bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒12‒25
forty-one papers selected by
Anna Vainshtein
Craft Science Inc.
  1. A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.
  2. Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival.
  3. CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells.
  4. Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1-Arih2 axis.
  5. Ammonium chloride administration prevents training-induced improvements in mitochondrial respiratory function in the soleus muscle of male rats.
  6. The role of mTORC1 in the regulation of skeletal muscle mass.
  7. In Skeletal Muscle Fibers, Protein Kinase Subunit CSNK2A1/CK2α Is Required for Proper Muscle Homeostasis and Structure and Function of Neuromuscular Junctions.
  8. Intensive Care Unit Acquired Weakness Is Associated with Rapid Changes to Skeletal Muscle Proteostasis.
  9. Structural functionality of skeletal muscle mitochondria and its correlation with metabolic diseases.
  10. The mini-IDLE 3D biomimetic culture assay enables interrogation of mechanisms governing muscle stem cell quiescence and niche repopulation.
  11. In Adult Skeletal Muscles, the Co-Receptors of Canonical Wnt Signaling, Lrp5 and Lrp6, Determine the Distribution and Size of Fiber Types, and Structure and Function of Neuromuscular Junctions.
  12. Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies.
  13. Muscle-Specific Ablation of Glucose Transporter 1 (GLUT1) Does Not Impair Basal or Overload-Stimulated Skeletal Muscle Glucose Uptake.
  14. Acylated Ghrelin Receptor Agonist HM01 Decreases Lean Body and Muscle Mass, but Unacylated Ghrelin Protects against Redox-Dependent Sarcopenia.
  15. Sulforaphane attenuates cancer cell-induced atrophy of C2C12 myotubes.
  16. Transcriptomic Analysis of the Acute Skeletal Muscle Effects after Intramuscular DNA Electroporation Reveals Inflammatory Signaling.
  17. The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease.
  18. Reactive Oxygen and Nitrogen Species (RONS) and Cytokines-Myokines Involved in Glucose Uptake and Insulin Resistance in Skeletal Muscle.
  19. Effect of Mechanical Loading of Senescent Myoblasts on Their Myogenic Lineage Progression and Survival.
  20. Improved Macrophage Enrichment from Mouse Skeletal Muscle.
  21. Impact of 4 weeks of western diet and aerobic exercise training on whole-body phenotype and skeletal muscle mitochondrial respiration in male and female mice.
  22. Skeletal muscle morphology, satellite cells and oxidative profile in relation to physical function and lifelong endurance training in very old men.
  23. Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.
  24. Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism.
  25. Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway.
  26. DNA Methylation Analysis Reveals Distinct Patterns in Satellite Cell-Derived Myogenic Progenitor Cells of Subjects with Spastic Cerebral Palsy.
  27. Exercise and mitochondrial mechanisms in patients with sarcopenia.
  28. Enhanced myogenesis through lncFAM-mediated recruitment of HNRNPL to the MYBPC2 promoter.
  29. Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage.
  30. Branched-chain amino acids promotes the repair of exercise-induced muscle damage via enhancing macrophage polarization.
  31. Effects of growth hormone on muscle and bone in female mice: role of follistatin.
  32. Tamoxifen improves muscle structure and function of Bin1- and Dnm2-related centronuclear myopathies.
  33. Genetic Manipulation of CB1 Cannabinoid Receptors Reveals a Role in Maintaining Proper Skeletal Muscle Morphology and Function in Mice.
  34. Adipose-Muscle crosstalk in age-related metabolic disorders: the emerging roles of adipo-myokines.
  35. Transcriptome and Methylome Profiling in Rat Skeletal Muscle: Impact of Post-Weaning Protein Restriction.
  36. Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy.
  37. Sodium fluoride induces skeletal muscle atrophy via changes in mitochondrial and sarcomeric proteomes.
  38. Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.
  39. Time to run: Late rather than early exercise training in mice remodels the gut microbiome and reduces atherosclerosis development.
  40. Metabolic Myopathies.
  41. GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans.
  1. J Physiol. 2022 Dec 19.
    A molecular signature defining exercise adaptation with ageing and in vivo partial reprogramming in skeletal muscle.
    Ronald G Jones, Andrea Dimet-Wiley, Amin Haghani, Francielly Morena da Silva, Camille R Brightwell, Seongkyun Lim, Sabin Khadgi, Yuan Wen, Cory M Dungan, Robert T Brooke, Nicholas P Greene, Charlotte A Peterson, John J McCarthy, Steve Horvath, Stanley J Watowich, Christopher S Fry, Kevin A Murach.
      KEY POINTS: Advances in the last decade related to cellular epigenetic reprogramming (e.g. DNA methylome remodeling) toward a pluripotent state via the Yamanaka transcription factors Oct3/4, Klf4, Sox2, and Myc (OKSM) provide a window into potential mechanisms for combatting the deleterious effects of cellular ageing Using global gene expression analysis, we compared the effects of in vivo OKSM-mediated partial reprogramming in skeletal muscle fibres of mice to the effects of late-life murine exercise training in muscle Myc is the Yamanaka factor most induced by exercise in skeletal muscle, so we compared the MYC-controlled transcriptome in muscle to Yamanaka factor-mediated and exercise adaptation gene landscapes in mice and humans A single pulse of MYC is sufficient to remodel the muscle methylome We identify partial reprogramming-associated genes that are innately altered by exercise training and conserved in humans, and propose that MYC contributes to some of these responses ABSTRACT: Exercise promotes functional improvements in aged tissues, but the extent to which it simulates partial molecular reprogramming is unknown. Using transcriptome profiling from 1) a skeletal muscle-specific in vivo Oct3/4, Klf4, Sox2, and Myc (OKSM) reprogramming-factor expression murine model, 2) an in vivo inducible muscle-specific Myc induction murine model, 3) a translatable high-volume hypertrophic exercise training approach in aged mice, and 4) human exercise muscle biopsies, we collectively defined exercise-induced genes that are common to partial reprogramming. Late-life exercise training lowered murine DNA methylation age according to several contemporary muscle-specific clocks. A comparison of the murine soleus transcriptome after late-life exercise training to the soleus transcriptome after OKSM induction revealed an overlapping signature that included higher JunB and Sun1. Also, within this signature, downregulation of specific mitochondrial and muscle-enriched genes was conserved in skeletal muscle of long-term exercise-trained humans; among these was muscle-specific Abra/Stars. Myc is the OKSM factor most induced by exercise in muscle and was elevated following exercise training in aged mice. A pulse of MYC rewired the global soleus muscle methylome, and the transcriptome after a MYC pulse partially recapitulated OKSM induction. A common signature also emerged in the murine MYC-controlled and exercise adaptation transcriptomes, including lower muscle-specific Melusin and reactive oxygen species-associated Romo1. With Myc, OKSM, and exercise training in mice as well habitual exercise in humans, the complex I accessory subunit Ndufb11 was lower; low Ndufb11 is linked to longevity in rodents. Collectively, exercise shares similarities with genetic in vivo partial reprogramming. Abstract figure legend Diverse forms of exercise training improve muscle function and whole-body health, even if initiated late in life. Information on conserved exercise-controlled molecular cues that underpin a younger muscle phenotype in aged muscle has potential utility in the development of anti-ageing therapies. Induction of the Yamanaka factors Oct3/4, Klf4, Sox2, and Myc are known to ameliorate ageing hallmarks. Comparison of transcriptomic data from aged exercise-trained mice and humans to muscle fibre-specific genetically driven models of epigenetic reprogramming (e.g. Yamanaka factor or Myc expression) unearthed conserved biomarkers associated with molecular age mitigation. Considering reduced biological age according to DNA methylome analysis, high-volume exercise training can be classified as an epigenetic reprogramming stimulus. Chronic exercise should be considered alongside and/or as a method to inform healthspan-extending longevity approaches such as pharmacologic and dietary interventions. This article is protected by copyright. All rights reserved.
    Keywords:  DNA methylation; MYC; Yamanaka factors; ageing
    DOI:  https://doi.org/10.1113/JP283836
  2. FASEB J. 2023 Jan;37(1): e22720
    Aerobic exercise training resets the human skeletal muscle methylome 10 years after breast cancer treatment and survival.
    Piotr P Gorski, Truls Raastad, Max Ullrich, Daniel C Turner, Jostein Hallén, Sebastian Imre Savari, Tormod S Nilsen, Adam P Sharples.
      Cancer survivors suffer impairments in skeletal muscle in terms of reduced mass and function. Interestingly, human skeletal muscle possesses an epigenetic memory of earlier stimuli, such as exercise. Long-term retention of epigenetic changes in skeletal muscle following cancer survival and/or exercise training has not yet been studied. We, therefore, investigated genome-wide DNA methylation (methylome) in skeletal muscle following a 5-month, 3/week aerobic-training intervention in breast cancer survivors 10-14 years after diagnosis and treatment. These results were compared to breast cancer survivors who remained untrained and to age-matched controls with no history of cancer, who undertook the same training intervention. Skeletal muscle biopsies were obtained from 23 females before(pre) and after(post) the 5-month training period. InfiniumEPIC 850K DNA methylation arrays and RT-PCR for gene expression were performed. The breast cancer survivors displayed a significant retention of increased DNA methylation (i.e., hypermethylation) at a larger number of differentially methylated positions (DMPs) compared with healthy age-matched controls pre training. Training in cancer survivors led to an exaggerated number of DMPs with a hypermethylated signature occurring at non-regulatory regions compared with training in healthy age-matched controls. However, the opposite occurred in important gene regulatory regions, where training in cancer survivors elicited a considerable reduction in methylation (i.e., hypomethylation) in 99% of the DMPs located in CpG islands within promoter regions. Importantly, training was able to reverse the hypermethylation identified in cancer survivors back toward a hypomethylated signature that was observed pre training in healthy age-matched controls at 300 (out of 881) of these island/promoter-associated CpGs. Pathway enrichment analysis identified training in cancer survivors evoked a predominantly hypomethylated signature in pathways associated with cell cycle, DNA replication/repair, transcription, translation, mTOR signaling, and the proteosome. Differentially methylated region (DMR) analysis also identified genes: BAG1, BTG2, CHP1, KIFC1, MKL2, MTR, PEX11B, POLD2, S100A6, SNORD104, and SPG7 as hypermethylated in breast cancer survivors, with training reversing these CpG island/promoter-associated DMRs toward a hypomethylated signature. Training also elicited a largely different epigenetic response in healthy individuals than that observed in cancer survivors, with very few overlapping changes. Only one gene, SIRT2, was identified as having altered methylation in cancer survivors at baseline and after training in both the cancer survivors and healthy controls. Overall, human skeletal muscle may retain a hypermethylated signature as long as 10-14 years after breast cancer treatment/survival. Five months of aerobic training reset the skeletal muscle methylome toward signatures identified in healthy age-matched individuals in gene regulatory regions.
    DOI:  https://doi.org/10.1096/fj.202201510RR
  3. Biochem Biophys Res Commun. 2022 Dec 10. pii: S0006-291X(22)01693-X. [Epub ahead of print]641 162-167
    CREG1 stimulates AMPK phosphorylation and glucose uptake in skeletal muscle cells.
    Ayumi Goto, Yuki Endo, Hitoshi Yamashita.
