Physiology - Research Publications

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    Metabolic remodeling of dystrophic skeletal muscle reveals biological roles for dystrophin and utrophin in adaptation and plasticity
    Hardee, JP ; Martins, KJB ; Miotto, PM ; Ryall, JG ; Gehrig, SM ; Reljic, B ; Naim, T ; Chung, JD ; Trieu, J ; Swiderski, K ; Philp, AM ; Philp, A ; Watt, MJ ; Stroud, DA ; Koopman, R ; Steinberg, GR ; Lynch, GS (ELSEVIER, 2021-01-12)
    OBJECTIVES: Preferential damage to fast, glycolytic myofibers is common in many muscle-wasting diseases, including Duchenne muscular dystrophy (DMD). Promoting an oxidative phenotype could protect muscles from damage and ameliorate the dystrophic pathology with therapeutic relevance, but developing efficacious strategies requires understanding currently unknown biological roles for dystrophin and utrophin in dystrophic muscle adaptation and plasticity. METHODS: Combining whole transcriptome RNA sequencing and mitochondrial proteomics with assessments of metabolic and contractile function, we investigated the roles of dystrophin and utrophin in fast-to-slow muscle remodeling with low-frequency electrical stimulation (LFS, 10 Hz, 12 h/d, 7 d/wk, 28 d) in mdx (dystrophin null) and dko (dystrophin/utrophin null) mice, two established preclinical models of DMD. RESULTS: Novel biological roles in adaptation were demonstrated by impaired transcriptional activation of estrogen-related receptor alpha-responsive genes supporting oxidative phosphorylation in dystrophic muscles. Further, utrophin expression in dystrophic muscles was required for LFS-induced remodeling of mitochondrial respiratory chain complexes, enhanced fiber respiration, and conferred protection from eccentric contraction-mediated damage. CONCLUSIONS: These findings reveal novel roles for dystrophin and utrophin during LFS-induced metabolic remodeling of dystrophic muscle and highlight the therapeutic potential of LFS to ameliorate the dystrophic pathology and protect from contraction-induced injury with important implications for DMD and related muscle disorders.
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    The Microenvironment Is a Critical Regulator of Muscle Stem Cell Activation and Proliferation
    Nguyen, JH ; Chung, JD ; Lynch, GS ; Ryall, JG (FRONTIERS MEDIA SA, 2019-10-29)
    Skeletal muscle has a remarkable capacity to regenerate following injury, a property conferred by a resident population of muscle stem cells (MuSCs). In response to injury, MuSCs must double their cellular content to divide, a process requiring significant new biomass in the form of nucleotides, phospholipids, and amino acids. This new biomass is derived from a series of intracellular metabolic cycles and alternative routing of carbon. In this review, we examine the link between metabolism and skeletal muscle regeneration with particular emphasis on the role of the cellular microenvironment in supporting the production of new biomass and MuSC proliferation.
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    HSP70 drives myoblast fusion during C2C12 myogenic differentiation
    Thakur, SS ; Swiderski, K ; Chhen, VL ; James, JL ; Cranna, NJ ; Islam, AMT ; Ryall, JG ; Lynch, GS (COMPANY BIOLOGISTS LTD, 2020-07-01)
    In response to injury, skeletal muscle stem cells (MuSCs) undergo myogenesis where they become activated, proliferate rapidly, differentiate and undergo fusion to form multinucleated myotubes. Dramatic changes in cell size, shape, metabolism and motility occur during myogenesis, which cause cellular stress and alter proteostasis. The molecular chaperone heat shock protein 70 (HSP70) maintains proteostasis by regulating protein biosynthesis and folding, facilitating transport of polypeptides across intracellular membranes and preventing stress-induced protein unfolding/aggregation. Although HSP70 overexpression can exert beneficial effects in skeletal muscle diseases and enhance skeletal muscle repair after injury, its effect on myogenesis has not been investigated. Plasmid-mediated overexpression of HSP70 did not affect the rate of C2C12 proliferation or differentiation, but the median number of myonuclei per myotube and median myotube width in differentiated C2C12 myotubes were increased with HSP70 overexpression. These findings reveal that increased HSP70 expression can promote myoblast fusion, identifying a mechanism for its therapeutic potential to enhance muscle repair after injury.This article has an associated First Person interview with the first author of the paper.
