bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2022‒03‒27
43 papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Senolytic treatment rescues blunted muscle hypertrophy in old mice.
  2. A negative feedback loop between fibroadipogenic progenitors and muscle fibres involving endothelin promotes human muscle fibrosis.
  3. Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independent of pathophysiological changes.
  4. Myogenic Precursor Cells Show Faster Activation and Enhanced Differentiation in a Male Mouse Model Selected for Advanced Endurance Exercise Performance.
  5. Fusion of Normoxic- and Hypoxic-Preconditioned Myoblasts Leads to Increased Hypertrophy.
  6. NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.
  7. IL-17A contributes skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.
  8. Can Exercise Training Alter Human Skeletal Muscle DNA Methylation?
  9. Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration.
  10. A User-Friendly Approach for Routine Histopathological and Morphometric Analysis of Skeletal Muscle Using CellProfiler Software.
  11. Regulation of Dystroglycan Gene Expression in Early Myoblast Differentiation.
  12. Development of a cell-free strategy to recover aged skeletal muscle after disuse.
  13. Polygenic mechanisms underpinning the response to exercise-induced muscle damage in humans: In vivo and in vitro evidence.
  14. Activation of Calpain Contributes to Mechanical Ventilation-Induced Depression of Protein Synthesis in Diaphragm Muscle.
  15. Beneficial impacts of neuromuscular electrical stimulation on muscle structure and function in the zebrafish model of Duchenne muscular dystrophy.
  16. Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight.
  17. Aldehyde dehydrogenase 2 deficiency promotes skeletal muscle atrophy in aged mice.
  18. Skeletal Muscle Possesses an Epigenetic Memory of Exercise: Role of Nucleus Type-Specific DNA Methylation.
  19. Anabolic Factors and Myokines Improve Differentiation of Human Embryonic Stem Cell Derived Skeletal Muscle Cells.
  20. Elevated numbers of infiltrating eosinophils accelerate the progression of Duchenne muscular dystrophy pathology in mdx mice.
  21. Evaluating Therapeutic Activity of Galectin-1 in Sarcolemma Repair of Skeletal Muscle.
  22. NMR Spectroscopy Identifies Chemicals in Cigarette Smoke Condensate That Impair Skeletal Muscle Mitochondrial Function.
  23. Apoptosis-Inducing Factor Deficiency Induces Tissue-Specific Alterations in Autophagy: Insights from a Preclinical Model of Mitochondrial Disease and Exercise Training Effects.
  24. A Spotlight on T Lymphocytes in Duchenne Muscular Dystrophy-Not Just a Muscle Defect.
  25. Assessment of Muscle Quantity, Quality and Function.
  26. Activating ATF6 in Spinal Muscular Atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway.
  27. Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations.
  28. Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity.
  29. Transcription Regulation of Tceal7 by the Triple Complex of Mef2c, Creb1 and Myod.
  30. Can the Energetic Profile of Skeletal Muscle Predict Risk of Cognitive Impairment?
  31. Stretch-Induced Healing of Injured Muscles Is Associated With Myogenesis and Decreased Fibrosis.
  32. Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice.
  33. Expanding Roles for Muscle Satellite Cells in Exercise-Induced Hypertrophy.
  34. Cancer-Related Cachexia: The Vicious Circle between Inflammatory Cytokines, Skeletal Muscle, Lipid Metabolism and the Possible Role of Physical Training.
  35. New Insight into a Classic Stem Cell: the Satellite Cell may Communicate with the Muscle Fiber via Extracellular Vesicles-A Perspective on "Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy".
  36. Muscle contraction and mitochondrial biogenesis - a brief historical reappraisal.
  37. A Boost for Muscle with Gene Therapy.
  38. Effects of Muscle Architecture on Eccentric Exercise Induced Muscle Damage Responses.
  39. VLCKD in Combination with Physical Exercise Preserves Skeletal Muscle Mass in Sarcopenic Obesity after Severe COVID-19 Disease: A Case Report.
  40. The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging.
  41. Physical Activity Modulates miRNAs Levels and Enhances MYOD Expression in Myoblasts.
  42. Development and Regeneration of Muscle, Tendon, and Myotendinous Junctions in Striated Skeletal Muscle.
  43. Differential expression profiles of miRNA in the serum of sarcopenic rats.
  1. Geroscience. 2022 Mar 24.
    Senolytic treatment rescues blunted muscle hypertrophy in old mice.
    Cory M Dungan, Vandre C Figueiredo, Yuan Wen, Georgia L VonLehmden, Christopher J Zdunek, Nicholas T Thomas, C Brooks Mobley, Kevin A Murach, Camille R Brightwell, Douglas E Long, Christopher S Fry, Philip A Kern, John J McCarthy, Charlotte A Peterson.
      With aging, skeletal muscle plasticity is attenuated in response to exercise. Here, we report that senescent cells, identified using senescence-associated β-galactosidase (SA β-Gal) activity and p21 immunohistochemistry, are very infrequent in resting muscle, but emerge approximately 2 weeks after a bout of resistance exercise in humans. We hypothesized that these cells contribute to blunted hypertrophic potential in old age. Using synergist ablation-induced mechanical overload (MOV) of the plantaris muscle to model resistance training in adult (5-6-month) and old (23-24-month) male C57BL/6 J mice, we found increased senescent cells in both age groups during hypertrophy. Consistent with the human data, there were negligible senescent cells in plantaris muscle from adult and old sham controls, but old mice had significantly more senescent cells 7 and 14 days following MOV relative to young. Old mice had blunted whole-muscle hypertrophy when compared to adult mice, along with smaller muscle fibers, specifically glycolytic type 2x + 2b fibers. To ablate senescent cells using a hit-and-run approach, old mice were treated with vehicle or a senolytic cocktail consisting of 5 mg/kg dasatinib and 50 mg/kg quercetin (D + Q) on days 7 and 10 during 14 days of MOV; control mice underwent sham surgery with or without senolytic treatment. Old mice given D + Q had larger muscles and muscle fibers after 14 days of MOV, fewer senescent cells when compared to vehicle-treated old mice, and changes in the expression of genes (i.e., Igf1, Ddit4, Mmp14) that are associated with hypertrophic growth. Our data collectively show that senescent cells emerge in human and mouse skeletal muscle following a hypertrophic stimulus and that D + Q improves muscle growth in old mice.
    Keywords:  Anabolic resistance; Hypertrophy; Senescence; Senolytics; Skeletal muscle
    DOI:  https://doi.org/10.1007/s11357-022-00542-2
  2. J Cachexia Sarcopenia Muscle. 2022 Mar 22.
    A negative feedback loop between fibroadipogenic progenitors and muscle fibres involving endothelin promotes human muscle fibrosis.
    Mona Bensalah, Laura Muraine, Alexis Boulinguiez, Lorenzo Giordani, Victorine Albert, Victor Ythier, Jamila Dhiab, Alison Oliver, Valentine Hanique, Teresa Gidaro, Sophie Perié, Jean Lacau St-Guily, Aurélien Corneau, Gillian Butler-Browne, Anne Bigot, Vincent Mouly, Elisa Negroni, Capucine Trollet.
      BACKGROUND: Fibrosis is defined as an excessive accumulation of extracellular matrix (ECM) components. Many organs are subjected to fibrosis including the lung, liver, heart, skin, kidney, and muscle. Muscle fibrosis occurs in response to trauma, aging, or dystrophies and impairs muscle function. Fibrosis represents a hurdle for the treatment of human muscular dystrophies. While data on the mechanisms of fibrosis have mostly been investigated in mice, dystrophic mouse models often do not recapitulate fibrosis as observed in human patients. Consequently, the cellular and molecular mechanisms that lead to fibrosis in human muscle still need to be identified.METHODS: Combining mass cytometry, transcriptome profiling, in vitro co-culture experiments, and in vivo transplantation in immunodeficient mice, we investigated the role and nature of nonmyogenic cells (fibroadipogenic progenitors, FAPs) from human fibrotic muscles of healthy individuals (FibMCT ) and individuals with oculopharyngeal muscular dystrophy (OPMD; FibMOP ), as compared with nonmyogenic cells from human nonfibrotic muscle (MCT ).
    RESULTS: We found that the proliferation rate of FAPs from fibrotic muscle is 3-4 times higher than those of FAPs from nonfibrotic muscle (population doubling per day: MCT 0.2 ± 0.1, FibMCT 0.7 ± 0.1, and FibMOP 0.8 ± 0.3). When cocultured with muscle cells, FAPs from fibrotic muscle impair the fusion index unlike MCT FAPs (myoblasts alone 57.3 ± 11.1%, coculture with MCT 43.1 ± 8.9%, with FibMCT 31.7 ± 8.2%, and with FibMOP 36.06 ± 10.29%). We also observed an increased proliferation of FAPs from fibrotic muscles in these co-cultures in differentiation conditions (FibMCT +17.4%, P < 0.01 and FibMOP +15.1%, P < 0.01). This effect is likely linked to the increased activation of the canonical TGFβ-SMAD pathway in FAPs from fibrotic muscles evidenced by pSMAD3 immunostaining (P < 0.05). In addition to the profibrogenic TGFβ pathway, we identified endothelin as a new actor implicated in the altered cross-talk between muscle cells and fibrotic FAPs, confirmed by an improvement of the fusion index in the presence of bosentan, an endothelin receptor antagonist (from 33.8 ± 10.9% to 52.9 ± 10.1%, P < 0.05).
    CONCLUSIONS: Our data demonstrate the key role of FAPs and their cross-talk with muscle cells through a paracrine signalling pathway in fibrosis of human skeletal muscle and identify endothelin as a new druggable target to counteract human muscle fibrosis.
