bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2021‒02‒14
forty-four papers selected by
Anna Vainshtein
Craft Science Inc.
  1. Exosomal microRNAs in cancer-related sarcopenia: Tumor-derived exosomal microRNAs in muscle atrophy.
  2. Relationship between Muscle Mass and Non-Alcoholic Fatty Liver Disease.
  3. ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy.
  4. Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.
  5. MOTS-c reduces myostatin and muscle atrophy signaling.
  6. Contextualizing the biological relevance of standardized high-resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle.
  7. Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load.
  8. Autophagy-dependent regulation of skeletal muscle regeneration and strength by a RHOGEF.
  9. Mitochondria-Cytokine Crosstalk Following Skeletal Muscle Injury and Disuse: A Mini-Review.
  10. Melatonin role in skeletal muscle disorders.
  11. Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy.
  12. Skeletal muscle mitochondria in health and disease.
  13. Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin-deficient mdx mice and humans.
  14. Lnc-ORA interacts with microRNA-532-3p and IGF2BP2 to inhibit skeletal muscle myogenesis.
  15. Evenness of dietary protein distribution is associated with higher muscle mass but not muscle strength or protein turnover in healthy adults: a systematic review.
  16. Vitamin D Restores Skeletal Muscle Cell Remodeling and Myogenic Program: Potential Impact on Human Health.
  17. Nuclear Mechanotransduction in Skeletal Muscle.
  18. Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.
  19. Towards stem cell therapies for skeletal muscle repair.
  20. Signature molecular changes in the skeletal muscle of hindlimb unloaded mice.
  21. Resveratrol Promotes Hypertrophy in Wildtype Skeletal Muscle and Reduces Muscle Necrosis and Gene Expression of Inflammatory Markers in Mdx Mice.
  22. Association between serum FGF21 level and sarcopenia in older adults.
  23. FOXP1 Interacts with MyoD to Repress its Transcription and Myoblast Conversion.
  24. Single-leg exercise training augments in vivo skeletal muscle oxidative flux and vascular content and function in adults with type 2 diabetes.
  25. Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle.
  26. Transgenic expression of SOD1 specifically in neurons of Sod1 deficient mice prevents defects in muscle mitochondrial function and calcium handling.
  27. Inhibition of mitochondrial and cytosolic calpain attenuates atrophy in myotubes co-cultured with colon carcinoma cells.
  28. MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.
  29. From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.
  30. The synthetic peptide SVVYGLR promotes cell motility of myogenic cells and facilitates differentiation in skeletal muscle regeneration.
  31. Assessing Autophagy in Muscle Stem Cells.
  32. Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation.
  33. Carbohydrate restriction following strenuous glycogen-depleting exercise does not potentiate the acute molecular response associated with mitochondrial biogenesis in human skeletal muscle.
  34. Muscle follistatin gene delivery increases muscle protein synthesis independent of periodical physical inactivity and fasting.
  35. Macrophages provide a transient muscle stem cell niche via NAMPT secretion.
  36. Purification and preservation of satellite cells from human skeletal muscle.
  37. Estradiol deficiency and skeletal muscle apoptosis: Possible contribution of microRNAs.
  38. Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle.
  39. Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype.
  40. Exercise exerts anti-inflammatory effects on muscle via the JAK-STAT pathway.
  41. Changes in Gene Expression of the MCU Complex Are Induced by Electrical Stimulation in Adult Skeletal Muscle.
  42. MEF2C shapes the microtranscriptome during differentiation of skeletal muscles.
  43. N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway.
  44. The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure.
  1. Exp Biol Med (Maywood). 2021 Feb 07. 1535370221990322
    Exosomal microRNAs in cancer-related sarcopenia: Tumor-derived exosomal microRNAs in muscle atrophy.
    Chenyuan Li, Qi Wu, Zhiyu Li, Zhong Wang, Yi Tu, Chuang Chen, Si Sun, Shengrong Sun.
      Cancer-associated sarcopenia is a complex metabolic syndrome marked by muscle mass wasting. Muscle wasting is a serious complication that is a primary contributor to cancer-related mortality. The underlying molecular mechanisms of cancer-associated sarcopenia have not been completely described to date. In general, evidence shows that the main pathophysiological alterations in sarcopenia are associated with the degradation of cellular components, an exceptional inflammatory secretome and mitochondrial dysfunction. Importantly, we highlight the prospect that several miRNAs carried by tumor-derived exosomes that have shown the ability to promote inflammatory secretion, activate catabolism, and even participate in the regulation of cellular degradation pathways can be delivered to and exert effects on muscle cells. In this review, we aim to describe the current knowledge about the functions of exosomal miRNAs in the induction of cancer-associated muscle wasting and propose potential treatment strategies.
    Keywords:  Exosome; cancer-associated sarcopenia; miRNA; muscle atrophy
    DOI:  https://doi.org/10.1177/1535370221990322
  2. Biology (Basel). 2021 Feb 05. pii: 122. [Epub ahead of print]10(2):
    Relationship between Muscle Mass and Non-Alcoholic Fatty Liver Disease.
    Jun-Hyuk Lee, Hye-Sun Lee, Byoung-Kwon Lee, Yu-Jin Kwon, Ji-Won Lee.
      Although sarcopenia is known to be a risk factor for non-alcoholic fatty liver disease (NAFLD), whether NAFLD is a risk factor for the development of sarcopenia is not clear. We investigated relationships between NAFLD and low skeletal muscle mass index (LSMI) using three different datasets. Participants were classified into LSMI and normal groups. LSMI was defined as a body mass index (BMI)-adjusted appendicular skeletal muscle mass <0.789 in men and <0.512 in women or as the sex-specific lowest quintile of BMI-adjusted total skeletal muscle mass. NAFLD was determined according to NAFLD liver fat score or abdominal ultrasonography. The NAFLD groups showed a higher hazard ratios (HRs) with 95% confidence intervals (CIs) for LSMI than the normal groups (HRs = 1.21, 95% CIs = 1.05-1.40). The LSMI groups also showed a higher HRs with 95% CIs for NAFLD than normal groups (HRs = 1.56, 95% CIs = 1.38-1.78). Participants with NAFLD had consistently less skeletal muscle mass over 12 years of follow-up. In conclusion, LSMI and NAFLD showed a relationship. Maintaining muscle mass should be emphasized in the management of NAFLD.
    Keywords:  inflammation; non-alcoholic fatty liver disease; obesity; sarcopenia; skeletal muscle mass
    DOI:  https://doi.org/10.3390/biology10020122
  3. Cell Rep. 2021 Feb 09. pii: S2211-1247(21)00044-9. [Epub ahead of print]34(6): 108731
    ARHGEF3 regulates skeletal muscle regeneration and strength through autophagy.
    Jae-Sung You, Nilmani Singh, Adriana Reyes-Ordonez, Nidhi Khanna, Zehua Bao, Huimin Zhao, Jie Chen.
      
    DOI:  https://doi.org/10.1016/j.celrep.2021.108731
  4. Mol Metab. 2021 Feb 06. pii: S2212-8778(21)00025-9. [Epub ahead of print] 101185
    Distinct roles of UVRAG and EGFR signaling in skeletal muscle homeostasis.
    Min Jeong Kim, Daniella Febbraro, Sofia Farkona, Taylor Gillmore, Joe Eun Son, Romario Regeenes, Huntley H Chang, Evan Pollock-Tahiri, Jiaqi Yang, Yoo Jin Park, Tharini Sivasubramaniyam, Soo Jung Oh, Punit Saraon, Igor Stagljar, Jonathan V Rocheleau, Chi-Chung Hui, Isabella Caniggia, Zhenyu Hao, Tak W Mak, Ana Konvalinka, Minna Woo.
      OBJECTIVE: Autophagy is a physiological self-eating process that can promote cell survival or activate cell death in eukaryotic cells. In skeletal muscle, it is important in the maintenance of muscle mass and function that is critical to sustain mobility and regulate metabolism. UV radiation resistance-associated gene (UVRAG) regulates early stages of autophagy and autophagosome maturation, while also playing a key role in endosomal trafficking. This study investigated the essential in vivo role of UVRAG in skeletal muscle biology.METHODS: To determine the role of UVRAG in skeletal muscle in vivo, we generated muscle specific UVRAG knock-out mice using the cre-loxP system driven by Myf6 promoter that is exclusively expressed in skeletal muscle. Myf6- Cre+ UVRAGfl/fl (M-UVRAG-/-) mice were compared to littermate Myf6-Cre+ UVRAG+/+ (M-UVRAG+/+) controls under basal conditions on normal chow diet. Body composition, muscle function and mitochondria morphology were assessed in muscles of WT and KO mice at 24 weeks of age.
    RESULTS: M-UVRAG-/- mice developed accelerated sarcopenia and impaired muscle function compared to M-UVRAG+/+ littermates at 24 weeks of age. Interestingly, these mice displayed improved glucose tolerance and increased energy expenditure likely related to up-regulated Fgf21, a marker of muscle dysfunction. Skeletal muscle of M-UVRAG-/- mice showed altered mitochondrial morphology with increased mitochondrial fission, as well as EGFR accumulation reflecting defects in endosomal trafficking. To determine whether increased EGFR signaling had a causal role in muscle dysfunction, mice were treated with an EGFR inhibitor, gefitinib, which partially restored markers of muscle and mitochondrial deregulation. Conversely, constitutively active EGFR transgenic expression in UVRAG deficient muscle led to further detrimental effects with non-overlapping distinct defects in muscle function, with EGFR activation affecting muscle fiber type whereas UVRAG deficiency impaired mitochondrial homeostasis.
    CONCLUSIONS: Our results show that both UVRAG and EGFR signaling are critical in the maintenance of muscle mass and function with distinct mechanisms in the differentiation pathway.
    Keywords:  EGFR; Fgf21; UVRAG; mitochondrial dynamics; skeletal muscle
    DOI:  https://doi.org/10.1016/j.molmet.2021.101185
  5. Am J Physiol Endocrinol Metab. 2021 Feb 08.
    MOTS-c reduces myostatin and muscle atrophy signaling.
