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  • 1.
    Aare, Sudhakar
    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.
    Norman, Holly S
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Eriksson, Lars I
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Chen, Yi-Wen
    Hoffman, Eric P
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Mechanisms underlying the sparing of masticatory versus limb muscle function in an experimental critical illness model2011In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 43, no 24, p. 1334-1350Article in journal (Refereed)
    Abstract [en]

    Acute quadriplegic myopathy (AQM) is a common debilitating acquired disorder in critically ill intensive care unit (ICU) patients which is characterized by tetraplegia/generalized weakness of limb and trunk muscles. Masticatory muscles, on the other hand, are typically spared or less affected, yet the mechanisms underlying this striking muscle-specific difference remain unknown. This study aims to evaluate physiological parameters and the gene expression profiles of masticatory and limb muscles exposed to factors suggested to trigger AQM, such as mechanical ventilation, immobilization, neuromuscular blocking agents (NMBA), corticosteroids (CS) and sepsis for five days by using a unique porcine model mimicking the ICU conditions. Single muscle fiber cross-sectional area and force-generating capacity, i.e., maximum force normalized to fiber cross-sectional area (specific force), revealed maintained masseter single muscle fiber cross-sectional area and specific-force after five days exposure to all triggering factors. This is in sharp contrast to observations in limb and trunk muscles, showing a dramatic decline in specific force in response to five days exposure to the triggering factors. Significant differences in gene expression were observed between craniofacial and limb muscles, indicating a highly complex and muscle specific response involving transcription and growth factors, heat shock proteins, matrix metalloproteinase inhibitor, oxidative stress responsive elements and sarcomeric proteins underlying the relative sparing of cranial versus spinal nerve innervated muscles during exposure to the ICU intervention.

  • 2.
    Aare, Sudhakar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Akkad, Hazem
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric
    Research center for genetic medicine.
    Lars, Larsson
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Effects of corticosteroids in the development of limb muscle weakness in a porcine intensive care unit model2013In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 8, p. 312-320Article in journal (Refereed)
    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.

     

  • 3.
    Aare, Sudhakar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Department of anesthesiology, Karolinska Inistitute.
    Eriksson, Lars
    Department of anesthesiology, Karolinska Inistitute.
    Chen, Yi-Wen
    Research center for genetic medicine.
    Hoffman, Eric P
    Research center for genetic medicine.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    The role of sepsis in the development of limb muscle weakness in a porcine intensive care unit model2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 18, p. 865-877Article in journal (Refereed)
    Abstract [en]

    Severe muscle wasting and loss of muscle function in critically ill mechanically ventilated intensive care unit (ICU) patients have significant negative consequences on their recovery and rehabilitation that persist long after their hospital discharge; moreover the underlying mechanisms are unclear. Mechanical ventilation (MV) and immobilization-induced modifications play an important role in these consequences, including endotoxin induced sepsis. The present study aims to investigate how sepsis aggravates ventilator and immobilization-related limb muscle dysfunction. Hence, biceps femoris muscle gene expression was investigated in pigs exposed to ICU intervention, i.e., immobilization, sedation, and MV, alone or in combination with sepsis for five days. In previous studies, we have shown that ICU intervention alone or in combination with sepsis did not affect muscle fiber size on day 5, but a significant decrease was observed in single fiber maximal force normalized to cross-sectional area (specific force) when sepsis was added to the ICU intervention. According to microarray data, the addition of sepsis to the ICU intervention induced a deregulation of more than 500 genes, such as an increased expression of genes involved in chemokine activity, kinase activity and transcriptional regulation. Genes involved in the regulation of the oxidative stress response, cytoskeletal/sarcomeric and heat shock proteins were on the other hand down-regulated when sepsis was added to the ICU intervention. Thus, sepsis has a significant negative effect on muscle function in critically ill ICU patients and chemokine activity and heat shock protein genes are forwarded to play an instrumental role in this specific muscle wasting condition.