    Keywords:  ECM; Endothelin; FAPs; Fibrosis; Human; Pharyngeal muscle; Regeneration; Skeletal muscle; TGFβ
    DOI:  https://doi.org/10.1002/jcsm.12974
  3. J Clin Invest. 2022 Mar 22. pii: e156125. [Epub ahead of print]
    Aerobic exercise elicits clinical adaptations in myotonic dystrophy type 1 patients independent of pathophysiological changes.
    Andrew I Mikhail, Peter L Nagy, Katherine Manta, Nicholas Rouse, Alexander Manta, Sean Y Ng, Michael F Nagy, Paul Smith, Jian-Qiang Lu, Joshua P Nederveen, Vladimir Ljubicic, Mark A Tarnopolsky.
      BACKGROUND: Myotonic dystrophy type 1 (DM1) is a complex life-limiting neuromuscular disorder characterized by severe skeletal muscle atrophy, weakness, and cardio-respiratory defects. Exercised DM1 mice exhibit numerous physiological benefits that are underpinned by reduced CUG foci and improved alternative splicing. However, the efficacy of physical activity in patients is unknown.METHODS: Eleven genetically diagnosed DM1 patients were recruited to examine the extent to which 12-weeks of cycling can recuperate clinical, and physiological metrics. Furthermore, we studied the underlying molecular mechanisms through which exercise elicits benefits in skeletal muscle of DM1 patients.
    RESULTS: DM1 was associated with impaired muscle function, fitness, and lung capacity. Cycling evoked several clinical, physical, and metabolic advantages in DM1 patients. We highlight that exercise-induced molecular and cellular alterations in patients do not conform with previously published data in murine models and propose a significant role of mitochondrial function in DM1 pathology. Lastly, we discovered a subset of small nucleolar RNAs (snoRNAs) that correlated to indicators of disease severity.
    CONCLUSION: With no available cures, our data supports the efficacy of exercise as a primary intervention to partially mitigate the clinical progression of DM1. Additionally, we provide evidence for the involvement of snoRNAs and other noncoding RNAs in DM1 pathophysiology.
    TRIAL REGISTRATION: This trial was approved by the HiREB committee (#7901) and registered under ClinicalTrials.gov (NCT04187482).
    FUNDING: This work was primarily supported by Neil and Leanne Petroff. This study was also supported by a Canadian Institutes of Health Research Foundation Grant to MAT (#143325).
    Keywords:  Cell Biology; Mitochondria; Muscle Biology; Neuromuscular disease; RNA processing
    DOI:  https://doi.org/10.1172/JCI156125
  4. Cells. 2022 Mar 16. pii: 1001. [Epub ahead of print]11(6):
    Myogenic Precursor Cells Show Faster Activation and Enhanced Differentiation in a Male Mouse Model Selected for Advanced Endurance Exercise Performance.
    Stefan Petkov, Julia Brenmoehl, Martina Langhammer, Andreas Hoeflich, Monika Röntgen.
      Satellite cells (SATC), the most abundant skeletal muscle stem cells, play a main role in muscle plasticity, including the adaptive response following physical activity. Thus, we investigated how long-term phenotype selection of male mice for high running performance (Dummerstorf high Treadmill Performance; DUhTP) affects abundance, creatine kinase activity, myogenic marker expression (Pax7, MyoD), and functionality (growth kinetics, differentiation) of SATC and their progeny. SATC were isolated from sedentary male DUhTP and control (Dummerstorf Control; DUC) mice at days 12, 43, and 73 of life and after voluntary wheel running for three weeks (day 73). Marked line differences occur at days 43 and 73 (after activity). At both ages, analysis of SATC growth via xCELLigence system revealed faster activation accompanied by a higher proliferation rate and lower proportion of Pax7+ cells in DUhTP mice, indicating reduced reserve cell formation and faster transition into differentiation. Cultures from sedentary DUhTP mice contain an elevated proportion of actively proliferating Pax7+/MyoD+ cells and have a higher fusion index leading to the formation of more large and very large myotubes at day 43. This robust hypertrophic response occurs without any functional load in the donor mice. Thus, our selection model seems to recruit myogenic precursor cells/SATC with a lower activation threshold that respond more rapidly to external stimuli and are more primed for differentiation at the expense of more primitive cells.
    Keywords:  MyoD; Pax7; muscle stem cells; myogenic differentiation; proliferation; voluntary physical activity
    DOI:  https://doi.org/10.3390/cells11061001
  5. Cells. 2022 Mar 21. pii: 1059. [Epub ahead of print]11(6):
    Fusion of Normoxic- and Hypoxic-Preconditioned Myoblasts Leads to Increased Hypertrophy.
    Tamara Pircher, Henning Wackerhage, Elif Akova, Wolfgang Böcker, Attila Aszodi, Maximilian M Saller.
      Injuries, high altitude, and endurance exercise lead to hypoxic conditions in skeletal muscle and sometimes to hypoxia-induced local tissue damage. Thus, regenerative myoblasts/satellite cells are exposed to different levels and durations of partial oxygen pressure depending on the spatial distance from the blood vessels. To date, it is unclear how hypoxia affects myoblasts proliferation, differentiation, and particularly fusion with normoxic myoblasts. To study this, we investigated how 21% and 2% oxygen affects C2C12 myoblast morphology, proliferation, and myogenic differentiation and evaluated the fusion of normoxic- or hypoxic-preconditioned C2C12 cells in 21% or 2% oxygen in vitro. Out data show that the long-term hypoxic culture condition does not affect the proliferation of C2C12 cells but leads to rounder cells and reduced myotube formation when compared with myoblasts exposed to normoxia. However, when normoxic- and hypoxic-preconditioned myoblasts were differentiated together, the resultant myotubes were significantly larger than the control myotubes. Whole transcriptome sequencing analysis revealed several novel candidate genes that are differentially regulated during the differentiation under normoxia and hypoxia in mixed culture conditions and may thus be involved in the increase in myotube size. Taken together, oxygen-dependent adaption and interaction of myoblasts may represent a novel approach for the development of innovative therapeutic targets.
    Keywords:  C2C12; fusion; hypoxia; myoblasts; myogenic differentiation; myotube; oxygen
    DOI:  https://doi.org/10.3390/cells11061059
  6. Mol Cell Biochem. 2022 Mar 25.
    NAD+ centric mechanisms and molecular determinants of skeletal muscle disease and aging.
    Sabrina Wagner, Ravikumar Manickam, Marco Brotto, Srinivas M Tipparaju.
      The nicotinamide adenine dinucleotide (NAD+) is an essential redox cofactor, involved in various physiological and molecular processes, including energy metabolism, epigenetics, aging, and metabolic diseases. NAD+ repletion ameliorates muscular dystrophy and improves the mitochondrial and muscle stem cell function and thereby increase lifespan in mice. Accordingly, NAD+ is considered as an anti-oxidant and anti-aging molecule. NAD+ plays a central role in energy metabolism and the energy produced is used for movements, thermoregulation, and defense against foreign bodies. The dietary precursors of NAD+ synthesis is targeted to improve NAD+ biosynthesis; however, studies have revealed conflicting results regarding skeletal muscle-specific effects. Recent advances in the activation of nicotinamide phosphoribosyltransferase in the NAD+ salvage pathway and supplementation of NAD+ precursors have led to beneficial effects in skeletal muscle pathophysiology and function during aging and associated metabolic diseases. NAD+ is also involved in the epigenetic regulation and post-translational modifications of proteins that are involved in various cellular processes to maintain tissue homeostasis. This review provides detailed insights into the roles of NAD+ along with molecular mechanisms during aging and disease conditions, such as the impacts of age-related NAD+ deficiencies on NAD+-dependent enzymes, including poly (ADP-ribose) polymerase (PARPs), CD38, and sirtuins within skeletal muscle, and the most recent studies on the potential of nutritional supplementation and distinct modes of exercise to replenish the NAD+ pool.
    Keywords:  Aging; Diabetes; Epigenetics; Muscle diseases; NAD+; Redox
    DOI:  https://doi.org/10.1007/s11010-022-04408-1
  7. Am J Physiol Cell Physiol. 2022 Mar 23.
    IL-17A contributes skeletal muscle atrophy in lung cancer-induced cachexia via JAK2/STAT3 pathway.
    Lin Ying, Yinan Yao, Handi Lv, Guohua Lu, Qin Zhang, Yunmei Yang, Jianying Zhou.
      Cachexia is a complex metabolic syndrome that occurs in approximately 50% of patients with cancer. Skeletal muscle atrophy is the primary clinical feature. Interleukin (IL)-17A, a pro-inflammatory factor, plays an important role in many chronic inflammatory diseases. Here, we describe a novel signaling pathway through which IL-17A induced muscle atrophy.We conducted a retrospective clinical study to investigate the relationship between IL-17A and the skeletal muscle index in patients with lung adenocarcinoma. We also investigated the involvement of JAK2/STAT3 signaling pathway regarding the main features of cachexia by injecting Lewis lung carcinoma (LLC) cells into C57BL/6 mice as a model to replicate cancer-induced cachexia. In vitro, C2C12 myotubes were treated with recombinant IL-17A, anti-IL-17A monoclonal antibody, STAT3 inhibitor AG490, and LLC-conditioned medium. Cell viability and aging was also evaluated. We found in cancer conditions, increased serum levels of IL-17A were related to muscle wasting. JAK2/STAT3 phosphorylation was observed in the muscle of LLC tumor-bearing mice, accompanied by decreased MHC/Myog levels and increased MuRF1/Atrogin-1 levels. Administration of anti-IL-17A monoclonal antibody and AG490 slowed muscle atrophy development. Consistent with the in vivo findings, C2C12 myotubes treated with IL-17A and LLC-conditioned medium demonstrated phosphorylated JAK2/STAT3 signaling, resulting in MHC loss and myotube atrophy. IL-17A also inhibited C2C12 cell proliferation, cell cycle breaking, and cellular senescence. Our results identify phosphorylation of IL-17A/JAK2/STAT3 signaling pathway appears to be an important component in the pathogenesis of LLC tumor-induced cachexia. Targeted therapy of IL-17A may be a promising approach to reduce skeletal muscle loss of patients with cancer.