    Hiroshi Kumagai, Ana Raquel Coelho, Junxiang Wan, Hemal Mehta, Kelvin Yen, Amy Huang, Hirofumi Zempo, Noriyuki Fuku, Seiji Maeda, Paulo J Oliveira, Pinchas Cohen, Su-Jeong Kim.
      Obesity and type 2 diabetes are metabolic diseases, often associated with sarcopenia and muscle dysfunction. MOTS-c, a mitochondrial-derived peptide, acts as a systemic hormone and has been implicated in metabolic homeostasis. Although MOTS-c improves insulin sensitivity in skeletal muscle, whether MOTS-c impacts muscle atrophy is not known. Myostatin is a negative regulator of skeletal muscle mass and also one of the possible mediators of insulin resistance-induced skeletal muscle wasting. Interestingly, we found that plasma MOTS-c levels are inversely correlated with myostatin levels in human subjects. We further demonstrated that MOTS-c prevents palmitic acid-induced atrophy in differentiated C2C12 myotubes, while MOTS-c administration decreased myostatin levels in plasma in diet-induced obese mice. By elevating AKT phosphorylation, MOTS-c inhibits the activity of an upstream transcription factor for myostatin and other muscle wasting genes, FOXO1. MOTS-c increases mTORC2 and inhibits PTEN activity, which modulates AKT phosphorylation. Further upstream, MOTS-c increases CK2 activity, which leads to PTEN inhibition. These results suggest that through inhibition of myostatin, MOTS-c could be a potential therapy for insulin resistance-induced skeletal muscle atrophy as well as other muscle wasting phenotypes including sarcopenia.
    Keywords:  FOXO1; MOTS-c; high-fat-diet; muscle atrophy; myostatin
    DOI:  https://doi.org/10.1152/ajpendo.00275.2020
  6. Acta Physiol (Oxf). 2021 Feb 11. e13625
    Contextualizing the biological relevance of standardized high-resolution respirometry to assess mitochondrial function in permeabilized human skeletal muscle.
    Robert A Jacobs, Carsten Lundby.
      AIM: This study sought to provide a statistically robust reference for measures of mitochondrial function from standardized high-resolution respirometry with permeabilized human skeletal muscle (ex vivo), compare analogous values obtained via indirect calorimetry, arterial-venous O2 differences, and 31 P magnetic resonance spectroscopy (in vivo), and attempt to resolve differences across complementary methodologies as necessary.METHODS: Data derived from 831 study participants across research published throughout March 2009 to November 2019 was amassed to examine the biological relevance of ex vivo assessments under standard conditions, i.e. physiological temperatures of 37 °C and respiratory chamber oxygen concentrations of ~250-500 μM.
    RESULTS: Standard ex vivo-derived measures are lower (Z ≥ 3.01, p ≤ 0.0258) en masse than corresponding in vivo-derived values. Correcting respiratory values to account for mitochondrial temperatures 10 °C higher than skeletal muscle temperatures at maximal exercise (~ 50 °C): i.) transforms data to resemble (Z ≤ 0.8, p > 0.9999) analogous yet context-specific in vivo measures, e.g. data collected during maximal 1-leg knee extension exercise; and ii.) supports the position that maximal skeletal muscle respiratory rates exceed (Z ≥ 13.2, p < 0.0001) those achieved during maximal whole-body exercise, e.g. maximal cycling efforts.
    CONCLUSION: This study outlines and demonstrates necessary considerations when actualizing the biological relevance of human skeletal muscle respiratory control, metabolic flexibility, and bioenergetics from standard ex vivo-derived assessments using permeabilized human muscle. These findings detail how cross-procedural comparisons of human skeletal muscle mitochondrial function may be collectively scrutinized in their relationship to human health and lifespan.
    Keywords:  carbohydrate oxidation rates; fatty acid oxidation rates; human bioenergetics; metabolic flexibility; skeletal muscle mitochondria; skeletal muscle temperature
    DOI:  https://doi.org/10.1111/apha.13625
  7. Sci Rep. 2021 Feb 10. 11(1): 3447
    Role of PDK1 in skeletal muscle hypertrophy induced by mechanical load.
    Naoki Kuramoto, Kazuhiro Nomura, Daisuke Kohno, Tadahiro Kitamura, Gerard Karsenty, Tetsuya Hosooka, Wataru Ogawa.
      Phosphatidylinositol 3-kinase (PI3K) plays an important role in protein metabolism and cell growth. We here show that mice (M-PDK1KO mice) with skeletal muscle-specific deficiency of 3'-phosphoinositide-dependent kinase 1 (PDK1), a key component of PI3K signaling pathway, manifest a reduced skeletal muscle mass under the static condition as well as impairment of mechanical load-induced muscle hypertrophy. Whereas mechanical load-induced changes in gene expression were not affected, the phosphorylation of ribosomal protein S6 kinase (S6K) and S6 induced by mechanical load was attenuated in skeletal muscle of M-PDK1KO mice, suggesting that PDK1 regulates muscle hypertrophy not through changes in gene expression but through stimulation of kinase cascades such as the S6K-S6 axis, which plays a key role in protein synthesis. Administration of the β2-adrenergic receptor (AR) agonist clenbuterol activated the S6K-S6 axis in skeletal muscle and induced muscle hypertrophy in mice. These effects of clenbuterol were attenuated in M-PDK1KO mice, and mechanical load-induced activation of the S6K-S6 axis and muscle hypertrophy were inhibited in mice with skeletal muscle-specific deficiency of β2-AR. Our results suggest that PDK1 regulates skeletal muscle mass under the static condition and that it contributes to mechanical load-induced muscle hypertrophy, at least in part by mediating signaling from β2-AR.
    DOI:  https://doi.org/10.1038/s41598-021-83098-z
  8. Autophagy. 2021 Feb 08.
    Autophagy-dependent regulation of skeletal muscle regeneration and strength by a RHOGEF.
    Jae-Sung You, Jie Chen.
      Macroautophagy/autophagy plays a critical role in restoring/maintaining skeletal muscle function under normal conditions as well as during damage-induced regeneration. This homeostatic degradation mechanism, however, rapidly declines with aging leading to functional deterioration of skeletal muscles. ARHGEF3 is a RHOA- and RHOB-specific GEF capable of inhibiting myogenic AKT signaling independently of its GEF function. Our recent study reveals that ARHGEF3 negatively regulates skeletal muscle autophagy during injury-induced regeneration and normal aging. By enhancing autophagy, arhgef3 knockout augments the regenerative capacity of muscles in both young and regeneration-defective middle-aged mice and prevents age-related loss of muscle strength. We further show that the GEF activity of ARHGEF3 toward ROCK, but not its downstream target AKT, mediates its function in muscle regeneration. These findings suggest that ARHGEF3 may be a candidate therapeutic target for impaired muscle regeneration, age-related muscle weakness, and potentially other diseases arising from aberrant regulation of autophagy.
    Keywords:  AKT; ARHGEF3; Aging; RHOA; ROCK; autophagy; injury; regeneration; skeletal muscle; strength
    DOI:  https://doi.org/10.1080/15548627.2021.1886721
  9. Am J Physiol Cell Physiol. 2021 Feb 10.
    Mitochondria-Cytokine Crosstalk Following Skeletal Muscle Injury and Disuse: A Mini-Review.
    Anita E Qualls, W Michael Southern, Jarrod A Call.
      Skeletal muscle mitochondria are highly adaptable, highly dynamic organelles that maintain the functional integrity of the muscle fiber by providing ATP for contraction and cellular homeostasis (e.g., Na+/K+ ATPase). Emerging as early modulators of inflammation, mitochondria sense and respond to cellular stress. Mitochondria communicate with the environment, in part, by release of physical signals called mitochondrial-derived damage-associated molecular patterns (mito-DAMPs) and deviation from routine function (e.g. reduced ATP production, Ca2+ overload). When skeletal muscle is compromised, mitochondria contribute to an acute inflammatory response necessary for myofibril regeneration; however, exhaustive signaling associated with altered or reduced mitochondrial function can be detrimental to muscle outcomes. Here we describe changes in mitochondrial content, structure, and function following skeletal muscle injury and disuse and highlight the influence of mitochondrial-cytokine crosstalk on muscle regeneration and recovery. While the appropriate therapeutic modulation following muscle stressors remains unknown, retrospective gene expression analysis reveal interleukin-6 (IL-6), interleukin-1b (IL-1b), chemokine C-X-C motif ligand 1 (CXCL1), and monocyte chemoattractant protein 1 (MCP-1) are significantly upregulated following three unique muscle injuries. These cytokines modulate mitochondrial function and execute bona fide pleiotropic roles that can aid functional recovery of muscle; however, when aberrant, chronically disrupt healing partly by exacerbating mitochondrial dysfunction. Multidisciplinary efforts to delineate the opposing regulatory roles of inflammatory cytokines in the muscle-mitochondrial environment are required to modulate regenerative behavior following skeletal muscle injury or disuse. Future therapeutic directions to consider include quenching or limited release of mito-DAMPs and cytokines present in cytosol or circulation.
    Keywords:  IL-6; inflammation; mito-DAMPs; mitochondria; skeletal muscle injury
    DOI:  https://doi.org/10.1152/ajpcell.00462.2020
  10. Eur Rev Med Pharmacol Sci. 2021 Jan;pii: 24672. [Epub ahead of print]25(2): 1024-1033
    Melatonin role in skeletal muscle disorders.
    S Salucci, S Taurone, S Burattini, P Gobbi, J Clausi, M Battistelli.
      OBJECTIVE: This review discusses the impact of the neuro-hormone melatonin on skeletal muscle disorders based on recent literature data with the aim to clarify the utility of the melatonin therapy in patients affected by muscle diseases.MATERIALS AND METHODS: It has been pointed out the possible role of melatonin as a food supplement to cure muscular disorders characterized by muscle wasting. Oxidative damage has been proposed as one of the major contributors of the skeletal muscle decline occurring both in physiological and pathological conditions. It is known that excessive oxidant levels lead to mitochondrial damage, and in turn, contribute to apoptotic signaling activation and autophagic impairment. This condition is common in a variety of skeletal muscle disorders.