  • 4.
    Banduseela, Varuna C.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Ochala, Julien
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Chen, Yi-Wen
    Göransson, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Norman, Holly
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Radell, Peter
    Eriksson, Lars I.
    Hoffman, Eric P.
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Gene expression and muscle fiber function in a porcine ICU model2009In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 39, no 3, p. 141-159Article in journal (Refereed)
    Abstract [en]

    Skeletal muscle wasting and impaired muscle function in response to mechanical ventilation and immobilization in intensive care unit (ICU) patients are clinically challenging partly due to 1) the poorly understood intricate cellular and molecular networks and 2) the unavailability of an animal model mimicking this condition. By employing a unique porcine model mimicking the conditions in the ICU with long-term mechanical ventilation and immobilization, we have analyzed the expression profile of skeletal muscle biopsies taken at three time points during a 5-day period. Among the differentially regulated transcripts, extracellular matrix, energy metabolism, sarcomeric and LIM protein mRNA levels were downregulated, while ubiquitin proteasome system, cathepsins, oxidative stress responsive genes and heat shock proteins (HSP) mRNAs were upregulated. Despite 5 days of immobilization and mechanical ventilation single muscle fiber cross-sectional areas as well as the maximum force generating capacity at the single muscle fiber level were preserved. It is proposed that HSP induction in skeletal muscle is an inherent, primary, but temporary protective mechanism against protein degradation. To our knowledge, this is the first study that isolates the effect of immobilization and mechanical ventilation in an ICU condition from various other cofactors.

  • 5.
    Banduseela, Varuna
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Chen, Yi-wen
    Göransson Kultima, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Norman, Holly
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Department of Medicine, University of Wisconsin, Madison, Wisconsin.
    Aare, Sudhakar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Radell, Peter
    Eriksson, Lars
    Hoffman, Eric
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology. Department of Biobehavioral Health, The Pennsylvania State University, University Park, Pennsylvania.
    Impaired autophagy, chaperone expression, and protein synthesis in response to critical illness interventions in porcine skeletal muscle2013In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 12, p. 477-486Article in journal (Refereed)
    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.

  • 6. Blizard, David A.
    et al.
    Lionikas, Arimantas
    Vandenberg, David
    Vasilopoulos, Terrie
    Gerhard, Glenn
    Griffith, James
    Klein, Laura
    Stout, Joseph
    Mack, Holly
    Lakoski, Joan
    Larsson, Lars
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Clinical Neurophysiology.
    Spicer, Jeanne
    Vogler, George
    McClearn, Gerald E.
    Blood pressure and heart rate QTL in mice of the B6/D2 lineage sex differences and environmental influences2009In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 36, no 3, p. 158-166Article in journal (Refereed)
    Abstract [en]

    A quantitative trait locus (QTL) approach was used to define the genetic architecture underlying variation in systolic blood pressure (SBP) and heart rate (HR), measured indirectly on seven occasions by the tail cuff procedure. The tests were conducted in 395 F(2) adult mice (197 males, 198 females) derived from a cross of the C57BL/6J (B6) and DBA/2J (D2) strains and in 22 BXD recombinant-inbred (RI) strains. Interval mapping of F(2) data for the first 5 days of measurement nominated one statistically significant and one suggestive QTL for SBP on chromosomes (Chr) 4 and 14, respectively, and two statistically significant QTL for HR on Chr 1 (which was specific to female mice) and Chr 5. New suggestive QTL emerged for SBP on Chr 3 (female-specific) and 8 and for HR on Chr 11 for measurements recorded several weeks after mice had undergone stressful blood sampling procedures. The two statistically significant HR QTL were confirmed by analyses of BXD RI strain means. Male and female F(2) mice did not differ in SBP or HR but RI strain analyses showed pronounced strain-by-sex interactions and a negative genetic correlation between the two measures in both sexes. Evidence for a role for mitochondrial DNA was found for both HR and SBP. QTL for HR and SBP may differ in males and females and may be sensitive to different environmental contexts.

  • 7. Ek, Weronica
    et al.
    Strömstedt, Lina
    Wahlberg, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Siegel, Paul
    Andersson, Leif
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Carlborg, Örjan
    SLU.
    Genetic analysis of metabolic traits in an intercross between body weight-selected chicken lines2010In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 42, no 1, p. 20-22Article in journal (Refereed)
    Abstract [en]

    A network of four interacting loci has been reported previously to influence growth in two lines of chickens divergently selected for body weight at 56 days of age. Located on chromosomes 3 (Growth4), 4 (Growth6), 7 (Growth9), and 20 (Growth12), they explained nearly half of the difference in body weight at selection age between the two lines. The original study reported effects on body weight and fat deposition, but no attempts were made to explore the effects of the network on other phenotypes measured in the F(2) population. In this study we conducted further analyses to evaluate the specific effects of the four-locus network on other metabolic traits as well as refining results from the original study by including a larger number of genetic markers in the quantitative trait locus (QTL) regions. We confirm the previously described effect of the epistatic network on body weight and show that the network increases the total amount of muscle and fat as well as the weight of the internal organs. The network as a whole did not change the relative content of any studied organs or tissues in the body. There was, however, a significant interaction between the loci on chromosomes 3 and 7 that changed the relative proportion of abdominal fat and breast muscle in the chicken by increasing abdominal fat weight without a corresponding increase in muscle mass.

