulation of apoptosis and transport activity. In order to eliminate a risk to confuse ALS with other denervations, muscle biopsies of patients with postpolio syndrome and Charcot Marie Tooth disease (negative controls) were compared to those of ALS and controls. Only few proteins significantly regulated in ALS patients compared to controls were affected differently in negative controls. These proteins (BTB and kelch domain-containing protein 10, myosin light chain 3, glycogen debranching enzyme, transitional endoplasmic reticulum ATPase), individually or as a panel, could be selected for estimation of ALS diagnosis and development. Biological significance ALS is a devastating neurodegenerative disease, and luckily, very rare: only one to two people out of 100,000 develop ALS yearly. This fact, however, makes studies of ALS very challenging since it is very difficult to collect the representative set of clinical samples and this may take up to several years. In this study we collected the muscle biopsies from 12 ALS patients and compared the ALS muscle proteome against the one from control subjects. We suggested the efficient method for such comprehensive quantitative analysis by LC-MS and performed it for the first time using human ALS material. This gel- and antibody-free method can be widely applied for muscle proteome studies and has been used by us for revealing of the specific protein alterations associated with ALS.

Keywords
Amyotrophic lateral sclerosis (ALS), Dimethyl labeling quantitative proteomics, Mass spectrometry (MS), Muscle biopsy
National Category
Biochemistry and Molecular Biology
Identifiers
urn:nbn:se:uu:diva-230939 (URN)10.1016/j.jprot.2014.05.004 (DOI)000340315400004 ()
Available from: 2014-09-04 Created: 2014-09-01 Last updated: 2017-12-05Bibliographically approved
Akkad, H., Corpeno Kalamgi, R. & Larsson, L. (2014). Masseter Muscle Myofibrillar Protein Synthesis and Degradation in an Experimental Critical Illness Myopathy Model. PLoS ONE, 9(4), e92622
Open this publication in new window or tab >>Masseter Muscle Myofibrillar Protein Synthesis and Degradation in an Experimental Critical Illness Myopathy Model
2014 (English)In: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 9, no 4, p. e92622-Article in journal (Refereed) Published
Abstract [en]

Critical illness myopathy (CIM) is a debilitating common consequence of modern intensive care, characterized by severe muscle wasting, weakness and a decreased myosin/actin (M/A) ratio. Limb/trunk muscles are primarily affected by this myopathy while cranial nerve innervated muscles are spared or less affected, but the mechanisms underlying these muscle-specific differences remain unknown. In this time-resolved study, the cranial nerve innervated masseter muscle was studied in a unique experimental rat intensive care unit (ICU) model, where animals were exposed to sedation, neuromuscular blockade (NMB), mechanical ventilation, and immobilization for durations varying between 6 h and 14d. Gel electrophoresis, immunoblotting, RT-PCR and morphological staining techniques were used to analyze M/A ratios, myofiber size, synthesis and degradation of myofibrillar proteins, and levels of heat shock proteins (HSPs). Results obtained in the masseter muscle were compared with previous observations in experimental and clinical studies of limb muscles. Significant muscle-specific differences were observed, i.e., in the masseter, the decline in M/A ratio and muscle fiber size was small and delayed. Furthermore, transcriptional regulation of myosin and actin synthesis was maintained, and Akt phosphorylation was only briefly reduced. In studied degradation pathways, only mRNA, but not protein levels of MuRF1, atrogin-1 and the autophagy marker LC3b were activated by the ICU condition. The matrix metalloproteinase MMP-2 was inhibited and protective HSPs were up-regulated early. These results confirm that the cranial nerve innervated masticatory muscles is less affected by the ICU-stress response than limb muscles, in accordance with clinical observation in ICU patients with CIM, supporting the model' credibility as a valid CIM model.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-224739 (URN)10.1371/journal.pone.0092622 (DOI)000334107500021 ()
Available from: 2014-05-21 Created: 2014-05-19 Last updated: 2017-12-05Bibliographically approved
Corpeno, R., Dworkin, B., Cacciani, N., Salah, H., Bergman, H.-M., Ravara, B., . . . Larsson, L. (2014). Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat. Journal of Physiology, 592(17), 3859-3880
Open this publication in new window or tab >>Time-course analysis of mechanical ventilation-induced diaphragm contractile muscle dysfunction in the rat
Show others...
2014 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 592, no 17, p. 3859-3880Article in journal (Refereed) Published
Abstract [en]