    Keywords:  Cancer cachexia; IL-17A; Inflammation; Muscle atrophy; STAT3
    DOI:  https://doi.org/10.1152/ajpcell.00463.2021
  8. Metabolites. 2022 Mar 02. pii: 222. [Epub ahead of print]12(3):
    Can Exercise Training Alter Human Skeletal Muscle DNA Methylation?
    Luis A Garcia, Rocio Zapata-Bustos, Samantha E Day, Baltazar Campos, Yassin Hamzaoui, Linda Wu, Alma D Leon, Judith Krentzel, Richard L Coletta, Eleanna De Filippis, Lori R Roust, Lawrence J Mandarino, Dawn K Coletta.
      Skeletal muscle is highly plastic and dynamically regulated by the body's physical demands. This study aimed to determine the plasticity of skeletal muscle DNA methylation in response to 8 weeks of supervised exercise training in volunteers with a range of insulin sensitivities. We studied 13 sedentary participants and performed euglycemic hyperinsulinemic clamps with basal vastus lateralis muscle biopsies and peak aerobic activity (VO2 peak) tests before and after training. We extracted DNA from the muscle biopsies and performed global methylation using Illumina's Methylation EPIC 850K BeadChip. Training significantly increased peak aerobic capacity and insulin-stimulated glucose disposal. Fasting serum insulin and insulin levels during the steady state of the clamp were significantly lower post-training. Insulin clearance rates during the clamp increased following the training. We identified 13 increased and 90 decreased differentially methylated cytosines (DMCs) in response to 8 weeks of training. Of the 13 increased DMCs, 2 were within the following genes, FSTL3, and RP11-624M8.1. Of the 90 decreased DMCs, 9 were within the genes CNGA1, FCGR2A, KIF21A, MEIS1, NT5DC1, OR4D1, PRPF4B, SLC26A7, and ZNF280C. Moreover, pathway analysis showed an enrichment in metabolic and actin-cytoskeleton pathways for the decreased DMCs, and for the increased DMCs, an enrichment in signal-dependent regulation of myogenesis, NOTCH2 activation and transmission, and SMAD2/3: SMAD4 transcriptional activity pathways. Our findings showed that 8 weeks of exercise training alters skeletal muscle DNA methylation of specific genes and pathways in people with varying degrees of insulin sensitivity.
    Keywords:  DNA methylation; VO2 peak; euglycemic hyperinsulinemic clamp; exercise training; insulin sensitivity; skeletal muscle
    DOI:  https://doi.org/10.3390/metabo12030222
  9. Elife. 2022 Mar 24. pii: e77610. [Epub ahead of print]11
    Lack of Tgfbr1 and Acvr1b synergistically stimulates myofibre hypertrophy and accelerates muscle regeneration.
    Michèle M G Hillege, Andi Shi, Ricardo A Galli, Gang Wu, Philippe Bertolino, Willem M H Hoogaars, Richard T Jaspers.
      In skeletal muscle, transforming growth factor-β (TGF-β) family growth factors, TGF-β1 and myostatin, are involved in atrophy and muscle wasting disorders. Simultaneous interference with their signalling pathways may improve muscle function, however little is known about their individual and combined receptor signalling. Here we show that inhibition of TGF-β signalling by simultaneous muscle-specific knockout of TGF-β type I receptors Tgfbr1 and Acvr1b in mice, induces substantial hypertrophy, while such effect does not occur by single receptor knockout. Hypertrophy is induced by increased phosphorylation of Akt and p70S6K and reduced E3 ligases expression, while myonuclear number remains unaltered. Combined knockout of both TGF-β type I receptors increases the number of satellite cells, macrophages and improves regeneration post cardiotoxin-induced injury by stimulating myogenic differentiation. Extra cellular matrix gene expression is exclusively elevated in muscle with combined receptor knockout. Tgfbr1 and Acvr1b are synergistically involved in regulation of myofibre size, regeneration and collagen deposition.
    Keywords:  cell biology; mouse
    DOI:  https://doi.org/10.7554/eLife.77610
  10. Diagnostics (Basel). 2022 Feb 22. pii: 561. [Epub ahead of print]12(3):
    A User-Friendly Approach for Routine Histopathological and Morphometric Analysis of Skeletal Muscle Using CellProfiler Software.
    Valerio Laghi, Valentina Ricci, Francesca De Santa, Alessio Torcinaro.
      Adult skeletal muscle is capable of active and efficient differentiation in the event of injury in both physiological and pathological conditions, such as in Duchenne muscular dystrophy (DMD). DMD is characterized by different features, such as continuous cycles of degeneration/regeneration, fiber heterogeneity, chronic inflammation and fibrosis. A well-defined and standardized approach for histological and morphometric analysis of muscle samples is necessary in order to measure and quantify specific regenerative parameters in myopathies. Indeed, non-automatic methods are time-consuming and prone to error. Here, we describe a simple automatized computational approach to quantify muscle parameters with specific pipelines to be run by CellProfiler software in an open-source and well-defined fashion. Our pipelines consist of running image-processing modules in CellProfiler with the aim of quantifying different histopathological muscle hallmarks in mdx mice compared to their wild-type littermates. Specifically, we quantified the minimum Feret diameter, centrally nucleated fibers and the number of macrophages, starting from multiple images. Finally, for extracellular matrix quantification, we used Sirius red staining. Collectively, we developed reliable and easy-to-use pipelines that automatically measure parameters of muscle histology, useful for research in myobiology. These findings should simplify and shorten the time needed for the quantification of muscle histological properties, avoiding challenging manual procedures.
    Keywords:  Duchenne muscular dystrophy; cell localization; histology; histopathological analysis; myopathies; quantitative analysis; skeletal muscle; skeletal muscle differentiation
    DOI:  https://doi.org/10.3390/diagnostics12030561
  11. Front Cell Dev Biol. 2022 ;10 818701
    Regulation of Dystroglycan Gene Expression in Early Myoblast Differentiation.
    Munerah Hamed, Jihong Chen, Qiao Li.
      Dystroglycan, a component of the dystrophin-associated glycoprotein complex, connects the extracellular matrix and cytoskeleton to maintain muscle membrane integrity. As such, abnormalities of dystroglycan are linked to different types of muscular dystrophies. In an effort to develop therapeutic approaches to re-establish signal integration for muscle repair and homeostasis, we have previously determined that a clinically approved agonist of retinoid X receptor enhances myoblast differentiation through direct regulation of gene expression of the muscle master regulator MyoD. Using comprehensive omics and molecular analyses, we found that dystroglycan gene expression is responsive to retinoid X receptor-selective signaling in early myoblast differentiation. In addition, the dystroglycan gene is a MyoD target, and residue-specific histone acetylation coincides with the occupancy of histone acetyltransferase p300 at the MyoD binding sites. Consequently, the p300 function is important for rexinoid-augmented dystroglycan gene expression. Finally, dystroglycan plays a role in myoblast differentiation. Our study sheds new light on dystroglycan regulation and function in myoblast differentiation and presents a potential avenue for re-establishing signal integration of a specific chromatin state pharmacologically to overcome muscle pathology and identify additional myogenic interactions for therapeutic applications.
    Keywords:  dystroglycan; dystrophies; gene regulation; histone acetylation; histone acetyltransferase; myogenesis; nuclear receptor
    DOI:  https://doi.org/10.3389/fcell.2022.818701
  12. J Physiol. 2022 Mar 22.
    Development of a cell-free strategy to recover aged skeletal muscle after disuse.
    Yu-Fu Wu, Eduardo A De La Toba, Svyatoslav Dvoretskiy, Rebecca Jung, Noah Kim, Laureen Daniels, Elena V Romanova, Jenny Drnevich, Jonathan V Sweedler, Marni D Boppart.
      KEY POINTS: Prior studies suggest that prolonged oxidative stress represents a barrier to skeletal muscle recovery after a period of immobilization In this study we demonstrate that muscle resident perivascular stromal cells (pericytes) become dysfunctional and lack the capacity to mount an antioxidant defense after disuse in mice Hydrogen peroxide treatment of healthy pericytes in vitro simulates the release of small extracellular vesicles (sEVs) that effectively recover skeletal muscle fiber size and ECM remodeling in young adult and aged mice after disuse Pericyte-derived sEVs represent a novel acellular strategy to recover skeletal muscle after disuse ABSTRACT: Extended periods of bed rest and limb immobilization are required for healing post-injury or disease, yet disuse can result in significant muscle atrophy and decreased quality of life in older adults. Physical rehabilitation is commonly prescribed to recover these deficits, yet accumulation of reactive oxygen species (ROS) and sustained rates of protein degradation persist during the rehabilitation period that can significantly delay or prevent recovery. Pericytes, considered the primary mesenchymal and vascular stromal cell in skeletal muscle, secrete beneficial factors that maintain baseline muscle mass, yet minimal information exists regarding the pericyte response to disuse and recovery. In the current study, single-cell RNA sequencing (scRNA-Seq) and functional assays were performed to demonstrate that pericytes in mouse skeletal muscle lose the capacity to synthesize antioxidants during disuse and recovery. This information was used to guide the design of a strategy in which healthy donor pericytes were stimulated with hydrogen peroxide (H2 O2 ) to produce small extracellular vesicles (sEVs) that effectively restored myofiber size in adult and aged muscle after disuse. Proteomic assessment detected 11 differentially regulated proteins in primed sEVs that may account for recovery of muscle, including proteins associated with extracellular matrix composition and anti-inflammatory and antioxidant processes. This study demonstrates that healthy H2 O2 -primed pericyte-derived sEVs effectively improve skeletal muscle recovery after immobilization, representing a novel acellular approach to rebuild muscle mass in older adults after a period of disuse. Abstract figure legend Hydrogen peroxide treatment of healthy, muscle-resident pericytes in vitro stimulates the release of small extracellular vesicles (sEVs) that effectively reduce oxidative stress and recover skeletal muscle fiber size and collagen remodeling in mice after disuse. This article is protected by copyright. All rights reserved.