      The cellular repressor of adenovirus early region 1A-stimulated gene 1 (CREG1) is a secreted glycoprotein involved in cell differentiation and energy metabolism. It also binds to insulin-like growth factor 2 receptor (IGF2R), a protein implicated in muscle regeneration. However, whether CREG1 regulates the regeneration and metabolism of skeletal muscles via IGF2R remains unclear. This study investigates the role of CREG1 in skeletal muscle regeneration and glucose uptake in C2C12 myotubes and a cardiotoxin (CTX)-induced mouse skeletal muscle regeneration model. CTX-treated skeletal muscle showed significantly higher levels of IGF2R, CREG1, phospho-AMPKα Thr172, and GLUT4 proteins. Similarly, treatment of myotubes with CREG1 also stimulated AMPKα phosphorylation and GLUT4 expression. CREG1-induced AMPKα phosphorylation and 2DG uptake in myotubes were suppressed by IGF2R knockdown and Compound C, an AMPK inhibitor. These results suggest that CREG1 stimulates glucose uptake in skeletal muscles partially through AMPK activation. Hence, CREG1 plays an essential role in muscle regeneration by affecting glucose metabolism in skeletal muscles.
    Keywords:  AMPK; CREG1; Glucose uptake; IGF2R; Muscle regeneration; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbrc.2022.12.028
  4. J Cachexia Sarcopenia Muscle. 2022 Dec 23.
    Pyruvate dehydrogenase B regulates myogenic differentiation via the FoxP1-Arih2 axis.
    Xuan Jiang, Siyu Ji, Fenglai Yuan, Tushuai Li, Siyuan Cui, Wei Wang, Xianlong Ye, Rong Wang, Yongquan Chen, Shenglong Zhu.
      BACKGROUND: Sarcopenia, the age-related decline in skeletal muscle mass and function, diminishes life quality in elderly people. Improving the capacity of skeletal muscle differentiation is expected to counteract sarcopenia. However, the mechanisms underlying skeletal muscle differentiation are complex, and effective therapeutic targets are largely unknown.METHODS: The human Gene Expression Omnibus database, aged mice and primary skeletal muscle cells were used to assess the expression level of pyruvate dehydrogenase B (PDHB) in human and mouse aged state. d-Galactose ( d-gal)-induced sarcopenia mouse model and two classic cell models (C2C12 and HSkMC) were used to assess the myogenic effect of PDHB and the underlying mechanisms via immunocytochemistry, western blotting, quantitative real-time polymerase chain reaction, RNA interference or overexpression, dual-luciferase reporter assay, RNA sequencing and untargeted metabolomics.
    RESULTS: We identified that a novel target PDHB promoted myogenic differentiation. PDHB expression decreased in aged mouse muscle relative to the young state (-50% of mRNA level, P < 0.01) and increased during mouse and primary human muscle cell differentiation (+3.97-fold, P < 0.001 and +3.79-fold, P < 0.001). Knockdown or overexpression of PDHB modulated the expression of genes related to muscle differentiation, namely, myogenic factor 5 (Myf5) (-46%, P < 0.01 and -27%, P < 0.05; +1.8-fold, P < 0.01), myogenic differentiation (MyoD) (-55%, P < 0.001 and -34%, P < 0.01; +2.27-fold, P < 0.001), myogenin (MyoG) (-60%, P < 0.001 and -70%, P < 0.001; +5.46-fold, P < 0.001) and myosin heavy chain (MyHC) (-70%, P < 0.001 and -69%, P < 0.001; +3.44-fold, P < 0.001) in both C2C12 cells and HSkMC. Metabolomic and transcriptomic analyses revealed that PDHB knockdown suppressed pyruvate metabolism (P < 0.001) and up-regulated ariadne RBR E3 ubiquitin protein ligase 2 (Arih2) (+7.23-fold, P < 0.001) in cellular catabolic pathways. The role of forkhead box P1 (FoxP1) (+4.18-fold, P < 0.001)-mediated Arih2 transcription was the key downstream regulator of PDHB in muscle differentiation. PDHB overexpression improved d-gal-induced muscle atrophy in mice, which was characterized by significant increases in grip strength, muscle mass and mean muscle cross-sectional area (1.19-fold to 1.5-fold, P < 0.01, P < 0.05 and P < 0.001).
    CONCLUSIONS: The comprehensive results show that PDHB plays a sarcoprotective role by suppressing the FoxP1-Arih2 axis and may serve as a therapeutic target in sarcopenia.
    Keywords:  PDHB; ageing; myogenesis; sarcopenia
    DOI:  https://doi.org/10.1002/jcsm.13166
  5. Am J Physiol Cell Physiol. 2022 Nov 28.
    Ammonium chloride administration prevents training-induced improvements in mitochondrial respiratory function in the soleus muscle of male rats.
    Amanda J Genders, Jujiao Kuang, Nicholas J Saner, Javier Botella, David J Bishop.
      Exercise training can increase both mitochondrial content and mitochondrial respiration. Despite its popularity, high-intensity exercise can be accompanied by mild acidosis (also present in certain pathological states), which may limit exercise-induced adaptations to skeletal muscle mitochondria. The aim of this study was to determine if administration of ammonium chloride (0.05 g/kg) to Wistar rats before each individual exercise session (5 high-intensity exercise sessions per week for eight weeks) reduced training-induced increases in mitochondrial content (measured by citrate synthase activity and protein content of electron transport system complexes) and respiration (measured in permeabilised muscle fibres). In the soleus muscle, the exercise-training-induced increase in mitochondrial respiration was reduced in rats administered ammonium chloride compared to control animals, but mitochondrial content was not altered. These effects were not present in the white gastrocnemius muscle. In conclusion, ammonium chloride administration before each exercise session over eight weeks reduced improvements in mitochondrial respiration in the soleus muscle but did not alter mitochondrial content. This suggests that mild acidosis may impact training-induced improvements in the respiration of mitochondria in some muscles.
    Keywords:  Exercise training; Mitochondria; Skeletal muscle; acidosis
    DOI:  https://doi.org/10.1152/ajpcell.00165.2022
  6. Fac Rev. 2022 ;11 32
    The role of mTORC1 in the regulation of skeletal muscle mass.
    Sue C Bodine.
      Skeletal muscle mass is a very plastic characteristic of skeletal muscle and is regulated by signaling pathways that control the balance between anabolic and catabolic processes. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR) has been shown to be critically important in the regulation of skeletal muscle mass through its regulation of protein synthesis and degradation pathways. In this commentary, recent advances in the understanding of the role of mTORC1 in the regulation of muscle mass under conditions that induce hypertrophy and atrophy will be highlighted.
    Keywords:  aging; atrophy; hypertrophy; protein synthesis
    DOI:  https://doi.org/10.12703/r/11-32
  7. Cells. 2022 Dec 07. pii: 3962. [Epub ahead of print]11(24):
    In Skeletal Muscle Fibers, Protein Kinase Subunit CSNK2A1/CK2α Is Required for Proper Muscle Homeostasis and Structure and Function of Neuromuscular Junctions.
    Mira Merholz, Yongzhi Jian, Johannes Wimberg, Lea Gessler, Said Hashemolhosseini.
      CSNK2 tetrameric holoenzyme is composed of two subunits with catalytic activity (CSNK2A1 and/or CSNK2A2) and two regulatory subunits (CSNK2B) and is involved in skeletal muscle homeostasis. Up-to-date, constitutive Csnk2a2 knockout mice demonstrated mild regenerative impairments in skeletal muscles, while conditional Csnk2b mice were linked to muscle weakness, impaired neuromuscular transmission, and metabolic and autophagic compromises. Here, for the first time, skeletal muscle-specific conditional Csnk2a1 mice were generated and characterized. The ablation of Csnk2a1 expression was ensured using a human skeletal actin-driven Cre reporter. In comparison with control mice, first, conditional knockout of CSNK2A1 resulted in age-dependent reduced grip strength. Muscle weakness was accompanied by impaired neuromuscular transmission. Second, the protein amount of other CSNK2 subunits was aberrantly changed. Third, the number of central nuclei in muscle fibers indicative of regeneration increased. Fourth, oxidative metabolism was impaired, reflected by an increase in cytochrome oxidase and accumulation of mitochondrial enzyme activity underneath the sarcolemma. Fifth, autophagic processes were stimulated. Sixth, NMJs were fragmented and accompanied by increased synaptic gene expression levels. Altogether, knockout of Csnk2a1 or Csnk2b results in diverse impairments of skeletal muscle biology.
    Keywords:  CSNK2A1; CSNK2A2; CSNK2B; myogenesis; neuromuscular junction; protein kinase CK2; skeletal muscle
    DOI:  https://doi.org/10.3390/cells11243962
  8. Cells. 2022 Dec 11. pii: 4005. [Epub ahead of print]11(24):
    Intensive Care Unit Acquired Weakness Is Associated with Rapid Changes to Skeletal Muscle Proteostasis.
    Mustafa Ozdemir, Matthew P Bomkamp, Hayden W Hyatt, Ashley J Smuder, Scott K Powers.
      Intensive care unit (ICU)-acquired weakness is a frequent consequence of critical illness that impacts both the limb and respiratory muscles. The cause of ICU-acquired weakness is multifactorial, but both prolonged limb muscle inactivity and mechanical ventilation are risk factors for muscle wasting, which predisposes ICU patients to both short-term complications and long-term disabilities resulting from muscle weakness. Unfortunately, the current research does not provide a detailed understanding of the cellular etiology of ICU-acquired weakness, and no standard treatment exists. Therefore, improving knowledge of the mechanisms promoting muscle atrophy in critically ill patients is essential to developing therapeutic strategies to protect against ICU-induced skeletal muscle wasting. To advance our understanding of the mechanism(s) responsible for ICU-acquired weakness, we tested the hypothesis that ICU-induced muscle inactivity promotes a rapid decrease in anabolic signaling/protein synthesis and accelerates proteolysis in both limb and respiratory muscles. To investigate ICU-induced changes in skeletal muscle proteostasis, adult Sprague Dawley rats were anesthetized and mechanically ventilated for 12 h to simulate ICU care. Measurements of anabolic signaling, protein synthesis, and proteolytic activity in the limb muscles (plantaris and soleus) and respiratory muscles (parasternal and intercostal) revealed ICU-induced reductions in both anabolic signaling (i.e., AKT/mTOR pathway) and muscle protein synthesis. Moreover, simulated ICU care resulted in increased biomarkers of accelerated proteolysis in both limb and respiratory muscles. These novel findings reveal that disturbances in limb and respiratory muscle proteostasis occur rapidly during ICU-induced muscle inactivity, irrespective of the muscle function or muscle fiber type.
    Keywords:  anabolic signaling; degradation; limb muscles; mechanical ventilation; protein synthesis; respiratory muscles
    DOI:  https://doi.org/10.3390/cells11244005
  9. Clin Sci (Lond). 2022 Dec 22. 136(24): 1851-1871
    Structural functionality of skeletal muscle mitochondria and its correlation with metabolic diseases.
    Gourabamani Swalsingh, Punyadhara Pani, Naresh C Bal.