Controlled mechanical ventilation (CMV) plays a key role in triggering the impaired diaphragm muscle function and the concomitant delayed weaning from the respirator in critically ill intensive care unit (ICU) patients. To date, experimental and clinical studies have primarily focused on early effects on the diaphragm by CMV, or at specific time points. To improve our understanding of the mechanisms underlying the impaired diaphragm muscle function in response to mechanical ventilation, we have performed time‐resolved analyses between 6 h and 14 days using an experimental rat ICU model allowing detailed studies of the diaphragm in response to long‐term CMV. A rapid and early decline in maximum muscle fibre force and preceding muscle fibre atrophy was observed in the diaphragm in response to CMV, resulting in an 85% reduction in residual diaphragm fibre function after 9–14 days of CMV. A modest loss of contractile proteins was observed and linked to an early activation of the ubiquitin proteasome pathway, myosin:actin ratios were not affected and the transcriptional regulation of myosin isoforms did not show any dramatic changes during the observation period. Furthermore, small angle X‐ray diffraction analyses demonstrate that myosin can bind to actin in an ATP‐dependent manner even after 9–14 days of exposure to CMV. Thus, quantitative changes in muscle fibre size and contractile proteins are not the dominating factors underlying the dramatic decline in diaphragm muscle function in response to CMV, in contrast to earlier observations in limb muscles. The observed early loss of subsarcolemmal neuronal nitric oxide synthase activity, onset of oxidative stress, intracellular lipid accumulation and post‐translational protein modifications strongly argue for significant qualitative changes in contractile proteins causing the severely impaired residual function in diaphragm fibres after long‐term mechanical ventilation. For the first time, the present study demonstrates novel changes in the diaphragm structure/function and underlying mechanisms at the gene, protein and cellular levels in response to CMV at a high temporal resolution ranging from 6 h to 14 days.

National Category
Physiology Neurology
Identifiers
urn:nbn:se:uu:diva-192529 (URN)10.1113/jphysiol.2014.277962 (DOI)000341771400013 ()
Funder
Swedish Research Council, 8651, 4423
Available from: 2013-01-22 Created: 2013-01-22 Last updated: 2018-01-11Bibliographically approved
Winbanks, C. E., Chen, J. L., Turner, B. J., Larsson, L., Harrison, C. A. & Gregorevic, P. (2013). Bone Morphogenetic Protein (BMP) Signaling Is A Positive Regulator Of Skeletal Muscle Mass. Paper presented at 8th Meeting of the Australasian-Gene-Therapy-Society, MAY 08-10, 2013, Sydney, AUSTRALIA. Journal of Gene Medicine, 15(8-9), 324-325
Open this publication in new window or tab >>Bone Morphogenetic Protein (BMP) Signaling Is A Positive Regulator Of Skeletal Muscle Mass
Show others...
2013 (English)In: Journal of Gene Medicine, ISSN 1099-498X, E-ISSN 1521-2254, Vol. 15, no 8-9, p. 324-325Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-210333 (URN)000325102500028 ()
Conference
8th Meeting of the Australasian-Gene-Therapy-Society, MAY 08-10, 2013, Sydney, AUSTRALIA
Available from: 2013-11-06 Created: 2013-11-05 Last updated: 2017-12-06Bibliographically approved
Ramamurthy, B. & Larsson, L. (2013). Detection of an aging-related increase in advanced glycation end products in fast- and slow-twitch skeletal muscles in the rat. Biogerontology (Dordrecht), 14(3), 293-301
Open this publication in new window or tab >>Detection of an aging-related increase in advanced glycation end products in fast- and slow-twitch skeletal muscles in the rat
2013 (English)In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 14, no 3, p. 293-301Article in journal (Refereed) Published
Abstract [en]