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    Expression profiling of skeletal muscle following acute and chronic beta(2)-adrenergic stimulation: implications for hypertrophy, metabolism and circadian rhythm
    Pearen, MA ; Ryall, JG ; Lynch, GS ; Muscat, GEO (BMC, 2009-09-23)
    BACKGROUND: Systemic administration of beta-adrenoceptor (beta-AR) agonists has been found to induce skeletal muscle hypertrophy and significant metabolic changes. In the context of energy homeostasis, the importance of beta-AR signaling has been highlighted by the inability of beta(1-3)-AR-deficient mice to regulate energy expenditure and susceptibility to diet induced obesity. However, the molecular pathways and gene expression changes that initiate and maintain these phenotypic modulations are poorly understood. Therefore, the aim of this study was to identify differential changes in gene expression in murine skeletal muscle associated with systemic (acute and chronic) administration of the beta(2)-AR agonist formoterol. RESULTS: Skeletal muscle gene expression (from murine tibialis anterior) was profiled at both 1 and 4 hours following systemic administration of the beta(2)-AR agonist formoterol, using Illumina 46K mouse BeadArrays. Illumina expression profiling revealed significant expression changes in genes associated with skeletal muscle hypertrophy, myoblast differentiation, metabolism, circadian rhythm, transcription, histones, and oxidative stress. Differentially expressed genes relevant to the regulation of muscle mass and metabolism (in the context of the hypertrophic phenotype) were further validated by quantitative RT-PCR to examine gene expression in response to both acute (1-24 h) and chronic administration (1-28 days) of formoterol at multiple timepoints. In terms of skeletal muscle hypertrophy, attenuation of myostatin signaling (including differential expression of myostatin, activin receptor IIB, phospho-Smad3 etc) was observed following acute and chronic administration of formoterol. Acute (but not chronic) administration of formoterol also significantly induced the expression of genes involved in oxidative metabolism, including hexokinase 2, sorbin and SH3 domain containing 1, and uncoupling protein 3. Interestingly, formoterol administration also appeared to influence some genes associated with the peripheral regulation of circadian rhythm (including nuclear factor interleukin 3 regulated, D site albumin promoter binding protein, and cryptochrome 2). CONCLUSION: This is the first study to utilize gene expression profiling to examine global gene expression in response to acute beta(2)-AR agonist treatment of skeletal muscle. In summary, systemic administration of a beta(2)-AR agonist had a profound effect on global gene expression in skeletal muscle. In terms of hypertrophy, beta(2)-AR agonist treatment altered the expression of several genes associated with myostatin signaling, a previously unreported effect of beta-AR signaling in skeletal muscle. This study also demonstrates a beta(2)-AR agonist regulation of circadian rhythm genes, indicating crosstalk between beta-AR signaling and circadian cycling in skeletal muscle. Gene expression alterations discovered in this study provides insight into many of the underlying changes in gene expression that mediate beta-AR induced skeletal muscle hypertrophy and altered metabolism.
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    Ageing prolongs inflammatory marker expression in regenerating rat skeletal muscles after injury
    van der Poel, C ; Gosselin, LE ; Schertzer, JD ; Ryall, JG ; Swiderski, K ; Wondemaghen, M ; Lynch, GS (BIOMED CENTRAL LTD, 2011-12-29)
    BACKGROUND: Some of the most serious consequences of normal ageing relate to its effects on skeletal muscle, particularly significant wasting and associated weakness, termed "sarcopenia". The underlying mechanisms of sarcopenia have yet to be elucidated completely but an altered muscle inflammatory response after injury is a likely contributing factor. In this study we investigated age-related changes in the expression of numerous inflammatory markers linked to successful muscle regeneration. METHODS: Right extensor digitorum longus (EDL) muscles from young (3 month), adult (12 month) and old (24 month) male F344 rats were injected with bupivacaine hydrochloride to cause complete muscle fibre degeneration, then excised 12, 24, 36, and 72 hours later (n = 5/age group/time point). We used qRT-PCR to quantify the mRNA expression levels of the inflammatory markers TNFα, IFNγ, IL1, IL18, IL6, and CD18 as well as regenerative markers MyoD and myogenin. RESULTS: Inflammatory markers were all increased significantly in all age groups after myotoxic injury. There was a trend for expression of inflammatory markers to be higher in uninjured muscles of old rats, especially at 72 hours post injury where the expression levels of several markers was significantly higher in old compared with young and adult rats. There was also a decrease in the expression of regenerative markers in old rats at 72 hours post injury. CONCLUSION: Our findings identify a prolonged inflammatory signature in injured muscles from old compared with young and adult rats together with a blunted expression of key markers of regeneration in muscles of old rats. Importantly, our findings identify potential targets for future therapeutic strategies for improving the regenerative capacity of skeletal muscle during ageing.
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    Functional beta-Adrenoceptors Are Important for Early Muscle Regeneration in Mice through Effects on Myoblast Proliferation and Differentiation
    Church, JE ; Trieu, J ; Sheorey, R ; Chee, AY-M ; Naim, T ; Baum, DM ; Ryall, JG ; Gregorevic, P ; Lynch, GS ; Alway, SE (PUBLIC LIBRARY SCIENCE, 2014-07-07)
    Muscles can be injured in different ways and the trauma and subsequent loss of function and physical capacity can impact significantly on the lives of patients through physical impairments and compromised quality of life. The relative success of muscle repair after injury will largely determine the extent of functional recovery. Unfortunately, regenerative processes are often slow and incomplete, and so developing novel strategies to enhance muscle regeneration is important. While the capacity to enhance muscle repair by stimulating β2-adrenoceptors (β-ARs) using β2-AR agonists (β2-agonists) has been demonstrated previously, the exact role β-ARs play in regulating the regenerative process remains unclear. To investigate β-AR-mediated signaling in muscle regeneration after myotoxic damage, we examined the regenerative capacity of tibialis anterior and extensor digitorum longus muscles from mice lacking either β1-AR (β1-KO) and/or β2-ARs (β2-KO), testing the hypothesis that muscles from mice lacking the β2-AR would exhibit impaired functional regeneration after damage compared with muscles from β1-KO or β1/β2-AR null (β1/β2-KO) KO mice. At 7 days post-injury, regenerating muscles from β1/β2-KO mice produced less force than those of controls but muscles from β1-KO or β2-KO mice did not exhibit any delay in functional restoration. Compared with controls, β1/β2-KO mice exhibited an enhanced inflammatory response to injury, which delayed early muscle regeneration, but an enhanced myoblast proliferation later during regeneration ensured a similar functional recovery (to controls) by 14 days post-injury. This apparent redundancy in the β-AR signaling pathway was unexpected and may have important implications for manipulating β-AR signaling to improve the rate, extent and efficacy of muscle regeneration to enhance functional recovery after injury.