    Keywords:  antioxidant; disuse atrophy; extracellular vesicles; pericyte; skeletal muscle
    DOI:  https://doi.org/10.1113/JP282867
  13. J Cell Physiol. 2022 Mar 21.
    Polygenic mechanisms underpinning the response to exercise-induced muscle damage in humans: In vivo and in vitro evidence.
    Philipp Baumert, Matthew Cocks, Juliette A Strauss, Sam O Shepherd, Barry Drust, Mark J Lake, Claire E Stewart, Robert M Erskine.
      We investigated in vivo whether 20 candidate single nucleotide polymorphisms (SNPs) were associated with in vivo exercise-induced muscle damage (EIMD), and with an in vitro skeletal muscle stem cell wound healing assay. Sixty-five young, untrained Caucasian adults performed 120 maximal eccentric knee-extensions on an isokinetic dynamometer to induce EIMD. Maximal voluntary isometric/isokinetic knee-extensor torque, knee joint range of motion (ROM), muscle soreness, serum creatine kinase activity and interleukin-6 concentration were assessed before, directly after and 48 h after EIMD. Muscle stem cells were cultured from vastus lateralis biopsies from a separate cohort (n = 12), and markers of repair were measured in vitro. Participants were genotyped for all 20 SNPs using real-time PCR. Seven SNPs were associated with the response to EIMD, and these were used to calculate a total genotype score, which enabled participants to be segregated into three polygenic groups: 'preferential' (more 'protective' alleles), 'moderate', and 'non-preferential'. The non-preferential group was consistently weaker than the preferential group (1.93 ± 0.81 vs. 2.73 ± 0.59 N ∙ m/kg; P = 9.51 × 10-4 ) and demonstrated more muscle soreness (p = 0.011) and a larger decrease in knee joint ROM (p = 0.006) following EIMD. Two TTN-AS1 SNPs in linkage disequilibrium were associated with in vivo EIMD (rs3731749, p ≤ 0.005) and accelerated muscle stem cell migration into the artificial wound in vitro (rs1001238, p ≤ 0.006). Thus, we have identified a polygenic profile, linked with both muscle weakness and poorer recovery following EIMD. Moreover, we provide evidence for a novel TTN gene-cell-skeletal muscle mechanism that may help explain some of the interindividual variability in the response to EIMD.
    Keywords:  eccentric exercise; extracellular matrix (ECM); fibroblast; myoblast; single-nucleotide polymorphism (SNP); total genotype score (TGS)
    DOI:  https://doi.org/10.1002/jcp.30723
  14. Cells. 2022 Mar 18. pii: 1028. [Epub ahead of print]11(6):
    Activation of Calpain Contributes to Mechanical Ventilation-Induced Depression of Protein Synthesis in Diaphragm Muscle.
    Hayden W Hyatt, Mustafa Ozdemir, Matthew P Bomkamp, Scott K Powers.
      Mechanical ventilation (MV) is a clinical tool that provides respiratory support to patients unable to maintain adequate alveolar ventilation on their own. Although MV is often a life-saving intervention in critically ill patients, an undesired side-effect of prolonged MV is the rapid occurrence of diaphragmatic atrophy due to accelerated proteolysis and depressed protein synthesis. Investigations into the mechanism(s) responsible for MV-induced diaphragmatic atrophy reveal that activation of the calcium-activated protease, calpain, plays a key role in accelerating proteolysis in diaphragm muscle fibers. Moreover, active calpain has been reported to block signaling events that promote protein synthesis (i.e., inhibition of mammalian target of rapamycin (mTOR) activation). While this finding suggests that active calpain can depress muscle protein synthesis, this postulate has not been experimentally verified. Therefore, we tested the hypothesis that active calpain plays a key role in the MV-induced depression of both anabolic signaling events and protein synthesis in the diaphragm muscle. MV-induced activation of calpain in diaphragm muscle fibers was prevented by transgene overexpression of calpastatin, an endogenous inhibitor of calpain. Our findings indicate that overexpression of calpastatin averts MV-induced activation of calpain in diaphragm fibers and rescues the MV-induced depression of protein synthesis in the diaphragm muscle. Surprisingly, deterrence of calpain activation did not impede the MV-induced inhibition of key anabolic signaling events including mTOR activation. However, blockade of calpain activation prevented the calpain-induced cleavage of glutaminyl-tRNA synthetase in diaphragm fibers; this finding is potentially important because aminoacyl-tRNA synthetases play a central role in protein synthesis. Regardless of the mechanism(s) responsible for calpain's depression of protein synthesis, these results provide the first evidence that active calpain plays an important role in promoting the MV-induced depression of protein synthesis within diaphragm fibers.
    Keywords:  anabolic signaling; calpastatin; oxidative stress; protein translation; proteolysis; redox signaling
    DOI:  https://doi.org/10.3390/cells11061028
  15. Elife. 2022 Mar 24. pii: e62760. [Epub ahead of print]11
    Beneficial impacts of neuromuscular electrical stimulation on muscle structure and function in the zebrafish model of Duchenne muscular dystrophy.
    Elisabeth A Kilroy, Amanda C Ignacz, Kaylee L Brann, Claire E Schaffer, Devon Varney, Sarah S Alrowaished, Kodey J Silknitter, Jordan N Miner, Ahmed Almaghasilah, Tashawna L Spellen, Alexandra D Lewis, Karissa Tilbury, Benjamin L King, Joshua B Kelley, Clarissa A Henry.
      Neuromuscular electrical stimulation (NMES) allows activation of muscle fibers in the absence of voluntary force generation. NMES could have the potential to promote muscle homeostasis in the context of muscle disease, but the impacts of NMES on diseased muscle are not well understood. We used the zebrafish Duchenne muscular dystrophy (dmd) mutant and a longitudinal design to elucidate the consequences of NMES on muscle health. We designed four neuromuscular stimulation paradigms loosely based on weightlifting regimens. Each paradigm differentially affected neuromuscular structure, function, and survival. Only endurance neuromuscular stimulation (eNMES) improved all outcome measures. We found that eNMES improves muscle and neuromuscular junction morphology, swimming, and survival. Heme oxygenase and integrin alpha7 are required for eNMES-mediated improvement. Our data indicate that neuromuscular stimulation can be beneficial, suggesting that the right type of activity may benefit patients with muscle disease.
    Keywords:  developmental biology; dystroglycanopathies; neuromuscular development; skeletal muscle; zebrafish
    DOI:  https://doi.org/10.7554/eLife.62760
  16. Genes (Basel). 2022 Mar 08. pii: 473. [Epub ahead of print]13(3):
    Detection of Target Genes for Drug Repurposing to Treat Skeletal Muscle Atrophy in Mice Flown in Spaceflight.
    Vidya Manian, Jairo Orozco-Sandoval, Victor Diaz-Martinez, Heeralal Janwa, Carlos Agrinsoni.
      Skeletal muscle atrophy is a common condition in aging, diabetes, and in long duration spaceflights due to microgravity. This article investigates multi-modal gene disease and disease drug networks via link prediction algorithms to select drugs for repurposing to treat skeletal muscle atrophy. Key target genes that cause muscle atrophy in the left and right extensor digitorum longus muscle tissue, gastrocnemius, quadriceps, and the left and right soleus muscles are detected using graph theoretic network analysis, by mining the transcriptomic datasets collected from mice flown in spaceflight made available by GeneLab. We identified the top muscle atrophy gene regulators by the Pearson correlation and Bayesian Markov blanket method. The gene disease knowledge graph was constructed using the scalable precision medicine knowledge engine. We computed node embeddings, random walk measures from the networks. Graph convolutional networks, graph neural networks, random forest, and gradient boosting methods were trained using the embeddings, network features for predicting links and ranking top gene-disease associations for skeletal muscle atrophy. Drugs were selected and a disease drug knowledge graph was constructed. Link prediction methods were applied to the disease drug networks to identify top ranked drugs for therapeutic treatment of skeletal muscle atrophy. The graph convolution network performs best in link prediction based on receiver operating characteristic curves and prediction accuracies. The key genes involved in skeletal muscle atrophy are associated with metabolic and neurodegenerative diseases. The drugs selected for repurposing using the graph convolution network method were nutrients, corticosteroids, anti-inflammatory medications, and others related to insulin.
    Keywords:  diseases; drugs; gradient boosting method; graph convolutional neural networks; graph neural network; knowledge graphs; link prediction; machine learning; node embeddings; random forest; random walk; skeletal muscle atrophy
    DOI:  https://doi.org/10.3390/genes13030473
  17. Am J Physiol Regul Integr Comp Physiol. 2022 Mar 23.
    Aldehyde dehydrogenase 2 deficiency promotes skeletal muscle atrophy in aged mice.
    Akane Kasai, Eunbin Jee, Yuki Tamura, Karina Kouzaki, Takaya Kotani, Koichi Nakazato.
      Aldehyde dehydrogenase 2 (ALDH2) detoxifies acetaldehyde produced from ethanol. A missense single nucleotide polymorphism (SNP) rs671 in ALDH2 exhibits a dominant-negative form of the ALDH2 protein. Nearly 40% of people in East Asia carry an inactive ALDH2*2 mutation. Previous studies reported that ALDH2*2 is associated with increased risk of several diseases. In this study, we examined the effect of ALDH2 deficiency on age-related muscle atrophy and its underlying mechanisms. We found that ALDH2 deficiency promotes age-related loss of muscle fiber cross-sectional areas, especially in oxidative fibers. Furthermore, ALDH2 deficiency exacerbated age-related accumulation of 4-hydroxy-2-nonenal (4-HNE), a marker of oxidative stress in the gastrocnemius muscle. Similarly, mitochondrial reactive oxygen species (ROS) production increased in aged ALDH2-knockout mice, indicating that ALDH2 deficiency induced mitochondrial dysfunction. In summary, ALDH2 deficiency promotes age-related muscle loss, especially in oxidative fibers, which may be associated with an increased accumulation of oxidative stress via mitochondrial dysfunction.