  • 8.
    Grundberg, Elin
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Brändström, Helena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Lam, Kevin C. L.
    Gurd, Scott
    Ge, Bing
    Harmsen, Eef
    Kindmark, Andreas
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Ljunggren, Östen
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Mallmin, Hans
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Nilsson, Olle
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Orthopaedics.
    Pastinen, Tomi
    Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells2008In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 33, no 3, p. 301-11Article in journal (Refereed)
    Abstract [en]

    Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.

  • 9.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Anaesthesiology and Intensive Care.
    Becriovic-Agic, Mediha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Jönsson, Sofia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Comparison of acute kidney injury of different aetiology reveals in-common mechanisms of tissue damage2018In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 50, no 3, p. 127-141Article, review/survey (Refereed)
    Abstract [en]

    Acute kidney injury (AKI) is a syndrome of reduced glomerular filtration rate (GFR) and urine production caused by a number of different diseases. It is associated with renal tissue damage. This tissue damage can cause tubular atrophy and interstitial fibrosis that leads to nephron loss and progression of chronic kidney disease (CKD). This review describes the in-common mechanisms behind tissue damage in AKI caused by different underlying diseases. Comparing six high-quality microarray studies of renal gene expression after AKI in disease models (gram-negative sepsis, gram-positive sepsis, ischemia-reperfusion, malignant hypertension, rhabdomyolysis and cisplatin toxicity) identified 5254 differentially expressed genes in at least one of the AKI models. 66% of genes were only found in one model showing that there are unique features to AKI depending on the underlying disease. There were in-common features in the form of four genes that were differentially expressed in all six models, 49 in at least five, and 215 were in-common between at least four models. Gene ontology enrichment analysis could be broadly categorized into the injurious processes hypoxia, oxidative stress, and inflammation, as well as the cellular outcomes of cell death and tissue remodeling in the form of epithelial to mesenchymal transition (EMT). Pathway analysis showed that MYC is a central connection in the network of activated genes in-common to AKI, which suggests that it may be a central regulator of renal gene expression in tissue injury during AKI. The outlining of this molecular network may be useful for understanding progression from AKI to CKD.

  • 10.
    Hultström, Michael
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Cell Biology, Integrative Physiology.
    Leh, Sabine
    Paliege, Alexander
    Bachmann, Sebastian
    Skogstrand, Trude
    Iversen, Bjarne M.
    Collagen-binding proteins in age-dependent changes in renal collagen turnover: microarray analysis of mRNA expression2012In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 44, no 10, p. 576-586Article in journal (Refereed)
    Abstract [en]

    Aging is associated with progressive structural and functional deterioration of the kidney. Among the morphological changes associated with renal aging is an accumulation of extracellular matrix (ECM) in the glomeruli and tubuloinsterstitium, which may ultimately lead to the development of renal fibrosis. The mechanisms governing the regulation of ECM metabolism during renal aging are only incompletely defined. We present data from a genome-wide mRNA expression study on renal tissue from 90 wk old male Wistar rats and 10 wk old controls using Illumina BeadArray cDNA microarray. Regulation of candidate gene products was verified by real-time PCR. Morphological changes were evaluated by routine histological methods. Activated fibroblasts were identified by their expression of alpha-smooth muscle actin and collagen I. Morphological analysis demonstrated an expansion of the tubulointerstitial compartment with increased amounts of fibrous collagen but no overt glomerular or tubular damage in the aged rats. Activated fibroblasts were readily detectable in the adventitial layer of large renal vessels in controls and were not found in the old animals. In agreement with this finding, gene expression analysis revealed significant downregulation of collagen I mRNA along with numerous other ECM components. Concomitantly, collagen-stabilizing proteins were induced, whereas matrix metalloproteinase 9, an enzyme involved in collagen breakdown, was reduced. In conclusion, our results suggest that ECM expansion during renal aging results from an augmented stabilization in conjunction with a reduced breakdown of collagen fibers. Collagen stabilizing proteins may be essential for the control of renal ECM turnover and the pathogenesis of kidney fibrosis.