    RESULTS: The scientific evidence enhances the antioxidant effect of melatonin, that has been demonstrated by several studies both in vitro and in vivo. This effect counteracts mitochondrial impairments and reduces oxidative stress and autophagic alterations in muscle fibers. Its beneficial role in restoring muscle decline, takes place mainly in atrophic conditions correlated to muscle aging.
    CONCLUSIONS: The findings of the research suggest that melatonin may be considered as a valid dietary supplement, useful to prevent muscle wasting, in particular, in sarcopenia-associated diseases.
    DOI:  https://doi.org/10.26355/eurrev_202101_24672
  11. FASEB J. 2021 Mar;35(3): e21378
    Enhancement of myogenic potential of muscle progenitor cells and muscle healing during pregnancy.
    Aiping Lu, Ping Guo, Haiying Pan, Chieh Tseng, Krishna M Sinha, Fan Yang, Alex Scibetta, Yan Cui, Matthieu Huard, Ling Zhong, Sudheer Ravuri, Johnny Huard.
      The decline of muscle regenerative potential with age has been attributed to a diminished responsiveness of muscle progenitor cells (MPCs). Heterochronic parabiosis has been used as a model to study the effects of aging on stem cells and their niches. These studies have demonstrated that, by exposing old mice to a young systemic environment, aged progenitor cells can be rejuvenated. One interesting idea is that pregnancy represents a unique biological model of a naturally shared circulatory system between developing and mature organisms. To test this hypothesis, we evaluated the muscle regeneration potential of pregnant mice using a cardiotoxin (CTX) injury mouse model. Our results indicate that the pregnant mice demonstrate accelerated muscle healing compared to nonpregnant control mice following muscle injury based on improved muscle histology, superior muscle regeneration, and a reduction in inflammation and necrosis. Additionally, we found that MPCs isolated from pregnant mice display a significant improvement of myogenic differentiation capacity in vitro and muscle regeneration in vivo when compared to the MPCs from nonpregnant mice. Furthermore, MPCs from nonpregnant mice display enhanced myogenic capacity when cultured in the presence of serum obtained from pregnant mice. Our proteomics data from these studies provides potential therapeutic targets to enhance the myogenic potential of progenitor cells and muscle repair.
    Keywords:  circulating factors; heterochronic parabiosis; myogenic differentiation; skeletal muscle injury
    DOI:  https://doi.org/10.1096/fj.202001914R
  12. Cell Calcium. 2021 Jan 30. pii: S0143-4160(21)00011-7. [Epub ahead of print]94 102357
    Skeletal muscle mitochondria in health and disease.
    Agnese De Mario, Gaia Gherardi, Rosario Rizzuto, Cristina Mammucari.
      Mitochondrial activity warrants energy supply to oxidative myofibres to sustain endurance workload. The maintenance of mitochondrial homeostasis is ensured by the control of fission and fusion processes and by the mitophagic removal of aberrant organelles. Many diseases are due to or characterized by dysfunctional mitochondria, and altered mitochondrial dynamics or turnover trigger myopathy per se. In this review, we will tackle the role of mitochondrial dynamics, turnover and metabolism in skeletal muscle, both in health and disease.
    Keywords:  Fusion and fission machinery; Mitochondrial calcium uptake; Mitochondrial myopathies; Mitophagy; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ceca.2021.102357
  13. Acta Physiol (Oxf). 2021 Feb 13. e13627
    Tetrahydrobiopterin synthesis and metabolism is impaired in dystrophin-deficient mdx mice and humans.
    Angus Lindsay, Bailey Kemp, Alexie A Larson, Cory W Baumann, Preston M McCourt, John Holm, Peter Karachunski, Dawn A Lowe, James M Ervasti.
      AIM: Loss of dystrophin causes oxidative stress and affects nitric oxide synthase-mediated vascular function in striated muscle. Because tetrahydrobiopterin is an antioxidant and co-factor for nitric oxide synthase, we tested the hypothesis that tetrahydrobiopterin would be low in mdx mice and humans deficient for dystrophin.METHODS: Tetrahydrobiopterin and its metabolites were measured at rest and in response to exercise in Duchenne and Becker muscular dystrophy patients, age-matched male controls as well as wildtype, mdx and mdx mice transgenically overexpressing skeletal muscle-specific dystrophins. Mdx mice were also supplemented with tetrahydrobiopterin and pathophysiology was assessed.
    RESULTS: Duchenne muscular dystrophy patients had lower urinary dihydrobiopterin + tetrahydrobiopterin/specific gravity1.020 compared to unaffected age-matched males and Becker muscular dystrophy patients. Mdx mice had low urinary and skeletal muscle dihydrobiopterin + tetrahydrobiopterin compared to wildtype mice. Mdx mice overexpressing dystrophins that localize neuronal nitric oxide synthase, restored dihydrobiopterin + tetrahydrobiopterin in mdx mice to wildtype levels while utrophin overexpression did not. Mdx mice and Duchenne muscular dystrophy patients did not increase tetrahydrobiopterin during exercise and in mdx mice tetrahydrobiopterin deficiency was likely due to lower levels of sepiapterin reductase in skeletal muscle. Tetrahydrobiopterin supplementation improved skeletal muscle strength, resistance to fatiguing and injurious contractions in vivo, increased utrophin and capillary density of skeletal muscle and lowered cardiac muscle fibrosis and left ventricular wall thickness in mdx mice.
    CONCLUSION: These data demonstrate that impaired tetrahydrobiopterin synthesis is associated with dystrophin loss and treatment with tetrahydrobiopterin improves striated muscle histopathology and skeletal muscle function and in mdx mice.
    Keywords:  Cardiac muscle; Duchenne muscular dystrophy; exercise; nitric oxide; skeletal muscle; utrophin
    DOI:  https://doi.org/10.1111/apha.13627
  14. J Biol Chem. 2021 Feb 03. pii: S0021-9258(21)00148-4. [Epub ahead of print] 100376
    Lnc-ORA interacts with microRNA-532-3p and IGF2BP2 to inhibit skeletal muscle myogenesis.
    Rui Cai, Que Zhang, Yingqian Wang, Wenlong Yong, Rui Zhao, Weijun Pang.
      Skeletal muscle is one of the most important organs of the animal body. Long noncoding RNAs (lncRNAs) play a crucial role in the regulation of skeletal muscle development via several mechanisms. We recently identified lnc-ORA in a search for lncRNAs that influence adipogenesis, finding it impacted adipocyte differentiation by regulating the PI3K/AKT/mTOR pathway. However, whether lnc-ORA has additional roles, specifically in skeletal muscle myogenesis, is not known. Here, we found that lnc-ORA was significantly differentially expressed with age in mouse skeletal muscle tissue and predominantly located in the cytoplasm. Overexpression of lnc-ORA promoted C2C12 myoblast proliferation and inhibited myoblast differentiation. In contrast, lnc-ORA knockdown repressed myoblast proliferation and facilitated myoblast differentiation. Interestingly, silencing of lnc-ORA rescued dexamethasone (Dex)-induced muscle atrophy in vitro. Furthermore, adeno-associated virus 9 (AAV9)-mediated overexpression of lnc-ORA decreased muscle mass and the cross-sectional area of muscle fiber by upregulating the levels of muscle atrophy-related genes and downregulating the levels of myogenic differentiation-related genes in vivo. Mechanistically, lnc-ORA inhibited skeletal muscle myogenesis by acting as a sponge of miR-532-3p, which targets the phosphatase and tensin homologue (PTEN) gene; the resultant changes in PTEN suppressed the phosphoinositide 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Additionally, lnc-ORA interacted with insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) and reduced the stability of myogenesis genes such as myogenic differentiation 1 (MyoD) and myosin heavy chain (MyHC). Collectively, these findings indicate that lnc-ORA could be a novel underlying regulator of skeletal muscle development.
    Keywords:  Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2); Myogenesis; PTEN/PI3K/AKT signaling pathway; Skeletal muscle; lnc-ORA; miR-532-3p
    DOI:  https://doi.org/10.1016/j.jbc.2021.100376
  15. Eur J Nutr. 2021 Feb 06.
    Evenness of dietary protein distribution is associated with higher muscle mass but not muscle strength or protein turnover in healthy adults: a systematic review.
    Simon E Jespersen, Jakob Agergaard.
      PURPOSE: Age-related decrease in muscle mass is, among several other factors, caused by suboptimal dietary protein intake. The protein intake of the general population has a skewed distribution towards the evening meal. However, it is hypothesised that an intake of protein with an even meal distribution leads to a more frequently maximised protein synthesis. This review investigates whether an even protein distribution is associated with preservation or gain in muscle mass, muscle strength, and protein turnover.METHODS: Seven databases: PubMed, Web of Science, Google Scholar, CINAHL, Cochrane Database of Systematic Reviews, Cochrane Central Register of Controlled Trials, and Embase were searched. Studies included had a healthy population between 20 and 85 years of age, with a BMI between 18.5 and 30.0, investigated even vs. skewed protein distribution, and measured skeletal muscle relevant outcomes. Case studies and systematic reviews were excluded. Studies were appraised using the AXIS scale for observational studies and the PEDro scale for the remaining studies.
    RESULTS: Fifteen studies met the eligibility criteria and were included. Three out of seven studies showed an association between even protein distribution and higher muscle mass. Two out of seven studies showed an association between greater muscle strength and an even protein distribution. Only one out of six studies found a positive association between protein synthesis and an even protein distribution.
    CONCLUSION: Evidence indicated an association between muscle mass and an even protein intake. However, the evidence is currently insufficient to conclude whether an even protein intake is positively associated with muscle strength or protein turnover.
    Keywords:  Dietary protein; Muscle mass; Muscle protein turnover; Muscle strength; Protein distribution
    DOI:  https://doi.org/10.1007/s00394-021-02487-2
  16. Int J Mol Sci. 2021 Feb 10. pii: 1760. [Epub ahead of print]22(4):
    Vitamin D Restores Skeletal Muscle Cell Remodeling and Myogenic Program: Potential Impact on Human Health.
    Clara Crescioli.