    Keywords:  aging; aldehyde dehydrogenase 2; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpregu.00304.2021
  18. Function (Oxf). 2021 ;2(5): zqab047
    Skeletal Muscle Possesses an Epigenetic Memory of Exercise: Role of Nucleus Type-Specific DNA Methylation.
    Adam P Sharples.
      
    DOI:  https://doi.org/10.1093/function/zqab047
  19. Cells. 2022 Mar 11. pii: 963. [Epub ahead of print]11(6):
    Anabolic Factors and Myokines Improve Differentiation of Human Embryonic Stem Cell Derived Skeletal Muscle Cells.
    Travis Ruan, Dylan Harney, Yen Chin Koay, Lipin Loo, Mark Larance, Leslie Caron.
      Skeletal muscle weakness is linked to many adverse health outcomes. Current research to identify new drugs has often been inconclusive due to lack of adequate cellular models. We previously developed a scalable monolayer system to differentiate human embryonic stem cells (hESCs) into mature skeletal muscle cells (SkMCs) within 26 days without cell sorting or genetic manipulation. Here, building on our previous work, we show that differentiation and fusion of myotubes can be further enhanced using the anabolic factors testosterone (T) and follistatin (F) in combination with a cocktail of myokines (C). Importantly, combined TFC treatment significantly enhanced both the hESC-SkMC fusion index and the expression levels of various skeletal muscle markers, including the motor protein myosin heavy chain (MyHC). Transcriptomic and proteomic analysis revealed oxidative phosphorylation as the most up-regulated pathway, and a significantly higher level of ATP and increased mitochondrial mass were also observed in TFC-treated hESC-SkMCs, suggesting enhanced energy metabolism is coupled with improved muscle differentiation. This cellular model will be a powerful tool for studying in vitro myogenesis and for drug discovery pertaining to further enhancing muscle development or treating muscle diseases.
    Keywords:  human embryonic stem cell; myokines; myosin heavy chain; myotubes; skeletal muscle
    DOI:  https://doi.org/10.3390/cells11060963
  20. Development. 2022 Apr 15. pii: dev200112. [Epub ahead of print]149(8):
    Elevated numbers of infiltrating eosinophils accelerate the progression of Duchenne muscular dystrophy pathology in mdx mice.
    Marine Theret, Lucas Rempel, Joshua Hashimoto, Morten Ritso, Lin Wei Tung, Fang Fang Li, Melina Messing, Michael Hughes, Kelly McNagny, Fabio Rossi.
      Eosinophils, best known for their role in anti-parasitic responses, have recently been shown to actively participate in tissue homeostasis and repair. Their regulation must be tightly controlled, as their absence or hyperplasia is associated with chronic disease (e.g. asthma or inflammatory bowel disease). In the context of skeletal muscle, eosinophils play a supportive role after acute damage. Indeed, their depletion leads to strong defects in skeletal muscle regeneration and, in the absence of eosinophil-secreted interleukin (IL) 4 and IL13, fibro-adipogenic progenitors fail to support muscle stem cell proliferation. However, the role of eosinophils in muscular dystrophy remains elusive. Although it has been shown that eosinophils are present in higher numbers in muscles from mdx mice (a mouse model for Duchenne muscular dystrophy), their depletion does not affect muscle histopathology at an early age. Here, we evaluated the impact of hyper-eosinophilia on the development of fibrofatty infiltration in aged mdx mice and found that muscle eosinophilia leads to defects in muscle homeostasis, regeneration and repair, and eventually hastens death.
    Keywords:  Eosinophil; Fibrosis; Inflammation; Mouse; Muscular dystrophy; Regeneration; Repair
    DOI:  https://doi.org/10.1242/dev.200112
  21. Methods Mol Biol. 2022 ;2442 663-683
    Evaluating Therapeutic Activity of Galectin-1 in Sarcolemma Repair of Skeletal Muscle.
    Mary L Vallecillo-Zúniga, Matthew Rathgeber, Daniel Poulson, Braden Kartchner, Jacob Luddington, Hailie Gill, Spencer Hayes, Matthew Teynor, Caleb S Stowell, Connie M Arthur, Sean R Stowell, Pam M Van Ry.
      Galectin-1 is a small (14.5 kDa) multifunctional protein with cell-cell and cell-ECM adhesion due to interactions with the carbohydrate recognition domain (CRD). In two types of muscular dystrophies, this lectin protein has shown therapeutic properties, including positive regulation of skeletal muscle differentiation and regeneration. Both Duchenne and limb-girdle muscular dystrophy 2B (LGMD2B) are subtypes of muscular dystrophies characterized by deficient membrane repair, muscle weakness, and eventual loss of ambulation. This chapter explains confocal techniques such as laser injury, calcium imaging, and galectin-1 localization to examine the effects of galectin-1 on membrane repair in injured LGMD2B models.
    Keywords:  Galectin-1; LGMD2B; Localization; Membrane repair; Muscular dystrophy; Protein labeling; Sarcolemma
    DOI:  https://doi.org/10.1007/978-1-0716-2055-7_36
  22. Toxics. 2022 Mar 14. pii: 140. [Epub ahead of print]10(3):
    NMR Spectroscopy Identifies Chemicals in Cigarette Smoke Condensate That Impair Skeletal Muscle Mitochondrial Function.
    Ram B Khattri, Trace Thome, Liam F Fitzgerald, Stephanie E Wohlgemuth, Russell T Hepple, Terence E Ryan.
      Tobacco smoke-related diseases such as chronic obstructive pulmonary disease (COPD) are associated with high healthcare burden and mortality rates. Many COPD patients were reported to have muscle atrophy and weakness, with several studies suggesting intrinsic muscle mitochondrial impairment as a possible driver of this phenotype. Whereas much information has been learned about muscle pathology once a patient has COPD, little is known about how active tobacco smoking might impact skeletal muscle physiology or mitochondrial health. In this study, we examined the acute effects of cigarette smoke condensate (CSC) on muscle mitochondrial function and hypothesized that toxic chemicals present in CSC would impair mitochondrial respiratory function. Consistent with this hypothesis, we found that acute exposure of muscle mitochondria to CSC caused a dose-dependent decrease in skeletal muscle mitochondrial respiratory capacity. Next, we applied an analytical nuclear magnetic resonance (NMR)-based approach to identify 49 water-soluble and 12 lipid-soluble chemicals with high abundance in CSC. By using a chemical screening approach in the Seahorse XF96 analyzer, several CSC-chemicals, including nicotine, o-Cresol, phenylacetate, and decanoic acid, were found to impair ADP-stimulated respiration in murine muscle mitochondrial isolates significantly. Further to this, several chemicals, including nicotine, o-Cresol, quinoline, propylene glycol, myo-inositol, nitrosodimethylamine, niacinamide, decanoic acid, acrylonitrile, 2-naphthylamine, and arsenic acid, were found to significantly decrease the acceptor control ratio, an index of mitochondrial coupling efficiency.
    Keywords:  bioenergetics; chronic obstructive pulmonary disease; cigarette smoke extract; mitochondria; skeletal muscle; smoking; tobacco
    DOI:  https://doi.org/10.3390/toxics10030140
  23. Antioxidants (Basel). 2022 Mar 07. pii: 510. [Epub ahead of print]11(3):
    Apoptosis-Inducing Factor Deficiency Induces Tissue-Specific Alterations in Autophagy: Insights from a Preclinical Model of Mitochondrial Disease and Exercise Training Effects.
    Sara Laine-Menéndez, Miguel Fernández-de la Torre, Carmen Fiuza-Luces, Aitor Delmiro, Joaquín Arenas, Miguel Ángel Martín, Patricia Boya, Alejandro Lucia, María Morán.
      We analyzed the effects of apoptosis-inducing factor (AIF) deficiency, as well as those of an exercise training intervention on autophagy across tissues (heart, skeletal muscle, cerebellum and brain), that are primarily affected by mitochondrial diseases, using a preclinical model of these conditions, the Harlequin (Hq) mouse. Autophagy markers were analyzed in: (i) 2, 3 and 6 month-old male wild-type (WT) and Hq mice, and (ii) WT and Hq male mice that were allocated to an exercise training or sedentary group. The exercise training started upon onset of the first symptoms of ataxia in Hq mice and lasted for 8 weeks. Higher content of autophagy markers and free amino acids, and lower levels of sarcomeric proteins were found in the skeletal muscle and heart of Hq mice, suggesting increased protein catabolism. Leupeptin-treatment demonstrated normal autophagic flux in the Hq heart and the absence of mitophagy. In the cerebellum and brain, a lower abundance of Beclin 1 and ATG16L was detected, whereas higher levels of the autophagy substrate p62 and LAMP1 levels were observed in the cerebellum. The exercise intervention did not counteract the autophagy alterations found in any of the analyzed tissues. In conclusion, AIF deficiency induces tissue-specific alteration of autophagy in the Hq mouse, with accumulation of autophagy markers and free amino acids in the heart and skeletal muscle, but lower levels of autophagy-related proteins in the cerebellum and brain. Exercise intervention, at least if starting when muscle atrophy and neurological symptoms are already present, is not sufficient to mitigate autophagy perturbations.
    Keywords:  Harlequin; OXPHOS; autophagy; brain; cerebellum; heart; mitochondrial diseases; skeletal muscle
    DOI:  https://doi.org/10.3390/antiox11030510
  24. Biomedicines. 2022 Feb 24. pii: 535. [Epub ahead of print]10(3):
    A Spotlight on T Lymphocytes in Duchenne Muscular Dystrophy-Not Just a Muscle Defect.