      The skeletal muscle is one of the largest organs in the mammalian body. Its remarkable ability to swiftly shift its substrate selection allows other organs like the brain to choose their preferred substrate first. Healthy skeletal muscle has a high level of metabolic flexibility, which is reduced in several metabolic diseases, including obesity and Type 2 diabetes (T2D). Skeletal muscle health is highly dependent on optimally functioning mitochondria that exist in a highly integrated network with the sarcoplasmic reticulum and sarcolemma. The three major mitochondrial processes: biogenesis, dynamics, and mitophagy, taken together, determine the quality of the mitochondrial network in the muscle. Since muscle health is primarily dependent on mitochondrial status, the mitochondrial processes are very tightly regulated in the skeletal muscle via transcription factors like peroxisome proliferator-activated receptor-γ coactivator-1α, peroxisome proliferator-activated receptors, estrogen-related receptors, nuclear respiratory factor, and Transcription factor A, mitochondrial. Physiological stimuli that enhance muscle energy expenditure, like cold and exercise, also promote a healthy mitochondrial phenotype and muscle health. In contrast, conditions like metabolic disorders, muscle dystrophies, and aging impair the mitochondrial phenotype, which is associated with poor muscle health. Further, exercise training is known to improve muscle health in aged individuals or during the early stages of metabolic disorders. This might suggest that conditions enhancing mitochondrial health can promote muscle health. Therefore, in this review, we take a critical overview of current knowledge about skeletal muscle mitochondria and the regulation of their quality. Also, we have discussed the molecular derailments that happen during various pathophysiological conditions and whether it is an effect or a cause.
    Keywords:  Ca2+-cycling; Type2 Diabetes; exercise; metabolic disorders; mitochondria; skeletal muscle
    DOI:  https://doi.org/10.1042/CS20220636
  10. Elife. 2022 Dec 20. pii: e81738. [Epub ahead of print]11
    The mini-IDLE 3D biomimetic culture assay enables interrogation of mechanisms governing muscle stem cell quiescence and niche repopulation.
    Erik Jacques, Yinni Kuang, Allison P Kann, Fabien Le Grand, Robert S Krauss, Penney M Gilbert.
      Adult skeletal muscle harbors a population of muscle stem cells (MuSCs) that are required to repair or reform multinucleated myofibers after tissue injury. In youth, MuSCs return to a reversible state of cell cycle arrest termed 'quiescence' after injury resolution. By contrast, a proportion of MuSCs in aged muscle remain in a semi-activated state, causing a premature response to subsequent injury cues that results in incomplete tissue repair and eventual stem cell depletion. Regulation of the balance between MuSC quiescence and activation in youth and in age may hold the key to restoring tissue homeostasis with age, but is incompletely understood. To fill this gap, we developed a simple and tractable in vitro method, with a 96-well footprint, to rapidly inactivate MuSCs freshly isolated from young murine skeletal muscle tissue, and return them to a quiescent-like state for at least one-week, which we name mini-IDLE (Inactivation and Dormancy LEveraged in vitro). This was achieved by introducing MuSCs into a three-dimensional (3D) bioartificial niche comprised of a thin sheet of multinucleated mouse myotubes, which we iterate, and analyze temporally, to show that these in vivo niche features provide the minimal cues necessary to inactivate MuSCs and induce quiescence. By seeding the 3D myotube sheets with different starting numbers of MuSCs, the assay revealed cellular heterogeneity and population-level adaptation activities that converged on a common steady-state niche repopulation density; behaviors previously observed only in vivo. Quiescence-associated hallmarks included a Pax7+CalcR+DDX6+MyoD-c-FOS- molecular signature, in vivo quiescent-like morphologies including oval-shaped nuclei and long cytoplasmic projections with N-cadherin+ tips, as well as the acquisition of polarized niche markers. Leveraging high-content imaging and bespoke CellProfilerTM-based image analysis pipelines, we demonstrate a relationship between morphology and cell fate signatures opening up the possibility of real-time morphology-based screening. When MuSCs from aged muscle were introduced into the assay, they displayed aberrant proliferative activities, delayed inactivation kinetics, persistence of activation-associated morphologies, and population depletion; quiescence-associated defects that we show are rescued by wortmannin treatment. Thus, the miniaturized assay offers an unprecedented opportunity to systematically investigate long-standing queries in areas such as regulation of adult stem cell pool size and functional heterogeneity within the MuSC population, and to uncover regulators of quiescence in youth and in age.
    Keywords:  mouse; regenerative medicine; stem cells
    DOI:  https://doi.org/10.7554/eLife.81738
  11. Cells. 2022 Dec 08. pii: 3968. [Epub ahead of print]11(24):
    In Adult Skeletal Muscles, the Co-Receptors of Canonical Wnt Signaling, Lrp5 and Lrp6, Determine the Distribution and Size of Fiber Types, and Structure and Function of Neuromuscular Junctions.
    Lea Gessler, Christopher Kurtek, Mira Merholz, Yongzhi Jian, Said Hashemolhosseini.
      Canonical Wnt signaling is involved in skeletal muscle cell biology. The exact way in which this pathway exerts its contribution to myogenesis or neuromuscular junctions (NMJ) is a matter of debate. Next to the common co-receptors of canonical Wnt signaling, Lrp5 and Lrp6, the receptor tyrosine kinase MuSK was reported to bind at NMJs WNT glycoproteins by its extracellular cysteine-rich domain. Previously, we reported canonical Wnt signaling being active in fast muscle fiber types. Here, we used conditional Lrp5 or Lrp6 knockout mice to investigate the role of these receptors in muscle cells. Conditional double knockout mice died around E13 likely due to ectopic expression of the Cre recombinase. Phenotypes of single conditional knockout mice point to a very divergent role for the two receptors. First, muscle fiber type distribution and size were changed. Second, canonical Wnt signaling reporter mice suggested less signaling activity in the absence of Lrps. Third, expression of several myogenic marker genes was changed. Fourth, NMJs were of fragmented phenotype. Fifth, recordings revealed impaired neuromuscular transmission. In sum, our data show fundamental differences in absence of each of the Lrp co-receptors and suggest a differentiated view of canonical Wnt signaling pathway involvement in adult skeletal muscle cells.
    Keywords:  Lrp5; Lrp6; canonical Wnt signaling; neuromuscular junction; synaptic gene expression
    DOI:  https://doi.org/10.3390/cells11243968
  12. Biosci Rep. 2022 Dec 20. pii: BSR20220284. [Epub ahead of print]
    Impaired muscle stem cell function and abnormal myogenesis in acquired myopathies.
    Alyson Deprez, Zakaria Orfi, Lupann Rieger, Nicolas Alexandre Dumont.
      Skeletal muscle possesses a high plasticity and a remarkable regenerative capacity that relies mainly on muscle stem cells. Molecular and cellular components of the muscle stem cell niche, such as immune cells, play key roles to coordinate muscle stem cell function and to orchestrate muscle regeneration. An abnormal infiltration of immune cells and/or imbalance of pro- and anti-inflammatory cytokines could lead to muscle stem cell dysfunctions that could have long lasting effects on muscle function. Different genetic variants were shown to cause muscular dystrophies that intrinsically compromise muscle stem cell function and disturb their microenvironment leading to impaired muscle regeneration that contributes to disease progression. Alternatively, many acquired myopathies caused by comorbidities (e.g., cardiopulmonary or kidney diseases), chronic inflammation/infection, or side effects of different drugs can also perturb muscle stem cell function and their microenvironment. The goal of this review is to comprehensively summarize the current knowledge on acquired myopathies and their impact on MuSC function. We further describe potential therapeutic strategies to restore muscle stem cell regenerative capacity.
    Keywords:  inflammation; muscle stem cell; myogenesis; myopathies; regeneration; therapeutics
    DOI:  https://doi.org/10.1042/BSR20220284
  13. Biomolecules. 2022 Nov 23. pii: 1734. [Epub ahead of print]12(12):
    Muscle-Specific Ablation of Glucose Transporter 1 (GLUT1) Does Not Impair Basal or Overload-Stimulated Skeletal Muscle Glucose Uptake.
    Shawna L McMillin, Parker L Evans, William M Taylor, Luke A Weyrauch, Tyler J Sermersheim, Steven S Welc, Monique R Heitmeier, Richard C Hresko, Paul W Hruz, Francoise Koumanov, Geoffrey D Holman, E Dale Abel, Carol A Witczak.
      Glucose transporter 1 (GLUT1) is believed to solely mediate basal (insulin-independent) glucose uptake in skeletal muscle; yet recent work has demonstrated that mechanical overload, a model of resistance exercise training, increases muscle GLUT1 levels. The primary objective of this study was to determine if GLUT1 is necessary for basal or overload-stimulated muscle glucose uptake. Muscle-specific GLUT1 knockout (mGLUT1KO) mice were generated and examined for changes in body weight, body composition, metabolism, systemic glucose regulation, muscle glucose transporters, and muscle [3H]-2-deoxyglucose uptake ± the GLUT1 inhibitor BAY-876. [3H]-hexose uptake ± BAY-876 was also examined in HEK293 cells-expressing GLUT1-6 or GLUT10. mGLUT1KO mice exhibited no impairments in body weight, lean mass, whole body metabolism, glucose tolerance, basal or overload-stimulated muscle glucose uptake. There was no compensation by the insulin-responsive GLUT4. In mGLUT1KO mouse muscles, overload stimulated higher expression of mechanosensitive GLUT6, but not GLUT3 or GLUT10. In control and mGLUT1KO mouse muscles, 0.05 µM BAY-876 impaired overload-stimulated, but not basal glucose uptake. In the GLUT-HEK293 cells, BAY-876 inhibited glucose uptake via GLUT1, GLUT3, GLUT4, GLUT6, and GLUT10. Collectively, these findings demonstrate that GLUT1 does not mediate basal muscle glucose uptake and suggest that a novel glucose transport mechanism mediates overload-stimulated glucose uptake.
    Keywords:  BAY-876; GLUT1; SLC2A1; bio-LC-ATB-BGPA; glucose transport; mechanical overload; skeletal muscle; synergist ablation
    DOI:  https://doi.org/10.3390/biom12121734
  14. Antioxidants (Basel). 2022 Nov 28. pii: 2358. [Epub ahead of print]11(12):
    Acylated Ghrelin Receptor Agonist HM01 Decreases Lean Body and Muscle Mass, but Unacylated Ghrelin Protects against Redox-Dependent Sarcopenia.
    Rojina Ranjit, Holly Van Remmen, Bumsoo Ahn.
      Sarcopenia, the progressive loss of muscle mass and dysfunction, universally affects the elderly and is closely associated with frailty and reduced quality of life. Despite the inevitable consequences of sarcopenia and its relevance to healthspan, no pharmacological therapies are currently available. Ghrelin is a gut-released hormone that increases appetite and body weight upon acylation, which activates its receptor GHSR1a. Recent studies have demonstrated that acyl and unacylated ghrelin are protective against acute pathological conditions of skeletal muscle. We hypothesized that both acyl ghrelin receptor agonist (HM01) and unacylated ghrelin ameliorate muscle atrophy and contractile dysfunction in oxidative stress-induced sarcopenia. HM01, unacylated ghrelin, or saline was delivered via osmotic pump. HM01 increased food consumption transiently, while the body weight remained elevated. It also decreased lean body mass and muscle mass of wildtype and Sod1KO. In contrast, unacylated ghrelin ameliorated loss of muscle mass by 15-30% in Sod1KO mice without changes in food consumption or body weights. Contractile force was decreased by ~30% in Sod1KO mice, but unacylated ghrelin prevented the force deficit by ~80%. We identified downregulation of transcription factor FoxO3a and its downstream E3 ligase MuRF1 by unacylated ghrelin. Our data show a direct role of unacylated ghrelin in redox-dependent sarcopenia independent of changes of food consumption or body weight.