      Skeletal muscle cells, albeit classified as vitamin D receptor (VDR)-poor cells, are finely controlled by vitamin D through genomic and non-genomic mechanisms. Skeletal muscle constantly undergoes cell remodeling, a complex system under multilevel regulation, mainly orchestrated by the satellite niche in response to a variety of stimuli. Cell remodeling is not limited to satisfy reparative and hypertrophic needs, but, through myocyte transcriptome/proteome renewal, it warrants the adaptations necessary to maintain tissue integrity. While vitamin D insufficiency promotes cell maladaptation, restoring vitamin D levels can correct/enhance the myogenic program. Hence, vitamin D fortified foods or supplementation potentially represents the desired approach to limit or avoid muscle wasting and ameliorate health. Nevertheless, consensus on protocols for vitamin D measurement and supplementation is still lacking, due to the high variability of lab tests and of the levels required in different contexts (i.e., age, sex, heath status, lifestyle). This review aims to describe how vitamin D can orchestrate skeletal muscle cell remodeling and myogenic programming, after reviewing the main processes and cell populations involved in this important process, whose correct progress highly impacts on human health. Topics on vitamin D optimal levels, supplementation and blood determination, which are still under debate, will be addressed.
    Keywords:  cell remodeling; health; skeletal muscle cells; vitamin D
    DOI:  https://doi.org/10.3390/ijms22041760
  17. Cells. 2021 Feb 04. pii: 318. [Epub ahead of print]10(2):
    Nuclear Mechanotransduction in Skeletal Muscle.
    Saline Jabre, Walid Hleihel, Catherine Coirault.
      Skeletal muscle is composed of multinucleated, mature muscle cells (myofibers) responsible for contraction, and a resident pool of mononucleated muscle cell precursors (MCPs), that are maintained in a quiescent state in homeostatic conditions. Skeletal muscle is remarkable in its ability to adapt to mechanical constraints, a property referred as muscle plasticity and mediated by both MCPs and myofibers. An emerging body of literature supports the notion that muscle plasticity is critically dependent upon nuclear mechanotransduction, which is transduction of exterior physical forces into the nucleus to generate a biological response. Mechanical loading induces nuclear deformation, changes in the nuclear lamina organization, chromatin condensation state, and cell signaling, which ultimately impacts myogenic cell fate decisions. This review summarizes contemporary insights into the mechanisms underlying nuclear force transmission in MCPs and myofibers. We discuss how the cytoskeleton and nuclear reorganizations during myogenic differentiation may affect force transmission and nuclear mechanotransduction. We also discuss how to apply these findings in the context of muscular disorders. Finally, we highlight current gaps in knowledge and opportunities for further research in the field.
    Keywords:  mechanics; mechanotransduction; muscle disorders; nucleo-cytoplasmic coupling; nucleus
    DOI:  https://doi.org/10.3390/cells10020318
  18. Commun Biol. 2021 Feb 12. 4(1): 194
    Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia.
    Anastasiya Börsch, Daniel J Ham, Nitish Mittal, Lionel A Tintignac, Eugenia Migliavacca, Jérôme N Feige, Markus A Rüegg, Mihaela Zavolan.
      Sarcopenia, the age-related loss of skeletal muscle mass and function, affects 5-13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.
    DOI:  https://doi.org/10.1038/s42003-021-01723-z
  19. NPJ Regen Med. 2020 May 11. 5(1): 10
    Towards stem cell therapies for skeletal muscle repair.
    Robert N Judson, Fabio M V Rossi.
      Skeletal muscle is an ideal target for cell therapy. The use of its potent stem cell population in the form of autologous intramuscular transplantation represents a tantalizing strategy to slow the progression of congenital muscle diseases (such as Duchenne Muscular Dystrophy) or regenerate injured tissue following trauma. The syncytial nature of skeletal muscle uniquely permits the engraftment of stem/progenitor cells to contribute to new myonuclei and restore the expression of genes mutated in myopathies. Historically however, the implementation of this approach has been significantly limited by the inability to expand undifferentiated muscle stem cells (MuSCs) in culture whilst maintaining transplantation potential. This is crucial, as MuSC expansion and/or genetic manipulation is likely necessary for therapeutic applications. In this article, we review recent studies that have provided a number of important breakthroughs to tackle this problem. Progress towards this goal has been achieved by exploiting biochemical, biophysical and developmental paradigms to construct innovative in vitro strategies that are guiding stem cell therapies for muscle repair towards the clinic.
    DOI:  https://doi.org/10.1038/s41536-020-0094-3
  20. Biochem Biophys Rep. 2021 Mar;25 100930
    Signature molecular changes in the skeletal muscle of hindlimb unloaded mice.
    Muhammad Azeem, Rizwan Qaisar, Asima Karim, Anu Ranade, Adel Elmoselhi.
      Hind-limb unloaded (HU) mouse is a well-recognized model of muscle atrophy; however, the molecular changes in the skeletal muscle during unloading are poorly characterized. We have used Raman spectroscopy to evaluate the structure and behavior of signature molecules involved in regulating muscle structural and functional health. The Raman spectroscopic analysis of gastrocnemius muscles was compared between 16-18 weeks old HU c57Bl/6J mice and ground-based controls. The spectra showed that the signals for asparagine and glutamine were reduced in HU mice, possibly indicating increased catabolism. The peaks for hydroxyproline and proline were split, pointing towards molecular breakdown and reduced tendon repair. We also report a consistently increased intensity in> 1300 cm-1 range in the Raman spectra along with a shift towards higher frequencies in the HU mice, indicating activation of sarcoplasmic reticulum (SR) stress during HU.
    Keywords:  Molecular changes; Raman spectroscopy; SR stress; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.bbrep.2021.100930
  21. Molecules. 2021 Feb 06. pii: 853. [Epub ahead of print]26(4):
    Resveratrol Promotes Hypertrophy in Wildtype Skeletal Muscle and Reduces Muscle Necrosis and Gene Expression of Inflammatory Markers in Mdx Mice.
    Keryn G Woodman, Chantal A Coles, Shireen R Lamandé, Jason D White.
      Duchenne muscular dystrophy (DMD) is a progressive fatal neuromuscular disorder with no cure. Therapies to restore dystrophin deficiency have been approved in some jurisdictions but long-term effectiveness is yet to be established. There is a need to develop alternative strategies to treat DMD. Resveratrol is a nutraceutical with anti-inflammatory properties. Previous studies have shown high doses (100-400 mg/kg bodyweight/day) benefit mdx mice. We treated 4-week-old mdx and wildtype mice with a lower dose of resveratrol (5 mg/kg bodyweight/day) for 15 weeks. Voluntary exercise was used to test if a lower dosage than previously tested could reduce exercise-induced damage where a greater inflammatory infiltrate is present. We found resveratrol promoted skeletal muscle hypertrophy in wildtype mice. In dystrophic muscle, resveratrol reduced exercise-induced muscle necrosis. Gene expression of immune cell markers, CD86 and CD163 were reduced; however, signalling targets associated with resveratrol's mechanism of action including Sirt1 and NF-κB were unchanged. In conclusion, a lower dose of resveratrol compared to the dosage used by other studies reduced necrosis and gene expression of inflammatory cell markers in dystrophic muscle suggesting it as a therapeutic candidate for treating DMD.
    Keywords:  duchenne; inflammation; mdx; muscle; muscular dystrophy; nutraceuticals; resveratrol
    DOI:  https://doi.org/10.3390/molecules26040853
  22. Bone. 2021 Feb 08. pii: S8756-3282(21)00039-9. [Epub ahead of print]145 115877
    Association between serum FGF21 level and sarcopenia in older adults.
    Hee-Won Jung, Jin Hoon Park, Da Ae Kim, Il-Young Jang, So Jeong Park, Jin Young Lee, Seungjoo Lee, Jeoung Hee Kim, Hyon-Seung Yi, Eunju Lee, Beom-Jun Kim.
      BACKGROUND: With emerging basic research evidence suggesting that fibroblast growth factor (FGF) 21 is a catabolic molecule on muscle metabolism, we aimed to analyze the serum FGF21 level in relation to sarcopenia in older adults.METHODS: Blood samples were collected from 125 participants who underwent evaluation for muscle mass and function in an outpatient geriatric clinic of a teaching hospital. Sarcopenia and related components were determined using cutoff values for the Asian population. The serum FGF21 level was measured using enzyme linked immunosorbent assay.
    RESULTS: After controlling for age, sex, and body mass index (BMI), participants with sarcopenia, low muscle mass, and weak muscle strength had 2.3-, 2.0-, and 1.5-fold higher serum FGF21 levels than controls, respectively (p = .033 to <0.001). The serum FGF21 level was positively correlated with sarcopenia phenotype score and inversely correlated with skeletal muscle mass index and grip strength by both crude and multivariate analysis adjusting potential confounders (p = .017 to <0.001). Consistently, higher serum FGF21 level was significantly associated with increased odds for sarcopenia, low muscle mass, and low muscle strength after adjusting for age, sex, and BMI (odds ratio, 1.53-2.61; p = .048 to <0.001).
    CONCLUSIONS: Higher circulating FGF21 was associated with the likelihood of sarcopenia, lower muscle mass, and worse grip strength in older adults, supporting a potential catabolic role of FGF21 on human muscle health.
    Keywords:  Biomarker; FGF21; Grip strength; Older adults; Sarcopenia
    DOI:  https://doi.org/10.1016/j.bone.2021.115877
  23. J Cell Signal. 2021 ;2(1): 9-26
    FOXP1 Interacts with MyoD to Repress its Transcription and Myoblast Conversion.
    Woodring E Wright, Chuan Li, Chang-Xue Zheng, Haley O Tucker.