    Chantal A Coles, Ian Woodcock, Daniel G Pellicci, Peter J Houweling.
      The lack of dystrophin in Duchenne muscular dystrophy (DMD) results in membrane fragility resulting in contraction-induced muscle damage and subsequent inflammation. The impact of inflammation is profound, resulting in fibrosis of skeletal muscle, the diaphragm and heart, which contributes to muscle weakness, reduced quality of life and premature death. To date, the innate immune system has been the major focus in individuals with DMD, and our understanding of the adaptive immune system, specifically T cells, is limited. Targeting the immune system has been the focus of multiple clinical trials for DMD and is considered a vital step in the development of better treatments. However, we must first have a complete picture of the involvement of the immune systems in dystrophic muscle disease to better understand how inflammation influences disease progression and severity. This review focuses on the role of T cells in DMD, highlighting the importance of looking beyond skeletal muscle when considering how the loss of dystrophin impacts disease progression. Finally, we propose that targeting T cells is a potential novel therapeutic in the treatment of DMD.
    Keywords:  T cells; Tregs; duchenne muscular dystrophy; dystrophic thymus; inflammation
    DOI:  https://doi.org/10.3390/biomedicines10030535
  25. J Obes Metab Syndr. 2022 Mar 23.
    Assessment of Muscle Quantity, Quality and Function.
    Bo Kyung Koo.
      Sarcopenia is a syndrome characterized by loss of skeletal muscle mass and strength that can increase the risk of physical disability, chronic conditions such as diabetes mellitus and cardiovascular diseases, and long-term mortality. Sarcopenia adversely affects not only the elderly population, but also young adults. This review provides updated definitions of sarcopenia and recommendations for the assessment of muscle quantity and quality.
    Keywords:  Guidelines; Muscle strength; Muscle weakness; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.7570/jomes22025
  26. Neuropathol Appl Neurobiol. 2022 Mar 26. e12816
    Activating ATF6 in Spinal Muscular Atrophy promotes SMN expression and motor neuron survival through the IRE1α-XBP1 pathway.
    Domenico D'Amico, Olivier Biondi, Camille Januel, Cynthia Bezier, Delphine Sapaly, Zoé Clerc, Mirella El Khoury, Venkat Krishnan Sundaram, Léo Houdebine, Thibaut Josse, Bruno Della Gaspera, Cécile Martinat, Charbel Massaad, Laure Weill, Frédéric Charbonnier.
      AIM: Spinal Muscular Atrophy (SMA) is a neuromuscular disease caused by Survival of Motor Neuron (SMN) deficiency that induces motor neuron (MN) degeneration and severe muscular atrophy. Gene therapies that increase SMN have proven their efficacy but not for all patients. Here, we explored the Unfolded Protein Response (UPR) status in SMA pathology and explored whether UPR modulation could be beneficial for SMA patients.METHODS: We analysed the expression and activation of key UPR proteins by RT-qPCR and by western blots in SMA patient iPSC-derived MNs and one SMA cell line in which SMN expression was re-established (rescue). We complemented this approach by using myoblast and fibroblast SMA patient cells and SMA mouse models of varying severities. Finally, we tested in vitro and in vivo the effect of IRE1α/XBP1 pathway restoration on SMN expression and subsequent neuroprotection.
    RESULTS: We report that the IRE1α/XBP1 branch of the unfolded protein response is disrupted in SMA, with a depletion of XBP1s irrespective of IRE1α activation pattern. The overexpression of XBP1s in SMA fibroblasts proved to transcriptionally enhance SMN expression. Importantly, rebalancing XBP1s expression in severe SMA-like mice, induced SMN expression and spinal MN protection.
    CONCLUSIONS: We have identified XBP1s depletion as a contributing factor in SMA pathogenesis, and the modulation of this transcription factor proves to be a plausible therapeutic avenue in the context of pharmacological interventions for patients.
    Keywords:  IRE1α; Neuroprotection; SMN; Spinal Muscular Atrophy; Unfolded Protein Response; XBP1
    DOI:  https://doi.org/10.1111/nan.12816
  27. Front Cell Dev Biol. 2022 ;10 822563
    Targeting the Ubiquitin-Proteasome System in Limb-Girdle Muscular Dystrophy With CAPN3 Mutations.
    Jaione Lasa-Elgarresta, Laura Mosqueira-Martín, Klaudia González-Imaz, Pablo Marco-Moreno, Gorka Gerenu, Kamel Mamchaoui, Vincent Mouly, Adolfo López de Munain, Ainara Vallejo-Illarramendi.
      LGMDR1 is caused by mutations in the CAPN3 gene that encodes calpain 3 (CAPN3), a non-lysosomal cysteine protease necessary for proper muscle function. Our previous findings show that CAPN3 deficiency leads to reduced SERCA levels through increased protein degradation. This work investigates the potential contribution of the ubiquitin-proteasome pathway to increased SERCA degradation in LGMDR1. Consistent with our previous results, we observed that CAPN3-deficient human myotubes exhibit reduced SERCA protein levels and high cytosolic calcium concentration. Treatment with the proteasome inhibitor bortezomib (Velcade) increased SERCA2 protein levels and normalized intracellular calcium levels in CAPN3-deficient myotubes. Moreover, bortezomib was able to recover mutated CAPN3 protein in a patient carrying R289W and R546L missense mutations. We found that CAPN3 knockout mice (C3KO) presented SERCA deficits in skeletal muscle in the early stages of the disease, prior to the manifestation of muscle deficits. However, treatment with bortezomib (0.8 mg/kg every 72 h) for 3 weeks did not rescue SERCA levels. No change in muscle proteasome activity was observed in bortezomib-treated animals, suggesting that higher bortezomib doses are needed to rescue SERCA levels in this model. Overall, our results lay the foundation for exploring inhibition of the ubiquitin-proteasome as a new therapeutic target to treat LGMDR1 patients. Moreover, patients carrying missense mutations in CAPN3 and presumably other genes may benefit from proteasome inhibition by rescuing mutant protein levels. Further studies in suitable models will be necessary to demonstrate the therapeutic efficacy of proteasome inhibition for different missense mutations.
    Keywords:  LGMD2A; SERCA1; SERCA2; bortezomib (BTZ); calcium; calpain 3 (CAPN3); muscular dystrophies
    DOI:  https://doi.org/10.3389/fcell.2022.822563
  28. Metabolites. 2022 Mar 17. pii: 259. [Epub ahead of print]12(3):
    Skeletal Muscle Uncoupling Proteins in Mice Models of Obesity.
    Lidija Križančić Bombek, Maša Čater.
      Obesity and accompanying type 2 diabetes are among major and increasing worldwide problems that occur fundamentally due to excessive energy intake during its expenditure. Endotherms continuously consume a certain amount of energy to maintain core body temperature via thermogenic processes, mainly in brown adipose tissue and skeletal muscle. Skeletal muscle glucose utilization and heat production are significant and directly linked to body glucose homeostasis at rest, and especially during physical activity. However, this glucose balance is impaired in diabetic and obese states in humans and mice, and manifests as glucose resistance and altered muscle cell metabolism. Uncoupling proteins have a significant role in converting electrochemical energy into thermal energy without ATP generation. Different homologs of uncoupling proteins were identified, and their roles were linked to antioxidative activity and boosting glucose and lipid metabolism. From this perspective, uncoupling proteins were studied in correlation to the pathogenesis of diabetes and obesity and their possible treatments. Mice were extensively used as model organisms to study the physiology and pathophysiology of energy homeostasis. However, we should be aware of interstrain differences in mice models of obesity regarding thermogenesis and insulin resistance in skeletal muscles. Therefore, in this review, we gathered up-to-date knowledge on skeletal muscle uncoupling proteins and their effect on insulin sensitivity in mouse models of obesity and diabetes.
    Keywords:  diabetes; insulin; obesity; skeletal muscle; uncoupling protein
    DOI:  https://doi.org/10.3390/metabo12030259
  29. Biology (Basel). 2022 Mar 16. pii: 446. [Epub ahead of print]11(3):
    Transcription Regulation of Tceal7 by the Triple Complex of Mef2c, Creb1 and Myod.
    Zhenzhen Xiong, Mengni Wang, Shanshan You, Xiaoyan Chen, Jiangguo Lin, Jianhua Wu, Xiaozhong Shi.
      Tceal7 has been identified as a direct, downstream target gene of MRF in the skeletal muscle. The overexpression of Tceal7 represses myogenic proliferation and promotes cell differentiation. Previous studies have defined the 0.7 kb upstream fragment of the Tceal7 gene. In the present study, we have further determined two clusters of transcription factor-binding motifs in the 0.7 kb promoter: CRE#2-E#1-CRE#1 in the proximal region and Mef2#3-CRE#3-E#4 in the distal region. Utilizing transcription assays, we have also shown that the reporter containing the Mef2#3-CRE#3-E#4 motifs is synergistically transactivated by Mef2c and Creb1. Further studies have mapped out the protein-protein interaction between Mef2c and Creb1. In summary, our present studies support the notion that the triple complex of Mef2c, Creb1 and Myod interacts with the Mef2#3-CRE#3-E#4 motifs in the distal region of the Tceal7 promoter, thereby driving Tceal7 expression during skeletal muscle development and regeneration.
    Keywords:  Creb1; Mef2c; Myod; Tceal7; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.3390/biology11030446
  30. Function (Oxf). 2021 ;2(6): zqab057
    Can the Energetic Profile of Skeletal Muscle Predict Risk of Cognitive Impairment?
    Espen E Spangenburg.
      
    DOI:  https://doi.org/10.1093/function/zqab057
  31. Am J Sports Med. 2022 Mar 22. 3635465221083995
    Stretch-Induced Healing of Injured Muscles Is Associated With Myogenesis and Decreased Fibrosis.