    Keywords:  HM01; muscle weakness; oxidative stress; sarcopenia; skeletal muscle; unacylated ghrelin
    DOI:  https://doi.org/10.3390/antiox11122358
  15. Am J Physiol Cell Physiol. 2022 Dec 19.
    Sulforaphane attenuates cancer cell-induced atrophy of C2C12 myotubes.
    Wenlan Li, Jennifer Trieu, Ronnie Blazev, Benjamin L Parker, Kate T Murphy, Kristy Swiderski, Gordon S Lynch.
      Cancer cachexia is common in many cancers and the loss of skeletal muscle mass compromises the response to therapies and quality of life. A contributing mechanism is oxidative stress and compounds able to attenuate it may be protective. Sulforaphane (SFN), a natural antioxidant in cruciferous vegetables, activates nuclear factor erythroid 2-related factor 2 (Nrf2) signaling to decrease oxidative stress. Although SFN has potential as a cancer therapeutic, whether it can attenuate muscle wasting in the absence or presence of chemotherapy is unknown. In healthy C2C12 myotubes, SFN administration for 48 h induced hypertrophy through increased myoblast fusion via Nrf2 and ERK signaling. To determine whether SFN could attenuate wasting induced by cancer cells, myotubes were co-cultured with or without Colon-26 (C-26) cancer cells for 48 h and treated with 5-fluorouracil (5-FU, 5 µM) or vehicle (DMSO). SFN (10 µM) or DMSO was added for the final 24 h. Co-culture with cancer cells in the absence and presence of 5-FU, reduced myotube width by ~30% (P < 0.001) and ~20% (P < 0.01), respectively, which was attenuated by SFN (P < 0.05). Exposure to C-26 conditioned media reduced myotube width by 15% (P < 0.001), which was attenuated by SFN. Western immunoblotting and qRT-PCR confirmed activation of Nrf2 signaling and antioxidant genes. Co-administration of Nrf2 inhibitors (ML-385) or MEK inhibitors (PD184352) revealed SFN's attenuation of atrophy was blocked by ERK inhibition. These data support the chemoprotective and antioxidative function of SFN in myotubes, highlighting its therapeutic potential for cancer-related muscle wasting.
    Keywords:  antioxidant; cancer cachexia; muscle wasting; skeletal muscle; sulforaphane
    DOI:  https://doi.org/10.1152/ajpcell.00025.2022
  16. Vaccines (Basel). 2022 Nov 29. pii: 2037. [Epub ahead of print]10(12):
    Transcriptomic Analysis of the Acute Skeletal Muscle Effects after Intramuscular DNA Electroporation Reveals Inflammatory Signaling.
    Amanda Sales Conniff, Jared Tur, Kristopher Kohena, Min Zhang, Justin Gibbons, Loree C Heller.
      Skeletal muscle is a promising tissue for therapeutic gene delivery because it is highly vascularized, accessible, and capable of synthesizing protein for therapies or vaccines. The application of electric pulses (electroporation) enhances plasmid DNA delivery and expression by increasing membrane permeability. Four hours after plasmid electroporation, we evaluated acute gene and protein expression changes in mouse skeletal muscle to identify regulated genes and genetic pathways. RNA sequencing followed by functional annotation was used to evaluate differentially expressed mRNAs. Our data highlighted immune signaling pathways that may influence the effectiveness of DNA electroporation. Cytokine and chemokine protein levels in muscle lysates revealed the upregulation of a subset of inflammatory proteins and confirmed the RNA sequencing analysis. Several regulated DNA-specific pattern recognition receptor mRNAs were also detected. Identifying unique molecular changes in the muscle will facilitate a better understanding of the underlying molecular mechanisms and the development of safety biomarkers and novel strategies to improve skeletal muscle targeted gene therapy.
    Keywords:  RNA sequencing; plasmid electroporation; signaling pathways; skeletal muscle
    DOI:  https://doi.org/10.3390/vaccines10122037
  17. J Cachexia Sarcopenia Muscle. 2022 Dec 23.
    The G protein-coupled receptor ligand apelin-13 ameliorates skeletal muscle atrophy induced by chronic kidney disease.
    Yuki Enoki, Tomoya Nagai, Yuna Hamamura, Sumika Osa, Hideaki Nakamura, Kazuaki Taguchi, Hiroshi Watanabe, Toru Maruyama, Kazuaki Matsumoto.
      BACKGROUND: Targeting of the apelin-apelin receptor (Apj) system may serve as a useful therapeutic intervention for the management of chronic kidney disease (CKD)-induced skeletal muscle atrophy. We investigated the roles and efficacy of the apelin-Apj system in CKD-induced skeletal muscle atrophy.METHODS: The 5/6-nephrectomized mice were used as CKD models. AST-120, a charcoal adsorbent of uraemic toxins (8 w/w% in diet), or apelin (1 μmol/kg) was administered to CKD mice to investigate the mechanism and therapeutic potential of apelin on CKD-induced skeletal muscle atrophy. The effect of indoxyl sulfate, a uraemic toxin, or apelin on skeletal muscle atrophy was evaluated using mouse myoblast cells (C2C12 cells) in vitro.
    RESULTS: Skeletal muscle atrophy developed over time following nephrectomy at 12 weeks, as confirmed by a significant increase of atrogin-1 and myostatin mRNA expression in the gastrocnemius (GA) muscle and a decrease of lower limb skeletal muscle weight (P < 0.05, 0.01 and 0.05, respectively). Apelin expression in GA muscle was significantly decreased (P < 0.05) and elabela, another Apj endogenous ligand, tended to show a non-significant decrease at 12 weeks after nephrectomy. Administration of AST-120 inhibited the decline of muscle weight and increase of atrogin-1 and myostatin expression. Apelin and elabela expression was slightly improved by AST-120 administration but Apj expression was not, suggesting the involvement of uraemic toxins in endogenous Apj ligand expression. The administration of apelin at 1.0 μmol/kg for 4 weeks to CKD mice suppressed the increase of atrogin-1 and myostatin, increased apelin and Apj mRNA expression at 30 min after apelin administration and significantly ameliorated weight loss and a decrease of the cross-sectional area of hindlimb skeletal muscle.
    CONCLUSIONS: This study demonstrated for the first time the association of the Apj endogenous ligand-uraemic toxin axis with skeletal muscle atrophy in CKD and the utility of therapeutic targeting of the apelin-Apj system.
    Keywords:  Apj; apelin; chronic kidney disease; elabela; skeletal muscle atrophy; uraemic toxin
    DOI:  https://doi.org/10.1002/jcsm.13159
  18. Cells. 2022 Dec 11. pii: 4008. [Epub ahead of print]11(24):
    Reactive Oxygen and Nitrogen Species (RONS) and Cytokines-Myokines Involved in Glucose Uptake and Insulin Resistance in Skeletal Muscle.
    Paola Llanos, Jesus Palomero.
      Insulin resistance onset in skeletal muscle is characterized by the impairment of insulin signaling, which reduces the internalization of glucose, known as glucose uptake, into the cell. Therefore, there is a deficit of intracellular glucose, which is the main source for energy production in the cell. This may compromise cellular viability and functions, leading to pathological dysfunction. Skeletal muscle fibers continuously generate reactive oxygen and nitrogen species (RONS). An excess of RONS produces oxidative distress, which may evoke cellular damage and dysfunction. However, a moderate level of RONS, which is called oxidative eustress, is critical to maintain, modulate and regulate cellular functions through reversible interactions between RONS and the components of cellular signaling pathways that control those functions, such as the facilitation of glucose uptake. The skeletal muscle releases peptides called myokines that may have endocrine and paracrine effects. Some myokines bind to specific receptors in skeletal muscle fibers and might interact with cellular signaling pathways, such as PI3K/Akt and AMPK, and facilitate glucose uptake. In addition, there are cytokines, which are peptides produced by non-skeletal muscle cells, that bind to receptors at the plasma membrane of skeletal muscle cells and interact with the cellular signaling pathways, facilitating glucose uptake. RONS, myokines and cytokines might be acting on the same signaling pathways that facilitate glucose uptake in skeletal muscle. However, the experimental studies are limited and scarce. The aim of this review is to highlight the current knowledge regarding the role of RONS, myokines and cytokines as potential signals that facilitate glucose uptake in skeletal muscle. In addition, we encourage researchers in the field to lead and undertake investigations to uncover the fundamentals of glucose uptake evoked by RONS, myokines, and cytokines.
    Keywords:  GLUT4; RNS; ROS; cytokines; glucose transport; hydrogen peroxide; insulin resistance; myokines; nitric oxide; skeletal muscle fibers
    DOI:  https://doi.org/10.3390/cells11244008
  19. Cells. 2022 Dec 09. pii: 3979. [Epub ahead of print]11(24):
    Effect of Mechanical Loading of Senescent Myoblasts on Their Myogenic Lineage Progression and Survival.
    Athanasios Moustogiannis, Anastassios Philippou, Evangelos Zevolis, Orjona S Taso, Antonios Giannopoulos, Antonios Chatzigeorgiou, Michael Koutsilieris.
      BACKGROUND: During aging, muscle cell apoptosis increases and myogenesis gradually declines. The impaired myogenic and survival potential of the aged skeletal muscle can be ameliorated by its mechanical loading. However, the molecular responses of aged muscle cells to mechanical loading remain unclear. This study examined the effect of mechanical loading of aged, proliferating, and differentiated myoblasts on the gene expression and signaling responses associated with their myogenic lineage progression and survival.METHODS: Control and aged C2C12 cells were cultured on elastic membranes and underwent passive stretching for 12 h at a low frequency (0.25 Hz) and different elongations, varying the strain on days 0 and 10 of myoblast differentiation. Activation of ERK1/2 and Akt, and the expression of focal adhesion kinase (FAK) and key myogenic regulatory factors (MRFs), MyoD and Myogenin, were determined by immunoblotting of the cell lysates derived from stretched and non-stretched myoblasts. Changes in the expression levels of the MRFs, muscle growth, atrophy, and pro-apoptotic factors in response to mechanical loading of the aged and control cells were quantified by real-time qRT-PCR.
    RESULTS: Mechanical stretching applied on myoblasts resulted in the upregulation of FAK both in proliferating (day 0) and differentiated (day 10) cells, as well as in increased phosphorylation of ERK1/2 in both control and aged cells. Moreover, Akt activation and the expression of early differentiation factor MyoD increased significantly after stretching only in the control myoblasts, while the late differentiation factor Myogenin was upregulated in both the control and aged myoblasts. At the transcriptional level, mechanical loading of the proliferating myoblasts led to an increased expression of IGF-1 isoforms and MRFs, and to downregulation of muscle atrophy factors mainly in control cells, as well as in the upregulation of pro-apoptotic factors both in control and aged cells. In differentiated cells, mechanical loading resulted in an increased expression of the IGF-1Ea isoform and Myogenin, and in the downregulation of atrophy and pro-apoptotic factors in both the control and aged cells.