      Forkhead transcription factors (TFs) often dimerize outside their extensive family, whereas bHLH transcription factors typically dimerize with E12/E47. Based on structural similarities, we predicted that a member of the former, Forkhead Box P1 (FOXP1), might heterodimerize with a member of the latter, MYOD1 (MyoD). Data shown here support this hypothesis and further demonstrate the specificity of this forkhead/myogenic interaction among other myogenic regulatory factors. We found that FOXP1-MyoD heterodimerization compromises the ability of MyoD to bind to E-boxes and to transactivate E box- containing promoters. We observed that FOXP1 is required for the full ability of MyoD to convert fibroblasts into myotubules. We provide a model in which FOXP1 displaces ID and E12/E47 to repress MyoD during the proliferative phase of myoblast differentiation. These data identify FOXP1 as a hitherto unsuspected transcriptional repressor of MyoD. We suggest that isolation of paired E-box and forkhead sites within 1 turn helical spacings provides potential for cooperative interactions among heretofore distinct classes of transcription factors.
    Keywords:  Forkhead box P1; Myoblast differentiation; Myogenic regulatory factors; Transcriptional regulation
  24. J Physiol. 2021 Feb 10.
    Single-leg exercise training augments in vivo skeletal muscle oxidative flux and vascular content and function in adults with type 2 diabetes.
    Rebecca L Scalzo, Irene E Schauer, Deirdre Rafferty, Leslie A Knaub, Nina Kvaratskhelia, Taro Kaelix Johnson, Gregory B Pott, Layla A Abushamat, Mary O Whipple, Amy G Huebschmann, Melanie Cree-Green, Jane E B Reusch, Judith G Regensteiner.
      KEY POINTS: People with type 2 diabetes (T2D) have impaired skeletal muscle oxidative flux due to limited oxygen delivery. In the current study, this impairment in oxidative flux in people with T2D was abrogated with a single-leg exercise training protocol. Additionally, single-leg exercise training increased skeletal muscle CD31 content, calf blood flow, and state 4 mitochondrial respiration in all participants.ABSTRACT: Cardiorespiratory fitness is impaired in type 2 diabetes (T2D) conferring significant cardiovascular risk in this population; interventions are needed. Previously, we reported that a T2D-associated decrement in skeletal muscle oxidative flux is ameliorated with acute use of supplemental oxygen, suggesting that skeletal muscle oxygenation is rate limiting to in vivo mitochondrial oxidative flux during exercise in T2D. We hypothesized that single-leg exercise training (SLET) would improve the T2D-specific impairment in in vivo mitochondrial oxidative flux during exercise. Adults with (n = 19) and without T2D (n = 22) with similar body mass indexes and levels of physical activity participated in two weeks of SLET. Following SLET, in vivo oxidative flux measured by 31 P-MRS increased in participants with T2D, but not people without T2D, measured by the increase in initial phosphocreatine synthesis (P = 0.0455 for the group x exercise interaction) and maximum rate of oxidative ATP synthesis (P = 0.0286 for the interaction). Additionally, oxidative phosphorylation increased in all participants with SLET (P = 0.0209). After SLET, there was no effect of supplemental oxygen on any of the in vivo oxidative flux measurements in either group (P>0.02), consistent with resolution of the T2D-associated oxygen limitation previously observed at baseline in subjects with T2D. State 4 mitochondrial respiration also improved in muscle fibers ex vivo. Skeletal muscle vasculature content and calf blood flow increased in all participants with SLET (P<0.0040); oxygen extraction in the calf increased only in T2D (P = 0.0461). SLET resolves the T2D-associated impairment of skeletal muscle in vivo mitochondrial oxidative flux potentially through improved effective blood flow/oxygen delivery. This article is protected by copyright. All rights reserved.
    Keywords:  blood flow; diabetes; exercise; skeletal muscle
    DOI:  https://doi.org/10.1113/JP280603
  25. Br J Nutr. 2021 Feb 08. 1-34
    Curcumin induces mitochondrial biogenesis by increasing cAMP levels via PDE4A inhibition in skeletal muscle.
    Hamidie Ronald D Ray, Tsubasa Shibaguchi, Tatsuya Yamada, Rikuhide Koma, Rie Ishizawa, Yoko Saito, Tatsunori Hosoi, Kazumi Masuda.
      Background: Previous research has suggested that curcumin potentially induces mitochondrial biogenesis in skeletal muscle via increasing cAMP levels. However, the regulatory mechanisms for this phenomenon remain unknown. The purpose of the present study was to clarify the mechanism by which curcumin activates cAMP-related signalling pathways that upregulate mitochondrial biogenesis and respiration in skeletal muscle. Methods: The effect of curcumin treatment (i.p., 100 mg/kg-BW/day for 28 days) on mitochondrial biogenesis was determined in rats. The effects of curcumin and exercise (swimming for 2 h/day for 3 days) on the cAMP signalling pathway were determined in the absence and presence of phosphodiesterase (PDE) or protein kinase A (PKA) inhibitors. Mitochondrial respiration, citrate synthase (CS) activity, cAMP content, and protein expression of cAMP/PKA signalling molecules were analysed. Results: Curcumin administration increased COX-IV protein expression, and CS and complex I activity, consistent with the induction of mitochondrial biogenesis by curcumin. Mitochondrial respiration was not altered by curcumin treatment. Curcumin and PDE inhibition tended to increase cAMP levels with or without exercise. In addition, exercise increased the phosphorylation of PDE4A, whereas curcumin treatment strongly inhibited PDE4A phosphorylation regardless of exercise. Furthermore, curcumin promoted AMPK phosphorylation and PGC-1α deacetylation. Inhibition of PKA abolished the phosphorylation of AMPK. Conclusion: The present results suggest that curcumin increases cAMP levels via inhibition of PDE4A phosphorylation, which induces mitochondrial biogenesis through a cAMP/PKA/AMPK signalling pathway. Our data also suggest the possibility that curcumin utilizes a regulatory mechanism for mitochondrial biogenesis that is distinct from the exercise-induced mechanism in skeletal muscle.
    Keywords:  PDE4A; curcumin; exercise; mitochondria respiration
    DOI:  https://doi.org/10.1017/S0007114521000490
  26. Free Radic Biol Med. 2021 Feb 06. pii: S0891-5849(21)00064-2. [Epub ahead of print]
    Transgenic expression of SOD1 specifically in neurons of Sod1 deficient mice prevents defects in muscle mitochondrial function and calcium handling.
    Yu Su, Bumsoo Ahn, Peter C D Macpherson, Rojina Ranjit, Dennis R Claflin, Holly Van Remmen, Susan V Brooks.
      Aging is accompanied by loss of muscle mass and force, known as sarcopenia. Muscle atrophy, weakness, and neuromuscular junction (NMJ) degeneration reminiscent of normal muscle aging are observed early in adulthood for mice deficient in Cu, Zn-superoxide dismutase (SOD, Sod1-/-). Muscles of Sod1-/- mice also display impaired mitochondrial ATP production and increased mitochondrial reactive oxygen species (ROS) generation implicating oxidative stress in sarcopenia. Restoration of CuZnSOD specifically in neurons of Sod1-/- mice (SynTgSod1-/-) prevents muscle atrophy and loss of force, but whether muscle mitochondrial function is preserved is not known. To establish links among CuZnSOD expression, mitochondrial function, and sarcopenia, we examined contractile properties, mitochondrial function and ROS production, intracellular calcium transients (ICT), and NMJ morphology in lumbrical muscles of 7-9 month wild type (WT), Sod1-/-, and SynTgSod1-/- mice. Compared with WT values, mitochondrial ROS production was increased 2.9-fold under basal conditions and 2.2-fold with addition of glutamate and malate in Sod1-/- muscle fibers while oxygen consumption was not significantly altered. In addition, NADH recovery was blunted following contraction and the peak of the ICT was decreased by 25%. Mitochondrial function, ROS generation and calcium handling were restored to WT values in SynTgSod1-/- mice, despite continued lack of CuZnSOD in muscle. NMJ denervation and fragmentation were also fully rescued in SynTgSod1-/- mice suggesting that muscle mitochondrial and calcium handling defects in Sod1-/- mice are secondary to neuronal oxidative stress and its effects on the NMJ rather than the lack of muscle CuZnSOD. We conclude that intact neuronal function and innervation are key to maintaining excitation-contraction coupling and muscle mitochondrial function.
    Keywords:  Aging; CuZnSOD; Excitation contraction coupling; Mitochondria; Oxidative stress; Sarcopenia
    DOI:  https://doi.org/10.1016/j.freeradbiomed.2021.01.047
  27. Oncol Lett. 2021 Feb;21(2): 124
    Inhibition of mitochondrial and cytosolic calpain attenuates atrophy in myotubes co-cultured with colon carcinoma cells.
    Xianliang Zeng, Li Zhao, Sizeng Chen, Xiantao Li.
      Cancer cachexia is a life-threatening syndrome characterized by muscle atrophy. Cancer cachectic muscle atrophy (CCMA) is associated with mitochondrial injury. Mitochondrial calpains have been reported to induce mitochondrial injury in mouse cardiomyocytes and pulmonary smooth muscle. In the present study, the presence of calpain in the mitochondria of skeletal muscle and its potential role in CCMA were investigated. Transwell plates were used to develop a myotube-carcinoma cell co-culture model to simulate the cancer cachexia environment in vitro. The calpain inhibitors, calpastatin (CAST) and calpeptin (CAPT), were used to inhibit calpain activity in myotubes during co-culture. Calpain-1, calpain-2 and CAST were found to be present in mouse myotube mitochondria. Co-culture activated calpain in both cytoplasm and mitochondria, which caused myotube atrophy. CAST and CAPT treatment prevented calpain activation in both cytoplasm and mitochondria, which inhibited myotube atrophy during co-culture. Additionally, CAST and CAPT treatment increased mitochondrial complex I activity, decreased mitochondrial permeability transition pore opening and improved mitochondrial membrane potential in myotubes during co-culture. In addition, CAST and CAPT treatment increased AKT/mTOR activity, inhibited FoxO3a activity and decreased atrogin-1 content in myotubes during co-culture. The present findings provide new insights to understand the mechanism of CCMA and further help the development of focused approaches to treat CCMA by manipulating the mitochondrial and cytosolic calpain activity.
    Keywords:  calpain; cancer cachexia; co-culture; mitochondria; muscle atrophy
    DOI:  https://doi.org/10.3892/ol.2020.12385
  28. PLoS One. 2021 ;16(2): e0245179
    MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.