Glycation, a non-enzymatic addition of reducing sugars to ε-amino groups of proteins, is a post-translational modification that results in the formation of irreversible advanced glycation end products (AGEs). Ageing related decline in myofibrillar protein function is effected by a number of structural and functional modifications including glycation. Functional properties of skeletal muscles, such as maximum velocity of unloaded shortening, are known to be profoundly affected by ageing at the motor unit, cellular and tissue levels. However, the contribution of protein modifications to a decline in muscle function is not well understood. In this study we measured AGEs of intracellular and sarcolemmal proteins, using an anti-AGE antibody in soleus (SOL) and extensor digiotorum longus (EDL) muscles of male and female rats of five different age groups. Using a fluorescent secondary antibody to visualize AGEs in the confocal microscope, we found that myosin is glycated in both fiber types in all age groups; an ageing related increase in AGEs was observed in both intracellular and sarcolemmal regions in all age groups, with the exception of sarcolemma of SOL (unchanged) and EDL (reduced) in female rats; the greatest concentration of AGEs was found intracellularly in the SOL of the oldest age group (27–30) of females. While an ageing related decline in motor properties can be partially attributed to the observed increase in myofibrillar protein glycation, our results also indicate that intracellular and the less well studied sarcolemmal protein modification likely contribute to an aging-related decline in muscle function. Further studies are required to establish a link between the observed ageing related increase in glycation and muscle function at the motor unit, cellular and tissue levels.

Place, publisher, year, edition, pages
Springer, 2013
National Category
Neurology
Research subject
Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-221290 (URN)10.1007/s10522-013-9430-y (DOI)000322115200006 ()23681254 (PubMedID)
Available from: 2014-03-27 Created: 2014-03-27 Last updated: 2017-12-05Bibliographically approved
Aare, S., Radell, P., Eriksson, L., Akkad, H., Chen, Y.-W., Hoffman, E. & Lars, L. (2013). Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model. Physiological Genomics, 45(8), 312-320
Open this publication in new window or tab >>Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model
Show others...
2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, p. 312-320Article in journal (Refereed) Published
Abstract [en]

Severe muscle wasting is a debilitating condition in critically ill intensive care unit (ICU) patients, characterized by general muscle weakness and dysfunction, resulting in a prolonged mobilization, delayed weaning from the ventilator and a decreased quality of life post-ICU. The mechanisms underlying limbmuscle weakness in ICU patients are complex and involve the impact of primary disease, but also factors common to critically ill ICU patients such as sepsis, mechanical ventilation (MV), immobilization and systemic administration of corticosteroids (CS).  These factors may have additive negative effects on skeletal muscle structure and function, but their respective role alone remain unknown. The primary aim of this study was to examine how CS administration potentiates ventilator and immobilization-related limb muscle dysfunction at the gene level. Comparing biceps femoris gene expression in pigs exposed to MV and CS for five days with only MV pigs for the same duration of time showed a distinct deregulation of 186 genes using microarray. Surprisingly, the decreased force-generation capacity at the single muscle fiber reported in response to the addition of CS administration in mechanically ventilated and immobilized pigs was not associated with an additional up-regulation of proteolytic pathways. On the other hand, an altered expression of genes regulating kinase activity, cell cycle, transcription, channel regulation, oxidative stress response , cytoskeletal, sarcomeric and heat shock protein as well as protein synthesis at the translational level appear to play an additive deleterious role for the  limb muscle weakness in immobilized ICU patients.