    CONCLUSIONS: This study revealed a diminished beneficial effect of mechanical loading on the myogenic and survival ability of the senescent muscle cells compared with the controls, with a low strain (2%) loading being most effective in upregulating myogenic/anabolic factors and downregulating atrophy and pro-apoptotic genes mainly in the aged myotubes.
    Keywords:  aging; cellular senescence; mechanical loading; muscle cells
    DOI:  https://doi.org/10.3390/cells11243979
  20. Bio Protoc. 2022 Dec 05. pii: e4561. [Epub ahead of print]12(23):
    Improved Macrophage Enrichment from Mouse Skeletal Muscle.
    Linda K Krasniewski, Dimitrios Tsitsipatis, Elizabeth K Izydore, Changyou Shi, Yulan Piao, Marc Michel, Payel Sen, Myriam Gorospe, Chang-Yi Cui.
      Macrophages are a heterogeneous class of innate immune cells that offer a primary line of defense to the body by phagocytizing pathogens, digesting them, and presenting the antigens to T and B cells to initiate adaptive immunity. Through specialized pro-inflammatory or anti-inflammatory activities, macrophages also directly contribute to the clearance of infections and the repair of tissue injury. Macrophages are distributed throughout the body and largely carry out tissue-specific functions. In skeletal muscle, macrophages regulate tissue repair and regeneration; however, the characteristics of these macrophages are not yet fully understood, and their involvement in skeletal muscle aging remains to be elucidated. To investigate these functions, it is critical to efficiently isolate macrophages from skeletal muscle with sufficient purity and yield for various downstream analyses. However, methods to prepare enriched skeletal muscle macrophages are scarce. Here, we describe in detail an optimized method to isolate skeletal muscle macrophages from mice. This method has allowed the isolation of CD45 + /CD11b + macrophage-enriched cells from young and old mice, which can be further used for flow cytometric analysis, fluorescence-activated cell sorting (FACS), and single-cell RNA sequencing. This protocol was validated in: eLife (2022), DOI: 10.7554/eLife.77974.
    Keywords:   Aging ; CD11b ; Macrophage ; Senescence ; Skeletal muscle
    DOI:  https://doi.org/10.21769/BioProtoc.4561
  21. Physiol Rep. 2022 Dec;10(24): e15543
    Impact of 4 weeks of western diet and aerobic exercise training on whole-body phenotype and skeletal muscle mitochondrial respiration in male and female mice.
    Erin M McGowan, Sarah E Ehrlicher, Harrison D Stierwalt, Matthew M Robinson, Sean A Newsom.
      High dietary fat intake induces significant whole-body and skeletal muscle adaptations in mice, including increased capacity for fat oxidation and mitochondrial biogenesis. The impact of a diet that is high in fat and simple sugars (i.e., western diet [WD]), particularly on regulation of skeletal muscle mitochondrial function, is less understood. The purpose of the current study was to determine physiologic adaptations in mitochondrial respiratory capacity in skeletal muscle during short-term consumption of WD, including if adaptive responses to WD-feeding are modified by concurrent exercise training or may be sex-specific. Male and female C57BL/6J mice were randomized to consume low-fat diet (LFD) or WD for 4 weeks, with some WD-fed mice also performing concurrent treadmill training (WD + Ex). Group sizes were n = 4-7. Whole-body metabolism was measured using in-cage assessment of food intake and energy expenditure, DXA body composition analysis and insulin tolerance testing. High-resolution respirometry of mitochondria isolated from quadriceps muscle was used to determine skeletal muscle mitochondrial respiratory function. Male mice fed WD gained mass (p < 0.001), due to increased fat mass (p < 0.001), and displayed greater respiratory capacity for both lipid and non-lipid substrates compared with LFD mice (p < 0.05). There was no effect of concurrent treadmill training on maximal respiration (WD + Ex vs. WD). Female mice had non-significant changes in body mass and composition as a function of the interventions, and no differences in skeletal muscle mitochondrial oxidative capacity. These findings indicate 4 weeks of WD feeding can increase skeletal muscle mitochondrial oxidative capacity among male mice; whereas WD, with or without exercise, had minimal impact on mass gain and skeletal muscle respiratory capacity among female mice. The translational relevance is that mitochondrial adaptation to increases in dietary fat intake that model WD may be related to differences in weight gain among male and female mice.
    Keywords:  lipid metabolism; obesity; respirometry; substrate oxidation
    DOI:  https://doi.org/10.14814/phy2.15543
  22. J Appl Physiol (1985). 2022 Dec 22.
    Skeletal muscle morphology, satellite cells and oxidative profile in relation to physical function and lifelong endurance training in very old men.
    Elisabeth Skoglund, Per Stål, Tommy R Lundberg, Thomas Gustafsson, Per A Tesch, Lars-Eric Thornell.
      In the current study, we compared muscle morphology in three advanced aging cohorts that differed in physical function, including a unique cohort of lifelong endurance athletes. Biopsies from the vastus lateralis muscle of seven lifelong endurance athletes (EA) aged 82-92 years, and nineteen subjects from the Uppsala Longitudinal Study of Adult Men (ULSAM) aged 87-91 years were analyzed. ULSAM subjects were divided into high (n=9, HF) and low (n=10, LF) function groups based on strength and physical function tests. The analysis included general morphology, fiber type and cross-sectional area, capillarization, deficient cytochrome C oxidase (COX) activity, number of myonuclei and satellite cells, and markers of regeneration and denervation. Fibers with central nuclei and/or nuclear clumps were observed in all groups. EA differed from LF and HF by having a higher proportion of type I fibers, 52% more capillaries in relation to fiber area, fewer COX-negative fibers, and less variation in fiber sizes (all P < 0.05). There were no differences between the groups in the number of myonuclei and satellite cells per fiber, and no significant differences between LF and HF (P > 0.05). In conclusion, signs of aging were evident in the muscle morphology of all groups, but neither endurance training status nor physical function influenced signs of regeneration and denervation processes. Lifelong endurance training, but not higher physical function, was associated with the preservation of muscle oxidative capacity, even beyond the age of 80.
    Keywords:  endurance exercise; healthy aging; skeletal muscle; skeletal muscle morphology
    DOI:  https://doi.org/10.1152/japplphysiol.00343.2022
  23. Cell Rep. 2022 Dec 20. pii: S2211-1247(22)01757-0. [Epub ahead of print]41(12): 111861
    Spatially resolved transcriptomics reveals innervation-responsive functional clusters in skeletal muscle.
    Chiara D'Ercole, Paolo D'Angelo, Veronica Ruggieri, Daisy Proietti, Laura Virtanen, Cristina Parisi, Carles Sanchez Riera, Alessandra Renzini, Alberto Macone, Marta Marzullo, Laura Ciapponi, Davide Bonvissuto, Claudio Sette, Lorenzo Giordani, Luca Madaro.
      Striated muscle is a highly organized structure composed of well-defined anatomical domains with integrated but distinct assignments. So far, the lack of a direct correlation between tissue architecture and gene expression has limited our understanding of how each unit responds to physio-pathologic contexts. Here, we show how the combined use of spatially resolved transcriptomics and immunofluorescence can bridge this gap by enabling the unbiased identification of such domains and the characterization of their response to external perturbations. Using a spatiotemporal analysis, we follow changes in the transcriptome of specific domains in muscle in a model of denervation. Furthermore, our approach enables us to identify the spatial distribution and nerve dependence of atrophic signaling pathway and polyamine metabolism to glycolytic fibers. Indeed, we demonstrate that perturbations of polyamine pathway can affect muscle function. Our dataset serves as a resource for future studies of the mechanisms underlying skeletal muscle homeostasis and innervation.
    Keywords:  Amd1; Amd2; CP: Molecular biology; Smox; denervation; muscular atrophy; polyamine; putrescin; skeletal muscle; spatial transcriptomics
    DOI:  https://doi.org/10.1016/j.celrep.2022.111861
  24. J Physiol. 2022 Dec 19.
    Restricted physical activity after volumetric muscle loss alters whole-body and local muscle metabolism.
    Christiana J Raymond-Pope, Alec M Basten, Angela S Bruzina, Jennifer McFaline-Figueroa, Thomas J Lillquist, Jarrod A Call, Sarah M Greising.
      Volumetric muscle loss (VML) is the traumatic loss of skeletal muscle, resulting in chronic functional deficits and pathologic comorbidities, including altered whole-body metabolic rate and respiratory exchange ratio (RER), despite no change in physical activity in animal models. In other injury models, treatment with β2 receptor agonists (e.g., formoterol) improves metabolic and skeletal muscle function. We first aimed to examine if restricting physical activity following injury affects metabolic and skeletal muscle function. Second, to enhance the metabolic and contractile function of the muscle remaining following VML injury through treatment with formoterol. Adult male C57Bl/6J mice (n = 32) underwent VML injury to the posterior hindlimb compartment and were randomly assigned to unrestricted or restricted activity and formoterol treatment or no treatment; age-matched injury naïve mice (n = 4) were controls for biochemical analyses. Longitudinal 24-hr physical activity and whole-body metabolism evaluations were conducted post-VML. In vivo muscle function was assessed terminally, and muscles were biochemically evaluated for protein expression, mitochondrial enzyme activity, and untargeted metabolomics. Restricting activity chronically post-VML had the greatest effect on physical activity and RER, reflected in reduced lipid oxidation, although changes were attenuated by formoterol treatment. Formoterol enhanced injured muscle mass, while mitigating functional deficits. These novel findings indicate physical activity restriction may recapitulate post-VML clinically, and adjunctive oxidative treatment may create a metabolically beneficial intramuscular environment while enhancing the injured muscle's mass and force producing capacity. Further investigation is needed to evaluate adjunctive oxidative treatment with rehabilitation, which may augment the muscle's regenerative and functional capacity following VML. KEY POINTS: The natural ability of skeletal muscle to regenerate and recover function is lost following complex traumatic musculoskeletal injury, such as volumetric muscle loss (VML), and physical inactivity following VML may incur additional deleterious consequences for muscle and metabolic health. Modeling VML injury-induced physical activity restriction altered whole-body metabolism, primarily by decreasing lipid oxidation, while preserving local skeletal muscle metabolic activity. The β2 adrenergic receptor agonist formoterol has shown promise in other severe injury models to improve regeneration, recover function and to enhance metabolism. Treatment with formoterol enhanced mass of the injured muscle and whole-body metabolism while mitigating functional deficits resulting from injury. Understanding of chronic effects of the clinically available and FDA-approved pharmaceutical formoterol could be a translational option to support muscle function after VML injury. Abstract Figure. This study evaluated the effects of physical activity restriction and treatment with a β2 adrenergic receptor agonist, formoterol, on whole-body and local muscle metabolism function 8 weeks following volumetric muscle loss (VML) injury. Physical activity restriction decreased ambulation and metabolic rate while increasing the respiratory exchange ratio (RER), an indication of the diurnal use of substrates used as fuel, due to decreased lipid oxidation. In contrast, formoterol treatment increased injured muscle mass and function while improving glucose uptake and metabolic flexibility, the ability to transition efficiently between fuels over the course of the day. Neither treatment or activity restriction affected markers related to atrophy (MuRF1, Atrogin-1), hypertrophy (Akt), or regulators of mitochondrial biogenesis (PGC-1α). This article is protected by copyright. All rights reserved.