    Clothilde Philouze, Sophie Turban, Beatrice Cremers, Audrey Caliez, Gwladys Lamarche, Catherine Bernard, Nicolas Provost, Philippe Delerive.
      In type 2 diabetes (T2D), both muscle and liver are severely resistant to insulin action. Muscle insulin resistance accounts for more than 80% of the impairment in total body glucose disposal in T2D patients and is often characterized by an impaired insulin signaling. Mitsugumin 53 (MG53), a muscle-specific TRIM family protein initially identified as a key regulator of cell membrane repair machinery has been suggested to be a critical regulator of muscle insulin signaling pathway by acting as ubiquitin E3 ligase targeting both the insulin receptor and insulin receptor substrate 1 (IRS1). Here, we show using in vitro and in vivo approaches that MG53 is not a critical regulator of insulin signaling and glucose homeostasis. First, MG53 expression is not consistently regulated in skeletal muscle from various preclinical models of insulin resistance. Second, MG53 gene knock-down in muscle cells does not lead to impaired insulin response as measured by Akt phosphorylation on Serine 473 and glucose uptake. Third, recombinant human MG53 does not alter insulin response in both differentiated C2C12 and human skeletal muscle cells. Fourth, ectopic expression of MG53 in HEK293 cells lacking endogenous MG53 expression fails to alter insulin response as measured by Akt phosphorylation. Finally, both male and female mg53 -/- mice were not resistant to high fat induced obesity and glucose intolerance compared to wild-type mice. Taken together, these results strongly suggest that MG53 is not a critical regulator of insulin signaling pathway in skeletal muscle.
    DOI:  https://doi.org/10.1371/journal.pone.0245179
  29. Curr Opin Clin Nutr Metab Care. 2021 Feb 05.
    From bench to bedside: updates in basic science, translational and clinical research on muscle fatigue in cancer cachexia.
    Katherine M Jackson, Calvin L Cole, Richard F Dunne.
      PURPOSE OF REVIEW: Cancer cachexia is a syndrome of loss of weight and muscle mass that leads to reduced strength, poor physical performance and functional impairment. Muscular fatigue is a distressing syndrome that patients with cachexia suffer from and can impair quality of life. Here, we review recent updates in muscular fatigue in cancer cachexia research with a focus on mechanisms, biomarkers and potential therapies.RECENT FINDINGS: Both in mice and humans, research has shown that muscle fatigue can be independent of muscular atrophy and can happen early in cancer development or in precachexia. Inflammatory pathways, mitochondrial dysfunction and gut microbiota have recently been studied to play an important role in muscle fatigue in preclinical models. Exercise can target these pathways and has been studied as a therapeutic intervention to improve muscle fatigue.
    SUMMARY: Heightened inflammation within muscle, altered muscle function and muscle fatigue can begin prior to clinical evidence of cachexia, making early recognition and intervention challenging. The emergence of cachexia mouse models and translational and clinical research studying muscle fatigue will hopefully lead to new therapies targeting the underlying mechanisms of cancer cachexia. Exercise will need to be tested in larger randomized studies before entering into daily practice.
    DOI:  https://doi.org/10.1097/MCO.0000000000000738
  30. Dent Mater J. 2021 Feb 10.
    The synthetic peptide SVVYGLR promotes cell motility of myogenic cells and facilitates differentiation in skeletal muscle regeneration.
    Susumu Tanaka, Yohei Fujishita, Naomasa Kawaguchi, Takasuke Usuki, Yuhki Yokoyama, Xin Wu, Seiji Mori, Hirofumi Yamamoto, Mikihiko Kogo.
      The present study was designed to evaluate the effects of the osteopontin-derived multifunctional short peptide, SVVYGLR (SV) peptide on the biological properties of skeletal muscle-specific myogenic cells. We employed human-derived satellite cells (HSkMSC) and skeletal muscle myoblasts (HSMM) and performed a series of biochemical experiments. The synthetic SV peptide showed no influence on the proliferation and adhesion properties of HSkMSC and HSMM, while it showed a significant increase in cell motility, including migration activities upon treatment with the SV peptide. In a rat model with volumetric loss of masticatory muscle, immunohistochemical staining of regenerating muscle tissue immediately after injury demonstrated an increase of the number of both MyoD- and myogenin-positive cells in SV peptide-treated group. These results suggest that SV peptide plays a potent role in facilitating skeletal muscle regeneration by promoting the migration, and differentiation of myogenic precursor and progenitor cells.
    Keywords:  Myogenic cells; Osteopontin; Regeneration; SVVYGLR; Skeletal muscle
    DOI:  https://doi.org/10.4012/dmj.2020-317
  31. Front Cell Dev Biol. 2020 ;8 620409
    Assessing Autophagy in Muscle Stem Cells.
    Silvia Campanario, Ignacio Ramírez-Pardo, Xiaotong Hong, Joan Isern, Pura Muñoz-Cánoves.
      The skeletal muscle tissue in the adult is relatively stable under normal conditions but retains a striking ability to regenerate by its resident stem cells (satellite cells). Satellite cells exist in a quiescent (G0) state; however, in response to an injury, they reenter the cell cycle and start proliferating to provide sufficient progeny to form new myofibers or undergo self-renewal and returning to quiescence. Maintenance of satellite cell quiescence and entry of satellite cells into the activation state requires autophagy, a fundamental degradative and recycling process that preserves cellular proteostasis. With aging, satellite cell regenerative capacity declines, correlating with loss of autophagy. Enhancing autophagy in aged satellite cells restores their regenerative functions, underscoring this proteostatic activity's relevance for tissue regeneration. Here we describe two strategies for assessing autophagic activity in satellite cells from GFP-LC3 reporter mice, which allows direct autophagosome labeling, or from non-transgenic (wild-type) mice, where autophagosomes can be immunostained. Treatment of GFP-LC3 or WT satellite cells with compounds that interfere with autophagosome-lysosome fusion enables measurement of autophagic activity by flow cytometry and immunofluorescence. Thus, the methods presented permit a relatively rapid assessment of autophagy in stem cells from skeletal muscle in homeostasis and in different pathological scenarios such as regeneration, aging or disease.
    Keywords:  autophagy; flow cytometry; immunofluorescence; quiescence; regeneration; satellite cell; skeletal muscle; stem cell
    DOI:  https://doi.org/10.3389/fcell.2020.620409
  32. Front Physiol. 2020 ;11 630910
    Elevated CO2 Levels Delay Skeletal Muscle Repair by Increasing Fatty Acid Oxidation.
    Ermelinda Ceco, Diego Celli, Samuel Weinberg, Masahiko Shigemura, Lynn C Welch, Lena Volpe, Navdeep S Chandel, Ankit Bharat, Emilia Lecuona, Jacob I Sznajder.
      Muscle dysfunction often occurs in patients with chronic obstructive pulmonary diseases (COPD) and affects ventilatory and non-ventilatory skeletal muscles. We have previously reported that hypercapnia (elevated CO2 levels) causes muscle atrophy through the activation of the AMPKα2-FoxO3a-MuRF1 pathway. In the present study, we investigated the effect of normoxic hypercapnia on skeletal muscle regeneration. We found that mouse C2C12 myoblasts exposed to elevated CO2 levels had decreased fusion index compared to myoblasts exposed to normal CO2. Metabolic analyses of C2C12 myoblasts exposed to high CO2 showed increased oxidative phosphorylation due to increased fatty acid oxidation. We utilized the cardiotoxin-induced muscle injury model in mice exposed to normoxia and 10% CO2 for 21 days and observed that muscle regeneration was delayed. High CO2-delayed differentiation in both mouse C2C12 myoblasts and skeletal muscle after injury and was restored to control levels when cells or mice were treated with a carnitine palmitoyltransfearse-1 (CPT1) inhibitor. Taken together, our data suggest that hypercapnia leads to changes in the metabolic activity of skeletal muscle cells, which results in impaired muscle regeneration and recovery after injury.
    Keywords:  cardiotoxin; chronic obstructive pulmonary diseases; hypercapnia; muscle differentiation; β-Oxidation
    DOI:  https://doi.org/10.3389/fphys.2020.630910
  33. Eur J Appl Physiol. 2021 Feb 10.
    Carbohydrate restriction following strenuous glycogen-depleting exercise does not potentiate the acute molecular response associated with mitochondrial biogenesis in human skeletal muscle.
    Catarina Ramos, Arthur J Cheng, Sigitas Kamandulis, Andrejus Subocius, Marius Brazaitis, Tomas Venckunas, Thomas Chaillou.
      PURPOSE: Carbohydrate (CHO) restriction could be a potent metabolic regulator of endurance exercise-induced muscle adaptations. Here, we determined whether post-exercise CHO restriction following strenuous exercise combining continuous cycling exercise (CCE) and sprint interval exercise could affect the gene expression related to mitochondrial biogenesis and oxidative metabolism in human skeletal muscle.METHODS: In a randomized cross-over design, 8 recreationally active males performed two cycling exercise sessions separated by 4 weeks. Each session consisted of 60-min CCE and six 30-s all-out sprints, which was followed by ingestion of either a CHO or placebo beverage in the post-exercise recovery period. Muscle glycogen concentration and the mRNA levels of several genes related to mitochondrial biogenesis and oxidative metabolism were determined before, immediately after, and at 3 h after exercise.
    RESULTS: Compared to pre-exercise, strenuous cycling led to a severe muscle glycogen depletion (> 90%) and induced a large increase in PGC1A and PDK4 mRNA levels (~ 20-fold and ~ 10-fold, respectively) during the acute recovery period in both trials. The abundance of the other transcripts was not changed or was only moderately increased during this period. CHO restriction during the 3-h post-exercise period blunted muscle glycogen resynthesis but did not increase the mRNA levels of genes associated with muscle adaptation to endurance exercise, as compared with abundant post-exercise CHO consumption.
    CONCLUSION: CHO restriction after a glycogen-depleting and metabolically-demanding cycling session is not effective for increasing the acute mRNA levels of genes involved in mitochondrial biogenesis and oxidative metabolism in human skeletal muscle.