    Ching-Fang Hu, Carl Pai-Chu Chen, Po-Hsiang Tsui, Chiao-Nan Chen, Chih-Chin Hsu.
      BACKGROUND: Alghouth therapeutic stretching exercise has been applied to accelerate the healing of injured skeletal muscles, mechanisms behind the mechanical stretch-induced muscle recovery remain unclear.PURPOSE: To examine stretch-associated antifibrotic and myogenic responses in injured muscles and to evaluate the feasibility of the ultrasonic Nakagami parametric index (NPI) in assessing muscle morphology during recovery.
    STUDY DESIGN: Controlled laboratory study.
    METHODS: Skeletal muscle fibrosis was induced in the right hind legs of 48 rats by making a posterior transverse incision in the gastrocnemius muscle; the left hind legs remained intact as a comparative normal reference. After surgery, the 48 rats were randomly divided into the stretch (S) and control (C) groups. The S group received stretching interventions on the injured hind leg from week 3 to week 7 after surgery, while the C group did not receive stretching throughout the study period. The muscle fibrosis percentage and the ultrasonic NPI were examined sequentially after surgery. Relative expressions of myogenesis-related proteins, including myoblast determination protein 1 (MyoD), myogenin, and embryonic myosin heavy chain (MHCemb), were also evaluated during the follow-up.
    RESULTS: Mean fibrosis percentages in the injured hind leg were approximately 25% at week 3 in both groups, but they were significantly decreased by approximately 20% from week 4 to the end of the follow-up in the S group only (all, P < .05). Upon injury, the NPI values of injured hind legs in both groups dramatically dropped. Within the S group, stretching increased the NPI values of injured hind legs, which approached those of control hind legs at weeks 6 and 7. The highest MyoD, myogenin, and MHCemb levels were observed at week 6 in both groups. The NPI values corresponded to the MyoD expression in the S group during the follow-up.
    CONCLUSION: Stretching induced a decrease in muscle fibrosis and an increase in myogenesis in injured muscles. The NPI values correspond to the myogenesis process.
    CLINICAL RELEVANCE: The NPI may be capable of continuously monitoring the injured skeletal muscle morphology during the healing process in clinical settings.
    Keywords:  Nakagami parametric index; connective tissue; muscle stretching exercise; myogenesis; skeletal muscle
    DOI:  https://doi.org/10.1177/03635465221083995
  32. J Cachexia Sarcopenia Muscle. 2022 Mar 20.
    Skeletal muscle mitoribosomal defects are linked to low bone mass caused by bone marrow inflammation in male mice.
    Jingwen Tian, Hyo Kyun Chung, Ji Sun Moon, Ha Thi Nga, Ho Yeop Lee, Jung Tae Kim, Joon Young Chang, Seul Gi Kang, Dongryeol Ryu, Xiangguo Che, Je-Yong Choi, Masayuki Tsukasaki, Takayoshi Sasako, Sang-Hee Lee, Minho Shong, Hyon-Seung Yi.
      BACKGROUND: Mitochondrial oxidative phosphorylation (OxPhos) is a critical regulator of skeletal muscle mass and function. Although muscle atrophy due to mitochondrial dysfunction is closely associated with bone loss, the biological characteristics of the relationship between muscle and bone remain obscure. We showed that muscle atrophy caused by skeletal muscle-specific CR6-interacting factor 1 knockout (MKO) modulates the bone marrow (BM) inflammatory response, leading to low bone mass.METHODS: MKO mice with lower muscle OxPhos were fed a normal chow or high-fat diet and then evaluated for muscle mass and function, and bone mineral density. Immunophenotyping of BM immune cells was also performed. BM transcriptomic analysis was used to identify key factors regulating bone mass in MKO mice. To determine the effects of BM-derived CXCL12 (C-X-C motif chemokine ligand 12) on regulation of bone homeostasis, a variety of BM niche-resident cells were treated with recombinant CXCL12. Vastus lateralis muscle and BM immune cell samples from 14 patients with hip fracture were investigated to examine the association between muscle function and BM inflammation.
    RESULTS: MKO mice exhibited significant reductions in both muscle mass and expression of OxPhos subunits but increased transcription of mitochondrial stress response-related genes in the extensor digitorum longus (P < 0.01). MKO mice showed a decline in grip strength and a higher drop rate in the wire hanging test (P < 0.01). Micro-computed tomography and von Kossa staining revealed that MKO mice developed a low mass phenotype in cortical and trabecular bone (P < 0.01). Transcriptomic analysis of the BM revealed that mitochondrial stress responses in skeletal muscles induce an inflammatory response and adipogenesis in the BM and that the CXCL12-CXCR4 (C-X-C chemokine receptor 4) axis is important for T-cell homing to the BM. Antagonism of CXCR4 attenuated BM inflammation and increased bone mass in MKO mice. In humans, patients with low body mass index (BMI = 17.2 ± 0.42 kg/m2 ) harboured a larger population of proinflammatory and cytotoxic senescent T-cells in the BMI (P < 0.05) and showed reduced expression of OxPhos subunits in the vastus lateralis, compared with controls with a normal BMI (23.7 ± 0.88 kg/m2 ) (P < 0.01).
    CONCLUSIONS: Defects in muscle mitochondrial OxPhos promote BM inflammation in mice, leading to decreased bone mass. Muscle mitochondrial dysfunction is linked to BM inflammatory cytokine secretion via the CXCL12-CXCR4 signalling axis, which is critical for inducing low bone mass.
    Keywords:  Bone loss; Bone marrow; Inflammation; Mitochondria
    DOI:  https://doi.org/10.1002/jcsm.12975
  33. Function (Oxf). 2021 ;2(1): zqaa040
    Expanding Roles for Muscle Satellite Cells in Exercise-Induced Hypertrophy.
    Thomas J Hawke.
      
    DOI:  https://doi.org/10.1093/function/zqaa040
  34. Int J Mol Sci. 2022 Mar 10. pii: 3004. [Epub ahead of print]23(6):
    Cancer-Related Cachexia: The Vicious Circle between Inflammatory Cytokines, Skeletal Muscle, Lipid Metabolism and the Possible Role of Physical Training.
    Giuseppe Donato Mangano, Malak Fouani, Daniela D'Amico, Valentina Di Felice, Rosario Barone.
      Cachexia is a multifactorial and multi-organ syndrome that is a major cause of morbidity and mortality in late-stage chronic diseases. The main clinical features of cancer-related cachexia are chronic inflammation, wasting of skeletal muscle and adipose tissue, insulin resistance, anorexia, and impaired myogenesis. A multimodal treatment has been suggested to approach the multifactorial genesis of cachexia. In this context, physical exercise has been found to have a general effect on maintaining homeostasis in a healthy life, involving multiple organs and their metabolism. The purpose of this review is to present the evidence for the relationship between inflammatory cytokines, skeletal muscle, and fat metabolism and the potential role of exercise training in breaking the vicious circle of this impaired tissue cross-talk. Due to the wide-ranging effects of exercise training, from the body to the behavior and cognition of the individual, it seems to be able to improve the quality of life in this syndrome. Therefore, studying the molecular effects of physical exercise could provide important information about the interactions between organs and the systemic mediators involved in the overall homeostasis of the body.
    Keywords:  cancer-related cachexia; inflammatory cytokines; physical training; skeletal muscle
    DOI:  https://doi.org/10.3390/ijms23063004
  35. Function (Oxf). 2020 ;1(2): zqaa015
    New Insight into a Classic Stem Cell: the Satellite Cell may Communicate with the Muscle Fiber via Extracellular Vesicles-A Perspective on "Fusion-Independent Satellite Cell Communication to Muscle Fibers During Load-Induced Hypertrophy".
    Zipora Yablonka-Reuveni, Christoph Lepper.
      
    DOI:  https://doi.org/10.1093/function/zqaa015
  36. Acta Physiol (Oxf). 2022 Mar 19. e13813
    Muscle contraction and mitochondrial biogenesis - a brief historical reappraisal.
    Javier Botella, Evgeniia S Motanova, David J Bishop.
      
    DOI:  https://doi.org/10.1111/apha.13813
  37. N Engl J Med. 2022 Mar 24. 386(12): 1184-1186
    A Boost for Muscle with Gene Therapy.
    Jeffrey S Chamberlain.
      
    DOI:  https://doi.org/10.1056/NEJMcibr2118576
  38. J Sports Sci Med. 2021 Dec;20(4): 655-664
    Effects of Muscle Architecture on Eccentric Exercise Induced Muscle Damage Responses.
    Seher Çağdaş Şenışık, Bedrettin Akova, Ufuk Şekir, Hakan Gür.
      There is a need to investigate the role of muscle architecture on muscle damage responses induced by exercise. The aim of this study was to determine the effect of muscle architecture and muscle length on eccentric exercise-induced muscle damage responses. Eccentric exercise-induced muscle damage was performed randomly to the elbow flexor (EF), knee extensor (KE), and knee flexor (KF) muscle groups with two week intervals in 12 sedentary male subjects. Before and after each eccentric exercise (immediately after, on the 1st, 2nd, 3rd, and 7th days) range of motion, delayed onset muscle soreness, creatine kinase activity, myoglobin concentration and isometric peak torque in short and long muscle positions were evaluated. Furthermore, muscle volume and pennation angle of each muscle group was evaluated before initiating the eccentric exercise protocol. Pennation angle and muscle volume was significantly higher and the workload per unit muscle volume was significantly lower in the KE muscles compared with the KF and EF muscles (p < 0.01). EF muscles showed significantly higher pain levels at post-exercise days 1 and 3 compared with the KE (p < 0.01-0.001) and KF (p < 0.01) muscles. The deficits in range of motion were higher in the EF muscles compared to the KE and KF muscles immediately after (day 0, p < 0.01), day 1 (p < 0.05-0.01), and day 3 (p < 0.05) evaluations. The EF muscles represented significantly greater increases in CK and Mb levels at day 1, 3, and 7 than the KE muscles (p < 0.05-0.01). The CK and Mb levels were also significantly higher in the KF muscles compared with the KE muscles (p < 0.05, p < 0.01 respectively). The KF and EF muscles represented higher isometric peak torque deficits in all the post-exercise evaluations at muscle short position (p < 0.05-0.001) compared with the KE muscle after eccentric exercise. Isometric peak torque deficits in muscle lengthened position was significantly higher in EF in all the post-exercise evaluations compared with the KE muscle (p < 0.05-0.01). According to the results of this study it can be concluded that muscle structural differences may be one of the responsible factors for the different muscle damage responses following eccentric exercise in various muscle groups.