 

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-180375 (URN)10.1152/physiolgenomics.00123.2012 (DOI)000317662000002 ()23429211 (PubMedID)
Available from: 2012-09-05 Created: 2012-09-05 Last updated: 2017-12-07Bibliographically approved
Qaisar, R., Renaud, G., Hedström, Y., Pollanen, E., Ronkainen, P., Kaprio, J., . . . Larsson, L. (2013). Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs. Journal of Physiology, 591(9), 2333-2344
Open this publication in new window or tab >>Hormone replacement therapy improves contractile function and myonuclear organization of single muscle fibres from postmenopausal monozygotic female twin pairs
Show others...
2013 (English)In: Journal of Physiology, ISSN 0022-3751, E-ISSN 1469-7793, Vol. 591, no 9, p. 2333-2344Article in journal (Refereed) Published
Abstract [en]

Ageing is associated with a decline in muscle mass and strength leading to increased physical dependency in old age. Postmenopausal women experience a greater decline than men of similar age in parallel with the decrease in female sex steroid hormone production. We recruited six monozygous female twin pairs (5559 years old) where only one twin pair was on hormone replacement therapy (HRT use = 7.8 +/- 4.3 years) to investigate the association of HRT with the cytoplasmic volume supported by individual myonuclei (myonuclear domain (MND) size,) together with specific force at the single fibre level. HRT use was associated with a significantly smaller (approximate to 27%; P < 0.05) mean MND size in muscle fibres expressing the type I but not the IIa myosin heavy chain (MyHC) isoform. In comparison to non-users, higher specific force was recorded in HRT users both in muscle fibres expressing type I (approximate to 27%; P < 0.05) and type IIa (approximate to 23%; P < 0.05) MyHC isoforms. These differences were fibre-type dependent, i.e. the higher specific force in fast-twitch muscle fibres was primarily caused by higher force per cross-bridge while slow-twitch fibres relied on both a higher number and force per cross-bridge. HRT use had no effect on fibre cross-sectional area (CSA), velocity of unloaded shortening (V0) and relative proportion of MyHC isoforms. In conclusion, HRT appears to have significant positive effects on both regulation of muscle contraction and myonuclei organization in postmenopausal women.

National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-200673 (URN)10.1113/jphysiol.2012.250092 (DOI)000318299200014 ()
Available from: 2013-06-03 Created: 2013-06-03 Last updated: 2017-12-06Bibliographically approved
Banduseela, V., Chen, Y.-w., Göransson Kultima, H., Norman, H., Aare, S., Radell, P., . . . Larsson, L. (2013). Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle. Physiological Genomics, 45(12), 477-486
Open this publication in new window or tab >>Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle
Show others...
2013 (English)In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 12, p. 477-486Article in journal (Refereed) Published
Abstract [en]

Critical illness myopathy (CIM) is characterized by a preferential loss of the motor protein myosin, muscle wasting, and impaired muscle function in critically ill intensive care unit (ICU) patients. CIM is associated with severe morbidity and mortality and has a significant negative socioeconomic effect. Neuromuscular blocking agents, corticosteroids, sepsis, mechanical ventilation, and immobilization have been implicated as important risk factors, but the causal relationship between CIM and the risk factors has not been established. A porcine ICU model has been used to determine the immediate molecular and cellular cascades that may contribute to the pathogenesis prior to myosin loss and extensive muscle wasting. Expression profiles have been compared between pigs exposed to the ICU interventions, i.e., mechanically ventilated, sedated, and immobilized for 5 days, with pigs exposed to critical illness interventions, i.e., neuromuscular blocking agents, corticosteroids, and induced sepsis in addition to the ICU interventions for 5 days. Impaired autophagy as well as impaired chaperone expression and protein synthesis were observed in the skeletal muscle in response to critical illness interventions. A novel finding in this study is impaired core autophagy machinery in response to critical illness interventions, which when in concert with downregulated chaperone expression and protein synthesis may collectively affect the proteostasis in skeletal muscle and may exacerbate the disease progression in CIM.