  • 11.
    Ka, Sojeong
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience.
    Markljung, Ellen
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Ring, Henrik
    Department of Evolutionary Genetics, Max Planck Institute for Evolutionary Anthropology, Leipzig, Germany.
    Albert, Frank W
    Harun-Or-Rashid, Mohammad
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    Wahlberg, Per
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Garcia-Roves, Pablo M
    Zierath, Juleen R
    Denbow, D Michael
    Pääbo, Svante
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Siegel, Paul B
    Andersson, Leif
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hallböök, Finn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Developmental Neuroscience.
    The expression of carnitine palmitoyl-CoA transferase-1B is influenced by a cis-acting eQTL in two chicken lines selected for high and low body weight2013In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 45, no 9, p. 367-376Article in journal (Refereed)
    Abstract [en]

    Carnitine palmitoyl-CoA transferase-1B is a mitochondrial enzyme in the fatty acid oxidation pathway. In a previous study, CPT1B was identified as differentially expressed in the hypothalamus of two lines of chickens established by long-term selection for high (HWS) or low (LWS) body weight. Mammals have three paralogs (CPT1a, b and c) while non-mammalian vertebrates only have two (CPT1A, B). CPT1A is expressed in liver and CPT1B in muscle. CPT1c is expressed in hypothalamus, where it regulates feeding and energy expenditure. We identified an intronic length polymorphism, fixed for different alleles in the two populations and mapped the hitherto missing CPT1B locus in the chicken genome assembly, to the distal tip of chromosome 1p. Based on molecular phylogeny and gene synteny we suggest that chicken CPT1B is pro-orthologous of the mammalian CPT1c. Chicken CPT1B was differentially expressed in both muscle and hypothalamus but in opposite directions: higher levels in hypothalamus but lower levels in muscle in the HWS than in the LWS line. Using an advanced inter-cross population of the lines, CPT1B expression was found to be influenced by a cis-acting expression quantitative trait locus in muscle. The increased expression in hypothalamus and reduced expression in muscle is consistent with an increased food intake in the HWS line and at the same time reduced fatty acid oxidation in muscle yielding a net accumulation of energy intake and storage. The altered expression of CPT1B in hypothalamus and peripheral tissue is likely to be a mechanism contributing to the remarkable difference between lines.

  • 12.
    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.

  • 13. Weinsheimer, Shantel
    et al.
    Lenk, Guy M
    van der Voet, Monique
    Land, Susan
    Ronkainen, Antti
    Alafuzoff, Irina
    Department of Neuroscience and Neurology, University of Kuopio Finland.
    Kuivaniemi, Helena
    Tromp, Gerard
    Integration of expression profiles and genetic mapping data to identify candidate genes in intracranial aneurysm.2007In: Physiological Genomics, ISSN 1094-8341, E-ISSN 1531-2267, Vol. 32, no 1, p. 45-57Article in journal (Refereed)
    Abstract [en]

    Intracranial aneurysm (IA) is a complex genetic disease for which, to date, 10 loci have been identified by linkage. Identification of the risk-conferring genes in the loci has proven difficult, since the regions often contain several hundreds of genes. An approach to prioritize positional candidate genes for further studies is to use gene expression data from diseased and nondiseased tissue. Genes that are not expressed, either in diseased or nondiseased tissue, are ranked as unlikely to contribute to the disease. We demonstrate an approach for integrating expression and genetic mapping data to identify likely pathways involved in the pathogenesis of a disease. We used expression profiles for IAs and nonaneurysmal intracranial arteries (IVs) together with the 10 reported linkage intervals for IA. Expressed genes were analyzed for membership in Kyoto Encyclopedia of Genes and Genomes (KEGG) biological pathways. The 10 IA loci harbor 1,858 candidate genes, of which 1,561 (84%) were represented on the microarrays. We identified 810 positional candidate genes for IA that were expressed in IVs or IAs. Pathway information was available for 294 of these genes and involved 32 KEGG biological function pathways represented on at least 2 loci. A likelihood-based score was calculated to rank pathways for involvement in the pathogenesis of IA. Adherens junction, MAPK, and Notch signaling pathways ranked high. Integration of gene expression profiles with genetic mapping data for IA provides an approach to identify candidate genes that are more likely to function in the pathology of IA.

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