    Keywords:  formoterol; metabolic flexibility; orthopaedic trauma; physical inactivity; skeletal muscle injury; β2 adrenergic receptor agonist
    DOI:  https://doi.org/10.1113/JP283959
  25. Eur J Pharmacol. 2022 Dec 17. pii: S0014-2999(22)00737-3. [Epub ahead of print]939 175476
    Irisin ameliorates D-galactose-induced skeletal muscle fibrosis via the PI3K/Akt pathway.
    Yaoxuan Wu, Yongxin Wu, Jing Yu, Yingxiao Zhang, Yuanfen Li, Rao Fu, Yue Sun, Kexiang Zhao, Qian Xiao.
      Primary sarcopenia is a multicausal skeletal muscle disease associated with muscle strength and mass loss. Skeletal muscle fibrosis is one of the significant pathological manifestations associated with the development of age-related sarcopenia. Irisin, which is cleaved by the extracellular domain of fibronectin type Ⅲ domain-containing protein 5 (FNDC5), has previously been reported to exert antifibrotic effects on the heart, liver, and pancreas, but whether it can rescue skeletal muscle fibrosis remains unknown. In this study, we examined the effects of irisin on D-galactose (D-gal)-induced skeletal muscle fibroblasts. We found that D-gal-induced senescence, fibrosis, and redox imbalance were inhibited by irisin treatment. Mechanistically, irisin or FNDC5 overexpression attenuated D-gal-induced senescence, redox imbalance, and fibrosis by regulating the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway. Overall, irisin might be a promising therapeutic candidate for age-related skeletal muscle fibrosis.
    Keywords:  Aging; Fibrosis; Irisin; Redox imbalance; Sarcopenia
    DOI:  https://doi.org/10.1016/j.ejphar.2022.175476
  26. J Pers Med. 2022 Nov 30. pii: 1978. [Epub ahead of print]12(12):
    DNA Methylation Analysis Reveals Distinct Patterns in Satellite Cell-Derived Myogenic Progenitor Cells of Subjects with Spastic Cerebral Palsy.
    Karyn G Robinson, Adam G Marsh, Stephanie K Lee, Jonathan Hicks, Brigette Romero, Mona Batish, Erin L Crowgey, M Wade Shrader, Robert E Akins.
      Spastic type cerebral palsy (CP) is a complex neuromuscular disorder that involves altered skeletal muscle microanatomy and growth, but little is known about the mechanisms contributing to muscle pathophysiology and dysfunction. Traditional genomic approaches have provided limited insight regarding disease onset and severity, but recent epigenomic studies indicate that DNA methylation patterns can be altered in CP. Here, we examined whether a diagnosis of spastic CP is associated with intrinsic DNA methylation differences in myoblasts and myotubes derived from muscle resident stem cell populations (satellite cells; SCs). Twelve subjects were enrolled (6 CP; 6 control) with informed consent/assent. Skeletal muscle biopsies were obtained during orthopedic surgeries, and SCs were isolated and cultured to establish patient-specific myoblast cell lines capable of proliferation and differentiation in culture. DNA methylation analyses indicated significant differences at 525 individual CpG sites in proliferating SC-derived myoblasts (MB) and 1774 CpG sites in differentiating SC-derived myotubes (MT). Of these, 79 CpG sites were common in both culture types. The distribution of differentially methylated 1 Mbp chromosomal segments indicated distinct regional hypo- and hyper-methylation patterns, and significant enrichment of differentially methylated sites on chromosomes 12, 13, 14, 15, 18, and 20. Average methylation load across 2000 bp regions flanking transcriptional start sites was significantly different in 3 genes in MBs, and 10 genes in MTs. SC derived MBs isolated from study participants with spastic CP exhibited fundamental differences in DNA methylation compared to controls at multiple levels of organization that may reveal new targets for studies of mechanisms contributing to muscle dysregulation in spastic CP.
    Keywords:  DNA methylation; cerebral palsy; epigenomics; humans; muscle; muscle spasticity; primary cell culture; regulatory non-coding RNAs; satellite cells; skeletal; skeletal muscle
    DOI:  https://doi.org/10.3390/jpm12121978
  27. Front Physiol. 2022 ;13 1040381
    Exercise and mitochondrial mechanisms in patients with sarcopenia.
    Hamed Alizadeh Pahlavani, Ismail Laher, Beat Knechtle, Hassane Zouhal.
      Sarcopenia is a severe loss of muscle mass and functional decline during aging that can lead to reduced quality of life, limited patient independence, and increased risk of falls. The causes of sarcopenia include inactivity, oxidant production, reduction of antioxidant defense, disruption of mitochondrial activity, disruption of mitophagy, and change in mitochondrial biogenesis. There is evidence that mitochondrial dysfunction is an important cause of sarcopenia. Oxidative stress and reduction of antioxidant defenses in mitochondria form a vicious cycle that leads to the intensification of mitochondrial separation, suppression of mitochondrial fusion/fission, inhibition of electron transport chain, reduction of ATP production, an increase of mitochondrial DNA damage, and mitochondrial biogenesis disorder. On the other hand, exercise adds to the healthy mitochondrial network by increasing markers of mitochondrial fusion and fission, and transforms defective mitochondria into efficient mitochondria. Sarcopenia also leads to a decrease in mitochondrial dynamics, mitophagy markers, and mitochondrial network efficiency by increasing the level of ROS and apoptosis. In contrast, exercise increases mitochondrial biogenesis by activating genes affected by PGC1-ɑ (such as CaMK, AMPK, MAPKs) and altering cellular calcium, ATP-AMP ratio, and cellular stress. Activation of PGC1-ɑ also regulates transcription factors (such as TFAM, MEFs, and NRFs) and leads to the formation of new mitochondrial networks. Hence, moderate-intensity exercise can be used as a non-invasive treatment for sarcopenia by activating pathways that regulate the mitochondrial network in skeletal muscle.
    Keywords:  aging; exercise; mechanism; mitochondria; sarcopenia
    DOI:  https://doi.org/10.3389/fphys.2022.1040381
  28. Nucleic Acids Res. 2022 Dec 19. pii: gkac1174. [Epub ahead of print]
    Enhanced myogenesis through lncFAM-mediated recruitment of HNRNPL to the MYBPC2 promoter.
    Ming-Wen Chang, Jen-Hao Yang, Dimitrios Tsitsipatis, Xiaoling Yang, Jennifer L Martindale, Rachel Munk, Poonam R Pandey, Nirad Banskota, Brigette Romero, Mona Batish, Yulan Piao, Krystyna Mazan-Mamczarz, Supriyo De, Kotb Abdelmohsen, Gerald M Wilson, Myriam Gorospe.
      The mammalian transcriptome comprises a vast family of long noncoding (lnc)RNAs implicated in physiologic processes such as myogenesis, through which muscle forms during embryonic development and regenerates in the adult. However, the specific molecular mechanisms by which lncRNAs regulate human myogenesis are poorly understood. Here, we identified a novel muscle-specific lncRNA, lncFAM71E1-2:2 (lncFAM), which increased robustly during early human myogenesis. Overexpression of lncFAM promoted differentiation of human myoblasts into myotubes, while silencing lncFAM suppressed this process. As lncFAM resides in the nucleus, chromatin isolation by RNA purification followed by mass spectrometry (ChIRP-MS) analysis was employed to identify the molecular mechanisms whereby it might promote myogenesis. Analysis of lncFAM-interacting proteins revealed that lncFAM recruited the RNA-binding protein HNRNPL to the promoter of MYBPC2, in turn increasing MYBPC2 mRNA transcription and enhancing production of the myogenic protein MYBPC2. These results highlight a mechanism whereby a novel ribonucleoprotein complex, lncFAM-HNRNPL, elevates MYBPC2 expression transcriptionally to promote myogenesis.
    DOI:  https://doi.org/10.1093/nar/gkac1174
  29. Epigenomes. 2022 Dec 09. pii: 43. [Epub ahead of print]6(4):
    Promoter-Adjacent DNA Hypermethylation Can Downmodulate Gene Expression: TBX15 in the Muscle Lineage.
    Kenneth C Ehrlich, Michelle Lacey, Carl Baribault, Sagnik Sen, Pierre Olivier Esteve, Sriharsa Pradhan, Melanie Ehrlich.
      TBX15, which encodes a differentiation-related transcription factor, displays promoter-adjacent DNA hypermethylation in myoblasts and skeletal muscle (psoas) that is absent from non-expressing cells in other lineages. By whole-genome bisulfite sequencing (WGBS) and enzymatic methyl-seq (EM-seq), these hypermethylated regions were found to border both sides of a constitutively unmethylated promoter. To understand the functionality of this DNA hypermethylation, we cloned the differentially methylated sequences (DMRs) in CpG-free reporter vectors and tested them for promoter or enhancer activity upon transient transfection. These cloned regions exhibited strong promoter activity and, when placed upstream of a weak promoter, strong enhancer activity specifically in myoblast host cells. In vitro CpG methylation targeted to the DMR sequences in the plasmids resulted in 86-100% loss of promoter or enhancer activity, depending on the insert sequence. These results as well as chromatin epigenetic and transcription profiles for this gene in various cell types support the hypothesis that DNA hypermethylation immediately upstream and downstream of the unmethylated promoter region suppresses enhancer/extended promoter activity, thereby downmodulating, but not silencing, expression in myoblasts and certain kinds of skeletal muscle. This promoter-border hypermethylation was not found in cell types with a silent TBX15 gene, and these cells, instead, exhibit repressive chromatin in and around the promoter. TBX18, TBX2,&amp;nbsp;TBX3 and TBX1 display TBX15-like hypermethylated DMRs at their promoter borders and preferential expression in myoblasts. Therefore, promoter-adjacent DNA hypermethylation for downmodulating transcription to prevent overexpression may be used more frequently for transcription regulation than currently appreciated.
    Keywords:  DMRs; DNA hypermethylation; EM-seq; T-box transcription factors; TBX15; enhancers; myoblasts; skeletal muscle; transfection; whole-genome bisulfite sequencing
    DOI:  https://doi.org/10.3390/epigenomes6040043
  30. Front Physiol. 2022 ;13 1037090
    Branched-chain amino acids promotes the repair of exercise-induced muscle damage via enhancing macrophage polarization.
    Yunfeng Dong, Xuejiao Zhang, Rui Miao, Wei Cao, Hao Wei, Wei Jiang, Ruirui Gao, Yanhui Yang, Haipeng Sun, Junqiang Qiu.