    Keywords:  Endurance exercise; Muscle glycogen; Oxidative metabolism; PGC1A; Sprint interval exercise; Train-low
    DOI:  https://doi.org/10.1007/s00421-021-04594-8
  34. FASEB J. 2021 Mar;35(3): e21387
    Muscle follistatin gene delivery increases muscle protein synthesis independent of periodical physical inactivity and fasting.
    Tuuli A Nissinen, Jaakko Hentilä, Vasco Fachada, Juulia H Lautaoja, Arja Pasternack, Olli Ritvos, Riikka Kivelä, Juha J Hulmi.
      Blocking of myostatin and activins effectively counteracts muscle atrophy. However, the potential interaction with physical inactivity and fasting in the regulation of muscle protein synthesis is poorly understood. We used blockade of myostatin and activins by recombinant adeno-associated virus (rAAV)-mediated follistatin (FS288) overexpression in mouse tibialis anterior muscle. To investigate the effects on muscle protein synthesis, muscles were collected 7 days after rAAV-injection in the nighttime or in the daytime representing high and low levels of activity and feeding, respectively, or after overnight fasting, refeeding, or ad libitum feeding. Muscle protein synthesis was increased by FS288 independent of the time of the day or the feeding status. However, the activation of mTORC1 signaling by FS288 was attenuated in the daytime and by overnight fasting. FS288 also increased the amount of mTOR colocalized with lysosomes, but did not alter their localization toward the sarcolemma. This study shows that FS288 gene delivery increases muscle protein synthesis largely independent of diurnal fluctuations in physical activity and food intake or feeding status, overriding the physiological signals. This is important for eg cachectic and sarcopenic patients with reduced physical activity and appetite. The FS288-induced increase in mTORC1 signaling and protein synthesis may be in part driven by increased amount of mTOR colocalized with lysosomes, but not by their localization toward sarcolemma.
    Keywords:  activins; fasting; mechanistic target of rapamycin protein; myostatin; physical activity
    DOI:  https://doi.org/10.1096/fj.202002008R
  35. Nature. 2021 Feb 10.
    Macrophages provide a transient muscle stem cell niche via NAMPT secretion.
    Dhanushika Ratnayake, Phong D Nguyen, Fernando J Rossello, Verena C Wimmer, Jean L Tan, Laura A Galvis, Ziad Julier, Alasdair J Wood, Thomas Boudier, Abdulsalam I Isiaku, Silke Berger, Viola Oorschot, Carmen Sonntag, Kelly L Rogers, Christophe Marcelle, Graham J Lieschke, Mikaël M Martino, Jeroen Bakkers, Peter D Currie.
      Skeletal muscle regenerates through the activation of resident stem cells. Termed satellite cells, these normally quiescent cells are induced to proliferate by wound-derived signals1. Identifying the source and nature of these cues has been hampered by an inability to visualize the complex cell interactions that occur within the wound. Here we use muscle injury models in zebrafish to systematically capture the interactions between satellite cells and the innate immune system after injury, in real time, throughout the repair process. This analysis revealed that a specific subset of macrophages 'dwell' within the injury, establishing a transient but obligate niche for stem cell proliferation. Single-cell profiling identified proliferative signals that are secreted by dwelling macrophages, which include the cytokine nicotinamide phosphoribosyltransferase (Nampt, which is also known as visfatin or PBEF in humans). Nampt secretion from the macrophage niche is required for muscle regeneration, acting through the C-C motif chemokine receptor type 5 (Ccr5), which is expressed on muscle stem cells. This analysis shows that in addition to their ability to modulate the immune response, specific macrophage populations also provide a transient stem-cell-activating niche, directly supplying proliferation-inducing cues that govern the repair process that is mediated by muscle stem cells. This study demonstrates that macrophage-derived niche signals for muscle stem cells, such as NAMPT, can be applied as new therapeutic modalities for skeletal muscle injury and disease.
    DOI:  https://doi.org/10.1038/s41586-021-03199-7
  36. STAR Protoc. 2021 Mar 19. 2(1): 100302
    Purification and preservation of satellite cells from human skeletal muscle.
    Katharine Striedinger, Emilie Barruet, Jason H Pomerantz.
      Regeneration and repair of skeletal muscle is driven by tissue-specific progenitor cells called satellite cells, which occupy a minority of the cells in the muscle. This protocol provides researchers with techniques to efficiently isolate and purify functional satellite cells from human muscle tissue. The proven techniques described here enable the preparation of purified and minimally altered satellite cells for in vitro and in vivo experimentation and for potential clinical applications. For complete details on the use and execution of this protocol, please refer to Barruet et al. (2020) and Garcia et al. (2018).
    Keywords:  Cell culture; Cell isolation; Flow cytometry/mass cytometry; Single cell
    DOI:  https://doi.org/10.1016/j.xpro.2021.100302
  37. Exp Gerontol. 2021 Feb 03. pii: S0531-5565(21)00042-5. [Epub ahead of print] 111267
    Estradiol deficiency and skeletal muscle apoptosis: Possible contribution of microRNAs.
    Sira Karvinen, Hanna-Kaarina Juppi, Gengyun Le, Christine A Cabelka, Tara L Mader, Dawn A Lowe, Eija K Laakkonen.
      BACKGROUND: Menopause leads to estradiol (E2) deficiency that is associated with decreases in muscle mass and strength. Here we studied the effect of E2 deficiency on miR-signaling that targets apoptotic pathways.METHODS: C57BL6 mice were divided into control (normal estrous cycle, n = 8), OVX (E2 deficiency, n = 7) and OVX + E2 groups (E2-pellet, n = 4). Six weeks following the OVX surgery, mice were sacrificed and RNA isolated from gastrocnemius muscles. miR-profiles were studied with Next-generation sequencing (NGS) and candidate miRs verified using qPCR. The target proteins of the miRs were found using in silico analysis and measured at mRNA (qPCR) and protein levels (Western blot).
    RESULTS: Of the apoptosis-linked miRs present, eleven (miRs-92a-3p, 122-5p, 133a-3p, 214-3p, 337-3p, 381-3p, 483-3p, 483-5p, 491-5p, 501-5p and 652-3p) indicated differential expression between OVX and OVX + E2 mice in NGS analysis. In qPCR verification, muscle from OVX mice had lower expression of all eleven miRs compared with OVX + E2 (p < 0.050). Accordingly, OVX had higher expression of cytochrome C and caspases 6 and 9 compared with OVX + E2 at the mRNA level (p < 0.050). At the protein level, OVX also had lower anti-apoptotic BCL-W and greater pro-apoptotic cytochrome C and active caspase 9 compared with OVX + E2 (p < 0.050).
    CONCLUSION: E2 deficiency down regulated several miRs related to apoptotic pathways thus releasing their targets from miR-mediated suppression, which may lead to increased apoptosis and contribute to reduced skeletal muscle mass.
    Keywords:  Caspase; Cytochrome C; Menopause; Muscle mass; Ovariectomy
    DOI:  https://doi.org/10.1016/j.exger.2021.111267
  38. Stem Cell Res Ther. 2021 Feb 12. 12(1): 131
    Pluripotent stem cell-induced skeletal muscle progenitor cells with givinostat promote myoangiogenesis and restore dystrophin in injured Duchenne dystrophic muscle.
    Wanling Xuan, Mahmood Khan, Muhammad Ashraf.
      BACKGROUND: Duchenne muscular dystrophy (DMD) is caused by mutations of the gene that encodes the protein dystrophin. A loss of dystrophin leads to severe and progressive muscle wasting in both skeletal and heart muscles. Human induced pluripotent stem cells (hiPSCs) and their derivatives offer important opportunities to treat a number of diseases. Here, we investigated whether givinostat (Givi), a histone deacetylase inhibitor, with muscle differentiation properties could reprogram hiPSCs into muscle progenitor cells (MPC) for DMD treatment.METHODS: MPC were generated from hiPSCs by treatment with CHIR99021 and givinostat called Givi-MPC or with CHIR99021 and fibroblast growth factor as control-MPC. The proliferation and migration capacity were investigated by CCK-8, colony, and migration assays. Engraftment, pathological changes, and restoration of dystrophin were evaluated by in vivo transplantation of MPC. Conditioned medium from cultured MPC was collected and analyzed for extracellular vesicles (EVs).
    RESULTS: Givi-MPC exhibited superior proliferation and migration capacity compared to control-MPC. Givi-MPC produced less reactive oxygen species (ROS) after oxidative stress and insignificant expression of IL6 after TNF-α stimulation. Upon transplantation in cardiotoxin (CTX)-injured hind limb of Mdx/SCID mice, the Givi-MPC showed robust engraftment and restored dystrophin in the treated muscle than in those treated with control-MPC or human myoblasts. Givi-MPC significantly limited infiltration of inflammatory cells and reduced muscle necrosis and fibrosis. Additionally, Givi-MPC seeded the stem cell pool in the treated muscle. Moreover, EVs released from Givi-MPC were enriched in several miRNAs related to myoangiogenesis including miR-181a, miR-17, miR-210 and miR-107, and miR-19b compared with EVs from human myoblasts.
    CONCLUSIONS: It is concluded that hiPSCs reprogrammed into MPC by givinostat possessing anti-oxidative, anti-inflammatory, and muscle gene-promoting properties effectively repaired injured muscle and restored dystrophin in the injured muscle.
    Keywords:  Angiogenesis; Duchenne muscular dystrophy; Givinostat; Histone deacetylase inhibitor; Human induced pluripotent stem cells; Muscle progenitor cells
    DOI:  https://doi.org/10.1186/s13287-021-02174-3
  39. NPJ Breast Cancer. 2020 Jun 04. 6(1): 18
    Skeletal muscle reprogramming by breast cancer regardless of treatment history or tumor molecular subtype.
    Hannah E Wilson, David A Stanton, Cortney Montgomery, Aniello M Infante, Matthew Taylor, Hannah Hazard-Jenkins, Elena N Pugacheva, Emidio E Pistilli.