    Keywords:  Muscle damage; biceps brachii muscle; eccentric exercise; hamstring muscle; pennation angle; quadriceps muscle
    DOI:  https://doi.org/10.52082/jssm.2021.655
  39. Healthcare (Basel). 2022 Mar 19. pii: 573. [Epub ahead of print]10(3):
    VLCKD in Combination with Physical Exercise Preserves Skeletal Muscle Mass in Sarcopenic Obesity after Severe COVID-19 Disease: A Case Report.
    Elisabetta Camajani, Alessandra Feraco, Sabrina Basciani, Lucio Gnessi, Luigi Barrea, Andrea Armani, Massimiliano Caprio.
      The prevalence of sarcopenic obesity is increasing worldwide, with a strong impact on public health and the national health care system. Sarcopenic obesity consists of fat depot expansion and associated systemic low-grade inflammation, exacerbating the decline in skeletal muscle mass and strength. Dietary approach and physical exercise represent essential tools for reducing body weight and preserving muscle mass and function in subjects with sarcopenic obesity. This case report describes the effects of a dietary intervention, based on a Very-Low-Calorie Ketogenic Diet (VLCKD) combined with physical exercise, on body composition, cardiometabolic risk factors, and muscle strength in a woman with sarcopenic obesity, two weeks after hospitalization for bilateral interstitial pneumonia due to COVID-19. To our knowledge, this is the first case report to describe the efficacy of a combined approach intervention including VLCKD along with physical exercise, in reducing fat mass, improving metabolic profile, and preserving skeletal muscle performance in a patient with obesity, soon after severe COVID-19 disease.
    Keywords:  SARS-CoV-2; ketogenic diet; ketone bodies; obesity; physical training; sarcopenia
    DOI:  https://doi.org/10.3390/healthcare10030573
  40. Int J Mol Sci. 2022 Mar 17. pii: 3232. [Epub ahead of print]23(6):
    The Role of MicroRNAs in Proteostasis Decline and Protein Aggregation during Brain and Skeletal Muscle Aging.
    Stephany Francisco, Vera Martinho, Margarida Ferreira, Andreia Reis, Gabriela Moura, Ana Raquel Soares, Manuel A S Santos.
      Aging can be defined as the progressive deterioration of cellular, tissue, and organismal function over time. Alterations in protein homeostasis, also known as proteostasis, are a hallmark of aging that lead to proteome imbalances and protein aggregation, phenomena that also occur in age-related diseases. Among the various proteostasis regulators, microRNAs (miRNAs) have been reported to play important roles in the post-transcriptional control of genes involved in maintaining proteostasis during the lifespan in several organismal tissues. In this review, we consolidate recently published reports that demonstrate how miRNAs regulate fundamental proteostasis-related processes relevant to tissue aging, with emphasis on the two most studied tissues, brain tissue and skeletal muscle. We also explore an emerging perspective on the role of miRNA regulatory networks in age-related protein aggregation, a known hallmark of aging and age-related diseases, to elucidate potential miRNA candidates for anti-aging diagnostic and therapeutic targets.
    Keywords:  age-related protein aggregation; mammalian tissue aging; miRNA; proteostasis network
    DOI:  https://doi.org/10.3390/ijms23063232
  41. Stem Cell Rev Rep. 2022 Mar 22.
    Physical Activity Modulates miRNAs Levels and Enhances MYOD Expression in Myoblasts.
    Luca Dalle Carbonare, Gianluigi Dorelli, Veronica Li Vigni, Arianna Minoia, Jessica Bertacco, Samuele Cheri, Michela Deiana, Giulio Innamorati, Mattia Cominacini, Cantor Tarperi, Federico Schena, Monica Mottes, Maria Teresa Valenti.
      Stem cells functions are regulated by different factors and non-conding RNAs, such as microRNA. MiRNAsplay an important role in modulating the expression of genes involved in the commitment and differentiation of progenitor cells. MiRNAs are post transcriptional regulators which may be modulated by physical exercise. MiRNAs, by regulating different signaling pathways, play an important role in myogenesis as well as in muscle activity. MiRNAs quantification may be considered for evaluating physical performance or muscle recovery. With the aim to identify specific miRNAs potentially involved in myogenesis and modulated by physical activity, we investigated miRNAs expression following physical performance in Peripheral Blood Mononuclear Cells (PBMCs) and in sera of half marathon (HM) runnners. The effect of runners sera on Myogenesis in in vitro cellular models was also explored. Therefore, we performed Microarray Analysis and Real Time PCR assays, as well as in vitro cell cultures analysis to investigate myogenic differentiation. Our data demonstrated gender-specific expression patterns of PBMC miRNAs before physical performance. In particular, miR223-3p, miR26b-5p, miR150-5p and miR15-5p expression was higher, while miR7a-5p and miR7i-5p expression was lower in females compared to males. After HM, miR152-3p, miR143-3p, miR27a-3p levels increased while miR30b-3p decreased in both females and males: circulating miRNAs mirrored these modulations. Furthermore, we also observed that the addition of post-HM participants sera to cell cultures exerted a positive effect in stimulating myogenesis. In conclusion, our data suggest that physical activity induces the modulation of myogenesis-associated miRNAs in bothfemales and males, despite the gender-associated different expression of certain miRNAs, Noteworthy, these findings might be useful for evaluating potential targets for microRNA based-therapies in diseases affecting the myogenic stem cells population.
    Keywords:  Half Marathon; MYOD; MicroRNAs; Myogenesis
    DOI:  https://doi.org/10.1007/s12015-022-10361-9
  42. Int J Mol Sci. 2022 Mar 10. pii: 3006. [Epub ahead of print]23(6):
    Development and Regeneration of Muscle, Tendon, and Myotendinous Junctions in Striated Skeletal Muscle.
    Masahito Yamamoto, Koji Sakiyama, Kei Kitamura, Yutaro Yamamoto, Takahiro Takagi, Sayo Sekiya, Genji Watanabe, Shuichiro Taniguchi, Yudai Ogawa, Satoshi Ishizuka, Yuki Sugiyama, Takeshi Takayama, Katsuhiko Hayashi, Wei-Jen Chang, Shinichi Abe.
      Owing to a rapid increase in aging population in recent years, the deterioration of motor function in older adults has become an important social problem, and several studies have aimed to investigate the mechanisms underlying muscle function decline. Furthermore, structural maintenance of the muscle-tendon-bone complexes in the muscle attachment sites is important for motor function, particularly for joints; however, the development and regeneration of these complexes have not been studied thoroughly and require further elucidation. Recent studies have provided insights into the roles of mesenchymal progenitors in the development and regeneration of muscles and myotendinous junctions. In particular, studies on muscles and myotendinous junctions have-through the use of the recently developed scRNA-seq-reported the presence of syncytia, thereby suggesting that fibroblasts may be transformed into myoblasts in a BMP-dependent manner. In addition, the high mobility group box 1-a DNA-binding protein found in nuclei-is reportedly involved in muscle regeneration. Furthermore, studies have identified several factors required for the formation of locomotor apparatuses, e.g., tenomodulin (Tnmd) and mohawk (Mkx), which are essential for tendon maturation.
    Keywords:  HMGB1 protein; myoblasts; single-cell analysis; skeletal muscle; small cytoplasmic RNA; staphylococcal protein A
    DOI:  https://doi.org/10.3390/ijms23063006
  43. Biochem Biophys Rep. 2022 Jul;30 101251
    Differential expression profiles of miRNA in the serum of sarcopenic rats.
    Wonjong Yu, Min-Kyu Yang, Dong Jun Sung, Tae Jun Park, Myungchul Kim, Eustache Ntigura, Sung Hea Kim, Bokyung Kim, Sang Woong Park, Young Min Bae.
      As the geriatric population and life expectancy increase, the interest in preventing geriatric diseases, such as sarcopenia, is increasing. However, the causes of sarcopenia are unclear, and current diagnostic methods for sarcopenia are unreliable. We hypothesized that the changes in the expression of certain miRNAs may be associated with the pathophysiology of sarcopenia. Herein, we analyzed the miRNA expression profiles in the blood of young (3-months-old) healthy rats, old sarcopenic (17-months-old) rats, and age-matched (17-months-old) control rats. The changes in miRNA expression levels were analyzed using Bowtie 2 software. A total of 523 miRNAs were detected in the rat serum. Using scatter plots and clustering heatmap data, we found 130 miRNAs that were differentially expressed in sarcopenic rats (>2-fold change) compared to the expression in young healthy and age-matched control rats. With a threshold of >5-fold change, we identified 14 upregulated miRNAs, including rno-miR-133b-3p, rno-miR-133a-3p, rno-miR-133c, rno-miR-208a-3p, and rno-miR434-5p among others in the serum of sarcopenic rats. A protein network map based on these 14 miRNAs identified the genes involved in skeletal muscle differentiation, among which Notch1, Egr2, and Myocd represented major nodes. The data obtained in this study are potentially useful for the early diagnosis of sarcopenia and for the identification of novel therapeutic targets for the treatment and/or prevention of sarcopenia.
    Keywords:  Aging; Diagnostics; Next-generation sequencing; Sarcopenia; Skeletal muscle; microRNA
    DOI:  https://doi.org/10.1016/j.bbrep.2022.101251
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