      The repair of exercise-induced muscle damage (EIMD) is closely related with inflammation. Branched-chain amino acids (BCAAs), as a nutritional supplement, promote EIMD repair; however, the underlying mechanism remains unclear. In vivo, Sprague-Dawley rats were subjected to Armstrong's eccentric exercise (a 120-min downhill run with a slope of -16° and a speed of 16 m min-1) to induce EIMD and BCAA supplement was administered by oral gavage. Protein expression of macrophages (CD68 and CD163) and myogenic regulatory factors (MYOD and MYOG) in gastrocnemius was analyzed. Inflammatory cytokines and creatine kinase (CK) levels in serum was also measured. In vitro, peritoneal macrophages from mice were incubated with lipopolysaccharide (LPS) or IL-4 with or without BCAAs in culture medium. For co-culture experiment, C2C12 cells were cultured with the conditioned medium from macrophages prestimulated with LPS or IL-4 in the presence or absence of BCAAs. The current study indicated BCAA supplementation enhanced the M1/M2 polarization of macrophages in skeletal muscle during EIMD repair, and BCAAs promoted M1 polarization through enhancing mTORC1-HIF1α-glycolysis pathway, and promoted M2 polarization independently of mTORC1. In addition, BCAA-promoted M1 macrophages further stimulated the proliferation of muscle satellite cells, whereas BCAA-promoted M2 macrophages stimulated their differentiation. Together, these results show macrophages mediate the BCAAs' beneficial impacts on EIMD repair via stimulating the proliferation and differentiation of muscle satellite cells, shedding light on the critical role of inflammation in EIMD repair and the potential nutritional strategies to ameliorate muscle damage.
    Keywords:  branched-chain amino acids; exercise-induced muscle damage; mTORC1; macrophage; muscle satellite cell
    DOI:  https://doi.org/10.3389/fphys.2022.1037090
  31. Exp Clin Endocrinol Diabetes. 2022 Dec 22.
    Effects of growth hormone on muscle and bone in female mice: role of follistatin.
    Takashi Ohira, Naoyuki Kawao, Yoshimasa Takafuji, Yuya Mizukami, Hiroshi Kaji.
      The interactions between muscle and bone are noted for the clinical relationships between sarcopenia and osteoporosis. Myokines secreted from the skeletal muscles play roles in the muscle-bone interactions related to various physiological and pathophysiological states. Although numerous evidence suggested that growth hormone (GH) influences both muscle and bone, the effects of GH on the muscle-bone interactions have remained unknown. We therefore investigated the influences of GH administration for 8 weeks on muscle and bone, including myokine expression, in mice with or without ovariectomy (OVX). GH administration significantly increased muscle mass in the whole body and lower limbs, as well as tissue weights of the extensor digitorum longus (EDL) and soleus muscles, in mice with or without OVX. Moreover, it markedly increased grip strength in both mice. As for femurs, GH administration significantly increased cortical thickness and area in mice with or without OVX. Moreover, GH significantly blunted the decrease in the ratio of bone volume to tissue volume at trabecular bone in mice with OVX. GH administration significantly decreased follistatin mRNA levels in the EDL, but not the soleus, muscles in mice with or without OVX, although it did not affect the other myokines examined. However, GH administration significantly elevated serum follistatin levels in mice. In conclusion, our study indicated that GH administration increases skeletal muscle mass and grip strength, as well as cortical and trabecular bone-related parameters obtained by µCT analyses, in mice. However, myokine regulation might not be critical for the effects of GH on muscle and bone.
    DOI:  https://doi.org/10.1055/a-2003-5704
  32. Brain. 2022 Dec 23. pii: awac489. [Epub ahead of print]
    Tamoxifen improves muscle structure and function of Bin1- and Dnm2-related centronuclear myopathies.
    Charlotte Gineste, Alix Simon, Marie Braun, David Reiss, Jocelyn Laporte.
      Congenital myopathies define a genetically heterogeneous group of disorders associated with severe muscle weakness, for which no therapies are currently available. Here we investigated repurposing of tamoxifen in mouse models of mild or severe forms of centronuclear myopathies (CNM) due to mutations in BIN1 (encoding amphiphysin 2) or DNM2 (encoding dynamin 2, DNM2), respectively. Exposure to tamoxifen-enriched diet from 3 weeks of age resulted in significant improvement in muscle contractility without increase in fiber size in both models, underlying an increase capacity of the muscle fiber to produce more force. In addition, the histological alterations were fully rescued in the BIN1-CNM mouse model. To assess the mechanism of the rescue, transcriptome analyses and targeted protein studies were performed. Albeit tamoxifen is known to modulate the transcriptional activity of the estrogen receptors, correction of the disease transcriptomic signature was marginal upon tamoxifen treatment. Conversely, tamoxifen lowered the abnormal increase in DNM2 protein level in both CNM models. Of note, it was previously reported that DNM2 increase is a main pathological cause of CNM. The Akt/mTOR muscle hypertrophic pathway and protein markers of the ubiquitin proteasome system, as the E3 ubiquitin ligase cullin 3, and the autophagy as p62 were all increased in both CNM models. Normalization of DNM2 level mainly correlated with normalization of cullin 3 protein level upon tamoxifen treatment, supporting the ubiquitin proteasome system is a main target for tamoxifen effect in the amelioration of these diseases. Overall, our data suggest that tamoxifen antagonizes disease development likely through DNM2 level regulation. In conclusion, the beneficial effect of tamoxifen on muscle function supports that tamoxifen may serve as a common therapy for several autosomal forms of centronuclear myopathies.
    Keywords:  Congenital myopathy; centronuclear myopathy; drug; force production; muscle structure; therapy
    DOI:  https://doi.org/10.1093/brain/awac489
  33. Int J Mol Sci. 2022 Dec 09. pii: 15653. [Epub ahead of print]23(24):
    Genetic Manipulation of CB1 Cannabinoid Receptors Reveals a Role in Maintaining Proper Skeletal Muscle Morphology and Function in Mice.
    Zoltán Singlár, Nyamkhuu Ganbat, Péter Szentesi, Nomin Osgonsandag, László Szabó, Andrea Telek, János Fodor, Beatrix Dienes, Mónika Gönczi, László Csernoch, Mónika Sztretye.
      The endocannabinoid system (ECS) refers to a widespread signaling system and its alteration is implicated in a growing number of human diseases. Cannabinoid receptors (CBRs) are highly expressed in the central nervous system and many peripheral tissues. Evidence suggests that CB1Rs are expressed in human and murine skeletal muscle mainly in the cell membrane, but a subpopulation is present also in the mitochondria. However, very little is known about the latter population. To date, the connection between the function of CB1Rs and the regulation of intracellular Ca2+ signaling has not been investigated yet. Tamoxifen-inducible skeletal muscle-specific conditional CB1 knock-down (skmCB1-KD, hereafter referred to as Cre+/-) mice were used in this study for functional and morphological analysis. After confirming CB1R down-regulation on the mRNA and protein level, we performed in vitro muscle force measurements and found that peak twitch, tetanus, and fatigue were decreased significantly in Cre+/- mice. Resting intracellular calcium concentration, voltage dependence of the calcium transients as well as the activity dependent mitochondrial calcium uptake were essentially unaltered by Cnr1 gene manipulation. Nevertheless, we found striking differences in the ultrastructural architecture of the mitochondrial network of muscle tissue from the Cre+/- mice. Our results suggest a role of CB1Rs in maintaining physiological muscle function and morphology. Targeting ECS could be a potential tool in certain diseases, including muscular dystrophies where increased endocannabinoid levels have already been described.
    Keywords:  cannabinoid receptor of type 1 (CBR1); contractility; endocannabinoid system (ECS); excitation-contraction coupling (ECC); intracellular calcium; mitochondria; skeletal muscle force
    DOI:  https://doi.org/10.3390/ijms232415653
  34. Ageing Res Rev. 2022 Dec 20. pii: S1568-1637(22)00271-9. [Epub ahead of print] 101829
    Adipose-Muscle crosstalk in age-related metabolic disorders: the emerging roles of adipo-myokines.
    Penghua Fang, Yuqing She, Mei Yu, Wen Min, Wenbin Shang, Zhenwen Zhang.
      Obesity and type 2 diabetes account for a considerable proportion of the global burden of age-related metabolic diseases. In age-related metabolic diseases, tissue crosstalk and metabolic regulation have been primarily linked to endocrine processes. Skeletal muscle and adipose tissue are endocrine organs that release myokines and adipokines into the bloodstream, respectively. These cytokines regulate metabolic responses in a variety of tissues, including skeletal muscle and adipose tissue. However, the intricate mechanisms underlying adipose-muscle crosstalk in age-related metabolic diseases are not fully understood. Recent exciting evidence suggests that myokines act to control adipose tissue functions, including lipolysis, browning, and inflammation, whereas adipokines mediate the beneficial actions of adipose tissue in the muscle, such as glucose uptake and metabolism. In this review, we assess the mechanisms of adipose-muscle crosstalk in age-related disorders and propose that the adipokines adiponectin and spexin, as well as the myokines irisin and interleukin-6 (IL-6), are crucial for maintaining the body's metabolic balance in age-related metabolic disorders. In addition, these changes of adipose-muscle crosstalk in response to exercise or dietary flavonoid consumption are part of the mechanisms of both functions in the remission of age-related metabolic disorders. A better understanding of the intricate relationships between adipose tissue and skeletal muscle could lead to more potent therapeutic approaches to prolong life and prevent age-related metabolic diseases.
    Keywords:  Adipo-myokines; Adipose tissue; Age-related diseases; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.arr.2022.101829
  35. Int J Mol Sci. 2022 Dec 12. pii: 15771. [Epub ahead of print]23(24):
    Transcriptome and Methylome Profiling in Rat Skeletal Muscle: Impact of Post-Weaning Protein Restriction.
    Sihui Ma, Emi Hasegawa, Yuji Nakai, Huijuan Jia, Hisanori Kato.
      Skeletal muscle is programmable, and early-life nutritional stimuli may form epigenetic memory in the skeletal muscle, thus impacting adult muscle function, aging, and longevity. In the present study, we designed a one-month protein restriction model using post-weaning rats, followed by a two-month rebound feeding, to investigate how early-life protein restriction affects overall body growth and muscle development and whether these influences could be corrected by rebound feeding. We observed comprehensive alterations immediately after protein restriction, including retarded growth, altered biochemical indices, and disturbed hormone secretion. Transcriptome profiling of the gastrocnemius muscle followed by gene ontology analyses revealed that "myogenic differentiation functions" were upregulated, while "protein catabolism" was downregulated as a compensatory mechanism, with enhanced endoplasmic reticulum stress and undesired apoptosis. Furthermore, methylome profiling of the gastrocnemius muscle showed that protein restriction altered the methylation of apoptotic and hormone secretion-related genes. Although most of the alterations were reversed after rebound feeding, 17 genes, most of which play roles during muscle development, remained altered at the transcriptional level. In summary, early-life protein restriction may undermine muscle function in the long term and affect skeletal muscle development at the both transcriptional and methylation levels, which may hazard future muscle health.
    Keywords:  methylome; post-weaning; protein restriction; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.3390/ijms232415771
  36. Int J Mol Sci. 2022 Dec 16. pii: 16080. [Epub ahead of print]23(24):
    Histological Methods to Assess Skeletal Muscle Degeneration and Regeneration in Duchenne Muscular Dystrophy.
    Nicolas Dubuisson, Romain Versele, Chloé Planchon, Camille M Selvais, Laurence Noel, Michel Abou-Samra, María A Davis-López de Carrizosa.