Keywords
intensive care unit; porcine ICU model; autophagy; chaperones; protein synthesis; skeletal muscle; critical illness myopathy and skeletal muscle proteostasis
National Category
Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
Research subject
Medical Cell Biology
Identifiers
urn:nbn:se:uu:diva-183955 (URN)10.1152/physiolgenomics.00141.2012 (DOI)000320507100003 ()
Available from: 2012-11-06 Created: 2012-11-06 Last updated: 2017-12-07Bibliographically approved
Santos, S., Baraibar, M., Le Boulch, M., Larsson, L. & Friguet, B. (2013). Optimization of a proteomic approach for evidencing and identifying oxidized proteins during human skeletal muscle aging. Paper presented at 11th International Symposium on the Neurobiology and Neuroendocrinology of Aging, JUL 29-AUG 03, 2012, Bregenz, AUSTRIA. Experimental Gerontology, 48(7), 687-688
Open this publication in new window or tab >>Optimization of a proteomic approach for evidencing and identifying oxidized proteins during human skeletal muscle aging
Show others...
2013 (English)In: Experimental Gerontology, ISSN 0531-5565, E-ISSN 1873-6815, Vol. 48, no 7, p. 687-688Article in journal, Meeting abstract (Other academic) Published
National Category
Medical and Health Sciences
Identifiers
urn:nbn:se:uu:diva-205462 (URN)10.1016/j.exger.2013.05.020 (DOI)000321069700036 ()
Conference
11th International Symposium on the Neurobiology and Neuroendocrinology of Aging, JUL 29-AUG 03, 2012, Bregenz, AUSTRIA
Available from: 2013-08-17 Created: 2013-08-17 Last updated: 2017-12-06Bibliographically approved
Sandri, M., Barberi, L., Bijlsma, A. Y., Blaauw, B., Dyar, K. A., Milan, G., . . . Schiaffino, S. (2013). Signalling pathways regulating muscle mass in ageing skeletal muscle: The role of the IGF1-Akt-mTOR-FoxO pathway. Biogerontology (Dordrecht), 14(3 SI), 303-323
Open this publication in new window or tab >>Signalling pathways regulating muscle mass in ageing skeletal muscle: The role of the IGF1-Akt-mTOR-FoxO pathway
Show others...
2013 (English)In: Biogerontology (Dordrecht), ISSN 1389-5729, E-ISSN 1573-6768, Vol. 14, no 3 SI, p. 303-323Article in journal (Refereed) Published
Abstract [en]

During ageing skeletal muscles undergo a process of structural and functional remodelling that leads to sarcopenia, a syndrome characterized by loss of muscle mass and force and a major cause of physical frailty. To determine the causes of sarcopenia and identify potential targets for interventions aimed at mitigating ageing-dependent muscle wasting, we focussed on the main signalling pathway known to control protein turnover in skeletal muscle, consisting of the insulin-like growth factor 1 (IGF1), the kinase Akt and its downstream effectors, the mammalian target of rapamycin (mTOR) and the transcription factor FoxO. Expression analyses at the transcript and protein level, carried out on well-characterized cohorts of young, old sedentary and old active individuals and on mice aged 200, 500 and 800 days, revealed only modest age-related differences in this pathway. Our findings suggest that during ageing there is no downregulation of IGF1/Akt pathway and that sarcopenia is not due to FoxO activation and upregulation of the proteolytic systems. A potentially interesting result was the increased phosphorylation of the ribosomal protein S6, indicative of increased activation of mTOR complex1 (mTORC1), in aged mice. This result may provide the rationale why rapamycin treatment and caloric restriction promote longevity, since both interventions blunt activation of mTORC1; however, this change was not statistically significant in humans. Finally, genetic perturbation of these pathways in old mice aimed at promoting muscle hypertrophy via Akt overexpression or preventing muscle loss through inactivation of the ubiquitin ligase atrogin1 were found to paradoxically cause muscle pathology and reduce lifespan, suggesting that drastic activation of the IGF1-Akt pathway may be counterproductive, and that sarcopenia is accelerated, not delayed, when protein degradation pathways are impaired.

National Category
Neurology
Research subject
Clinical Neurophysiology
Identifiers
urn:nbn:se:uu:diva-200415 (URN)10.1007/s10522-013-9432-9 (DOI)000322115200007 ()23686362 (PubMedID)
Available from: 2013-05-27 Created: 2013-05-27 Last updated: 2017-12-06Bibliographically approved
Organisations

Search in DiVA

Show all publications