      Increased susceptibility to fatigue is a negative predictor of survival commonly experienced by women with breast cancer (BC). Here, we sought to identify molecular changes induced in human skeletal muscle by BC regardless of treatment history or tumor molecular subtype using RNA-sequencing (RNA-seq) and proteomic analyses. Mitochondrial dysfunction was apparent across all molecular subtypes, with the greatest degree of transcriptomic changes occurring in women with HER2/neu-overexpressing tumors, though muscle from patients of all subtypes exhibited similar pathway-level dysregulation. Interestingly, we found no relationship between anticancer treatments and muscle gene expression, suggesting that fatigue is a product of BC per se rather than clinical history. In vitro and in vivo experimentation confirmed the ability of BC cells to alter mitochondrial function and ATP content in muscle. These data suggest that interventions supporting muscle in the presence of BC-induced mitochondrial dysfunction may alleviate fatigue and improve the lives of women with BC.
    DOI:  https://doi.org/10.1038/s41523-020-0162-2
  40. Nat Rev Rheumatol. 2021 Feb 08.
    Exercise exerts anti-inflammatory effects on muscle via the JAK-STAT pathway.
    Joanna Clarke.
      
    DOI:  https://doi.org/10.1038/s41584-021-00581-7
  41. Front Physiol. 2020 ;11 601313
    Changes in Gene Expression of the MCU Complex Are Induced by Electrical Stimulation in Adult Skeletal Muscle.
    Esteban R Quezada, Alexis Díaz-Vegas, Enrique Jaimovich, Mariana Casas.
      The slow calcium transient triggered by low-frequency electrical stimulation (ES) in adult muscle fibers and regulated by the extracellular ATP/IP3/IP3R pathway has been related to muscle plasticity. A regulation of muscular tropism associated with the MCU has also been described. However, the role of transient cytosolic calcium signals and signaling pathways related to muscle plasticity over the regulation of gene expression of the MCU complex (MCU, MICU1, MICU2, and EMRE) in adult skeletal muscle is completely unknown. In the present work, we show that 270 0.3-ms-long pulses at 20-Hz ES (and not at 90 Hz) transiently decreased the mRNA levels of the MCU complex in mice flexor digitorum brevis isolated muscle fibers. Importantly, when ATP released after 20-Hz ES is hydrolyzed by the enzyme apyrase, the repressor effect of 20 Hz on mRNA levels of the MCU complex is lost. Accordingly, the exposure of muscle fibers to 30 μM exogenous ATP produces the same effect as 20-Hz ES. Moreover, the use of apyrase in resting conditions (without ES) increased mRNA levels of MCU, pointing out the importance of extracellular ATP concentration over MCU mRNA levels. The use of xestospongin B (inhibitor of IP3 receptors) also prevented the decrease of mRNA levels of MCU, MICU1, MICU2, and EMRE mediated by a low-frequency ES. Our results show that the MCU complex can be regulated by electrical stimuli in a frequency-dependent manner. The changes observed in mRNA levels may be related to changes in the mitochondria, associated with the phenotypic transition from a fast- to a slow-type muscle, according to the described effect of this stimulation frequency on muscle phenotype. The decrease in mRNA levels of the MCU complex by exogenous ATP and the increase in MCU levels when basal ATP is reduced with the enzyme apyrase indicate that extracellular ATP may be a regulator of the MCU complex. Moreover, our results suggest that this regulation is part of the axes linking low-frequency stimulation with ATP/IP3/IP3R.
    Keywords:  ATP release; IP3R; calcium handling; mitochondria; muscle plasticity
    DOI:  https://doi.org/10.3389/fphys.2020.601313
  42. Sci Rep. 2021 Feb 10. 11(1): 3476
    MEF2C shapes the microtranscriptome during differentiation of skeletal muscles.
    Agnieszka Piasecka, Michał Sekrecki, Michał Wojciech Szcześniak, Krzysztof Sobczak.
      Myocyte enhancer factor 2C (MEF2C) is a transcription factor that regulates heart and skeletal muscle differentiation and growth. Several protein-encoding genes were identified as targets of this factor; however, little is known about its contribution to the microtranscriptome composition and dynamics in myogenic programs. In this report, we aimed to address this question. Deep sequencing of small RNAs of human muscle cells revealed a set of microRNAs (miRNAs), including several muscle-specific miRNAs, that are sensitive to MEF2C depletion. As expected, in cells with knockdown of MEF2C, we found mostly downregulated miRNAs; nevertheless, as much as one-third of altered miRNAs were upregulated. The majority of these changes are driven by transcription efficiency. Moreover, we found that MEF2C affects nontemplated 3'-end nucleotide addition of miRNAs, mainly oligouridylation. The rate of these modifications is associated with the level of TUT4 which mediates RNA 3'-uridylation. Finally, we found that a quarter of miRNAs which significantly changed upon differentiation of human skeletal myoblasts is inversely altered in MEF2C deficient cells. We concluded that MEF2C is an essential factor regulating both the quantity and quality of the microtranscriptome, leaving an imprint on the stability and perhaps specificity of many miRNAs during the differentiation of muscle cells.
    DOI:  https://doi.org/10.1038/s41598-021-82706-2
  43. Mol Med Rep. 2021 Apr;pii: 270. [Epub ahead of print]23(4):
    N1‑methylnicotinamide ameliorates insulin resistance in skeletal muscle of type 2 diabetic mice by activating the SIRT1/PGC‑1α signaling pathway.
    Yu Chen, Jingfan Zhang, Ping Li, Cong Liu, Ling Li.
      Insulin resistance is one of important factors causing type 2 diabetes; therefore, regulating insulin sensitivity is considered a beneficial therapeutic approach against type 2 diabetes. The present study aimed to determine the effects of N1‑methylnicotinamide (MNAM) on insulin resistance (IR) in skeletal muscle from a mouse model of type 2 diabetes mellitus (T2DM), and to investigate the regulatory mechanisms of the sirtuin 1 (SIRT1)/peroxisome proliferator‑activated receptor γ coactivator‑1α (PGC‑1α) signaling pathway. C57BL/6 mice were fed a normal diet with or without 1% MNAM and ob/ob mice were also fed a normal diet with or without 0.3 or 1% MNAM. Blood glucose, insulin levels, insulin resistance (IR), sensitivity indices and triglyceride (TG) content were detected using ELISAs. The expression of gluconeogenesis‑related, insulin signaling‑related and SIRT1/PGC‑1α pathway‑related proteins was analyzed using reverse transcription‑quantitative PCR (RT‑qPCR) and western blotting. In vitro, C2C12 cells were used to establish an IR muscle cell model by 0.75 mM palmitic acid (PA) treatment (PA group). The IR cell model was subsequently supplemented with 1 mM MNAM (PM group) or 1 mM MNAM + 30 µM SIRT1 inhibitor, EX527 (PME group). After treatment the glucose levels and insulin signaling‑related proteins were detected by ELISAs and western blotting, respectively. Furthermore, the expression levels of SIRT1/PGC‑1α signaling pathway‑related mRNA and proteins under MNAM treatment were detected by RT‑qPCR and western blotting. MNAM reduced body weight gain in T2DM mice, decreased fasting blood glucose and fasting insulin levels, and inhibited IR. MNAM also regulated insulin signal transduction and promoted glucose utilization in skeletal muscle, and reduced lipid deposition. Thus, MNAM improved IR in the skeletal muscle of T2DM mice. Following application of a SIRT1 inhibitor, the effects of MNAM on the increased glucose utilization in insulin‑resistant myocytes and the insulin signaling pathway were suppressed. The mechanism of action was associated with activation of the SIRT1/PGC‑1α signaling pathway, which promoted the activation of the insulin receptor substrate IRS1/PI3K/AKT pathway.
    DOI:  https://doi.org/10.3892/mmr.2021.11909
  44. J Biol Chem. 2021 Feb 07. pii: S0021-9258(21)00167-8. [Epub ahead of print] 100395
    The role of striated muscle Pik3r1 in glucose and protein metabolism following chronic glucocorticoid exposure.
    Tzu-Chieh Chen, Taiyi Kuo, Mohamad Dandan, Rebecca A Lee, Maggie Chang, Sneha D Villivalam, Szu-Chi Liao, Damian Costello, Mahalakshmi Shankaran, Hussein Mohammed, Sona Kang, Marc K Hellerstein, Jen-Chywan Wang.
      Chronic glucocorticoid exposure causes insulin resistance and muscle atrophy in skeletal muscle. We previously identified phosphoinositide-3-kinase regulatory subunit 1 (Pik3r1) as a primary target gene of skeletal muscle glucocorticoid receptors involved in the glucocorticoid-mediated suppression of insulin action. However, the in vivo functions of Pik3r1 remains unclear. Here, we generated striated muscle-specific Pik3r1 knockout (MKO) mice and treated them with a dexamethasone, a synthetic glucocorticoid. Treating wild type (WT) mice with DEX attenuated insulin activated Akt activity in liver, epididymal white adipose tissue and gastrocnemius muscle. This DEX effect was diminished in gastrocnemius muscle of MKO mice, therefore, resulting in improved glucose and insulin tolerance in DEX-treated MKO mice. Stable isotope labeling techniques revealed that in WT mice, DEX treatment decreased protein fractional synthesis rates in gastrocnemius muscle. Furthermore, histology showed that in WT mice, DEX treatment reduced gastrocnemius myotube diameters. In MKO mice, myotube diameters were smaller than in WT mice and there were more fast oxidative fibers. Importantly, DEX failed to further reduce myotube diameters. Pik3r1 knockout also decreased basal protein synthesis rate (likely caused by lower 4E-BP1 phosphorylation at Thr37/Thr46) and curbed the ability of DEX to attenuate protein synthesis rate. Finally, the ability of DEX to inhibit eIF2α phosphorylation and insulin-induced 4E-BP1 phosphorylation was reduced in MKO mice. Taken together, these results demonstrate the role of Pik3r1 in glucocorticoid-mediated effects on glucose and protein metabolism in skeletal muscle.
    Keywords:  Glucocorticoids; Pik3r1; glucocorticoid receptor; insulin resistance; protein synthesis; skeletal muscle; striated muscle
    DOI:  https://doi.org/10.1016/j.jbc.2021.100395
This page is being maintained by Thomas Krichel. It was last updated on 2021‒07‒23 at 10:22:31.