      Duchenne muscular dystrophy (DMD) is a progressive disease caused by the loss of function of the protein dystrophin. This protein contributes to the stabilisation of striated cells during contraction, as it anchors the cytoskeleton with components of the extracellular matrix through the dystrophin-associated protein complex (DAPC). Moreover, absence of the functional protein affects the expression and function of proteins within the DAPC, leading to molecular events responsible for myofibre damage, muscle weakening, disability and, eventually, premature death. Presently, there is no cure for DMD, but different treatments help manage some of the symptoms. Advances in genetic and exon-skipping therapies are the most promising intervention, the safety and efficiency of which are tested in animal models. In addition to in vivo functional tests, ex vivo molecular evaluation aids assess to what extent the therapy has contributed to the regenerative process. In this regard, the later advances in microscopy and image acquisition systems and the current expansion of antibodies for immunohistological evaluation together with the development of different spectrum fluorescent dyes have made histology a crucial tool. Nevertheless, the complexity of the molecular events that take place in dystrophic muscles, together with the rise of a multitude of markers for each of the phases of the process, makes the histological assessment a challenging task. Therefore, here, we summarise and explain the rationale behind different histological techniques used in the literature to assess degeneration and regeneration in the field of dystrophinopathies, focusing especially on those related to DMD.
    Keywords:  Duchenne muscular dystrophy; animal model; degeneration; dystrophin; histology; immunofluorescence; immunohistology; myofibre; regeneration; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms232416080
  37. PLoS One. 2022 ;17(12): e0279261
    Sodium fluoride induces skeletal muscle atrophy via changes in mitochondrial and sarcomeric proteomes.
    Apoorva H Nagendra, Animikh Ray, Debajit Chaudhury, Akash Mitra, Anu Vinod Ranade, Bipasha Bose, Sudheer Shenoy P.
      Sodium Fluoride (NaF) can change the expression of skeletal muscle proteins. Since skeletal muscle is rich in mitochondrial and contractile (sarcomeric) proteins, these proteins are sensitive to the effects of NaF, and the changes are dose-and time-dependent. In the current study, we have analysed the effect of high concentrations of NaF (80ppm) on mouse skeletal muscle at two different time points, i.e., 15 days and 60 days. At the end of the experimental time, the animals were sacrificed, skeletal muscles were isolated, and proteins were extracted and subjected to bioinformatic (Mass Spectrometric) analysis. The results were analysed based on changes in different mitochondrial complexes, contractile (sarcomeric) proteins, 26S proteasome, and ubiquitin-proteasome pathway. The results showed that the mitochondrial proteins of complex I, II, III, IV and V were differentially regulated in the groups treated with 80ppm of NaF for 15 days and 60 days. The network analysis indicated more changes in mitochondrial proteins in the group treated with the higher dose for 15 days rather than 60 days. Furthermore, differential expression of (sarcomeric) proteins, downregulation of 26S proteasome subunits, and differential expression in proteins related to the ubiquitin-proteasome pathway lead to muscle atrophy. The differential expression might be due to the adaptative mechanism to counteract the deleterious effects of NaF on energy metabolism. Data are available via ProteomeXchange with identifier PXD035014.
    DOI:  https://doi.org/10.1371/journal.pone.0279261
  38. Nature. 2022 Dec 21.
    Senescence atlas reveals an aged-like inflamed niche that blunts muscle regeneration.
    Victoria Moiseeva, Andrés Cisneros, Valentina Sica, Oleg Deryagin, Yiwei Lai, Sascha Jung, Eva Andrés, Juan An, Jessica Segalés, Laura Ortet, Vera Lukesova, Giacomo Volpe, Alberto Benguria, Ana Dopazo, Salvador Aznar-Benitah, Yasuteru Urano, Antonio Del Sol, Miguel A Esteban, Yasuyuki Ohkawa, Antonio L Serrano, Eusebio Perdiguero, Pura Muñoz-Cánoves.
      Tissue regeneration requires coordination between resident stem cells and local niche cells1,2. Here we identify that senescent cells are integral components of the skeletal muscle regenerative niche that repress regeneration at all stages of life. The technical limitation of senescent-cell scarcity3 was overcome by combining single-cell transcriptomics and a senescent-cell enrichment sorting protocol. We identified and isolated different senescent cell types from damaged muscles of young and old mice. Deeper transcriptome, chromatin and pathway analyses revealed conservation of cell identity traits as well as two universal senescence hallmarks (inflammation and fibrosis) across cell type, regeneration time and ageing. Senescent cells create an aged-like inflamed niche that mirrors inflammation associated with ageing (inflammageing4) and arrests stem cell proliferation and regeneration. Reducing the burden of senescent cells, or reducing their inflammatory secretome through CD36 neutralization, accelerates regeneration in young and old mice. By contrast, transplantation of senescent cells delays regeneration. Our results provide a technique for isolating in vivo senescent cells, define a senescence blueprint for muscle, and uncover unproductive functional interactions between senescent cells and stem cells in regenerative niches that can be overcome. As senescent cells also accumulate in human muscles, our findings open potential paths for improving muscle repair throughout life.
    DOI:  https://doi.org/10.1038/s41586-022-05535-x
  39. FASEB J. 2023 Jan;37(1): e22719
    Time to run: Late rather than early exercise training in mice remodels the gut microbiome and reduces atherosclerosis development.
    Milena Schönke, Zhixiong Ying, Artemiy Kovynev, Wietse In Het Panhuis, Anne Binnendijk, Sabine van der Poel, Amanda C M Pronk, Trea C M Streefland, Menno Hoekstra, Sander Kooijman, Patrick C N Rensen.
      The metabolic and inflammatory processes that are implicated in the development of cardiovascular diseases are under control of the biological clock. While skeletal muscle function exhibits circadian rhythms, it is unclear to what extent the beneficial health effects of exercise are restricted to unique time windows. We aimed to study whether the timing of exercise training differentially modulates the development of atherosclerosis and elucidate underlying mechanisms. We endurance-trained atherosclerosis-prone female APOE*3-Leiden.CETP mice fed a Western-type diet, a well-established human-like model for cardiometabolic diseases, for 1 h five times a week for 4 weeks either in their early or in their late active phase on a treadmill. We monitored metabolic parameters, the development of atherosclerotic lesions in the aortic root and assessed the composition of the gut microbiota. Late, but not early, exercise training reduced fat mass by 19% and the size of early-stage atherosclerotic lesions by as much as 29% compared to sedentary animals. No correlation between cholesterol exposure and lesion size was evident, as no differences in plasma lipid levels were observed, but circulating levels of the pro-inflammatory markers ICAM-1 and VCAM-1 were reduced with late exercise. Strikingly, we observed a time-of-day-dependent effect of exercise training on the composition of the gut microbiota as only late training increased the abundance of gut bacteria producing short-chain fatty acids with proposed anti-inflammatory properties. Together, these findings indicate that timing is a critical factor to the beneficial anti-atherosclerotic effects of exercise with a great potential to further optimize training recommendations for patients.
    Keywords:  atherosclerosis; circadian rhythms; exercise; gut microbiota; lipid metabolism
    DOI:  https://doi.org/10.1096/fj.202201304R
  40. Continuum (Minneap Minn). 2022 Dec 01. 28(6): 1752-1777
    Metabolic Myopathies.
    Mark A Tarnopolsky.
      PURPOSE OF REVIEW: Metabolic myopathies are disorders that affect skeletal muscle substrate oxidation. Although some drugs and hormones can affect metabolism in skeletal muscle, this review will focus on the genetic metabolic myopathies.RECENT FINDINGS: Impairments in glycogenolysis/glycolysis (glycogen storage disease), fatty acid transport/oxidation (fatty acid oxidation defects), and mitochondrial metabolism (mitochondrial myopathies) represent most metabolic myopathies; however, they often overlap clinically with structural genetic myopathies, referred to as pseudometabolic myopathies. Although metabolic myopathies can present in the neonatal period with hypotonia, hypoglycemia, and encephalopathy, most cases present clinically in children or young adults with exercise intolerance, rhabdomyolysis, and weakness. In general, the glycogen storage diseases manifest during brief bouts of high-intensity exercise; in contrast, fatty acid oxidation defects and mitochondrial myopathies usually manifest during longer-duration endurance-type activities, often with fasting or other metabolic stressors (eg, surgery, fever). The neurologic examination is often normal between events (except in the pseudometabolic myopathies) and evaluation requires one or more of the following tests: exercise stress testing, blood (eg, creatine kinase, acylcarnitine profile, lactate, amino acids), urine (eg, organic acids, myoglobin), muscle biopsy (eg, histology, ultrastructure, enzyme testing), and targeted (specific gene) or untargeted (myopathy panels) genetic tests.
    SUMMARY: Definitive identification of a specific metabolic myopathy often leads to specific interventions, including lifestyle, exercise, and nutritional modifications; cofactor treatments; accurate genetic counseling; avoidance of specific triggers; and rapid treatment of rhabdomyolysis.
    DOI:  https://doi.org/10.1212/CON.0000000000001182
  41. Front Endocrinol (Lausanne). 2022 ;13 1037948
    GDF15 is an exercise-induced hepatokine regulated by glucagon and insulin in humans.
    Peter Plomgaard, Jakob S Hansen, Logan K Townsend, Anders Gudiksen, Niels H Secher, Jens O Clemmesen, Rene K Støving, Jens P Goetze, David C Wright, Henriette Pilegaard.
      Objective: Growth differentiation factor (GDF)-15 is implicated in regulation of metabolism and circulating GDF15 increases in response to exercise. The source and regulation of the exercise-induced increase in GDF15 is, however not known.Method: Plasma GDF15 was measured by ELISA under the following conditions: 1) Arterial-to-hepatic venous differences sampled before, during, and after exercise in healthy male subjects (n=10); 2) exogenous glucagon infusion compared to saline infusion in resting healthy subjects (n=10); 3) an acute exercise bout with and without a pancreatic clamp (n=6); 4) healthy subjects for 36 hours (n=17), and 5) patients with anorexia nervosa (n=25) were compared to healthy age-matched subjects (n=25). Tissue GDF15 mRNA content was determined in mice in response to exhaustive exercise (n=16).
    Results: The splanchnic bed released GDF15 to the circulation during exercise and increasing the glucagon-to-insulin ratio in resting humans led to a 2.7-fold (P<0.05) increase in circulating GDF15. Conversely, inhibiting the exercise-induced increase in the glucagon-to-insulin ratio blunted the exercise-induced increase in circulating GDF15. Fasting for 36 hours did not affect circulating GDF15, whereas resting patients with anorexia nervosa displayed elevated plasma concentrations (1.4-fold, P<0.05) compared to controls. In mice, exercise increased GDF15 mRNA contents in liver, muscle, and adipose tissue.
    Conclusion: In humans, GDF15 is a "hepatokine" which increases during exercise and is at least in part regulated by the glucagon-to-insulin ratio. Moreover, chronic energy deprivation is associated with elevated plasma GDF15, which supports that GDF15 is implicated in metabolic signalling in humans.
    Keywords:  anorexia nervosa; appetite; fasting; insulin resistance; liver; splanchnic bed
    DOI:  https://doi.org/10.3389/fendo.2022.1037948
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