bims-moremu Biomed News
on Molecular regulators of muscle mass
Issue of 2021–07–04
forty-six papers selected by
Anna Vainshtein, Craft Science Inc.
  1. Targeting cancer via ribosome biogenesis: the cachexia perspective.
  2. Resistance Exercise, Aging, Disuse, and Muscle Protein Metabolism.
  3. Exercise-induced gene expression changes in skeletal muscle of old mice.
  4. Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.
  5. RNA Sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice.
  6. Altered Ca2+ Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease.
  7. Identification of the MuRF1 Skeletal Muscle Ubiquitylome Through Quantitative Proteomics.
  8. MuRF1 Deficiency Prevents Age-Related Fat Weight Gain, Possibly Through Accumulation of PDK4 in Skeletal Muscle Mitochondria in Older Mice.
  9. Age-related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression.
  10. Advanced Fiber Type-Specific Protein Profiles Derived from Adult Murine Skeletal Muscle.
  11. Beta-catenin is required for optimal exercise and contraction stimulated skeletal muscle glucose uptake.
  12. Transdifferentiation of Human Fibroblasts into Skeletal Muscle Cells: Optimization and Assembly into Engineered Tissue Constructs through Biological Ligands.
  13. The effects of acute aerobic and resistance exercise on mTOR signaling and autophagy markers in untrained human skeletal muscle.
  14. Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase.
  15. Magnesium Deficiency Alters Expression of Genes Critical for Muscle Magnesium Homeostasis and Physiology in Mice.
  16. Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control.
  17. Skeletal Muscle progenitors are sensitive to collagen architectural features of fibril size and crosslinking.
  18. Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice.
  19. Inhibition of the Combinatorial Signaling of Transforming Growth Factor-Beta and NOTCH Promotes Myotube Formation of Human Pluripotent Stem Cell-Derived Skeletal Muscle Progenitor Cells.
  20. Lipid Dynamics due to Muscle Atrophy Induced by Immobilization.
  21. Skeletal Muscle Specific Calpastatin Overexpression Mitigates Muscle Weakness in Aging and Extends Lifespan.
  22. Proximity Tagging Identifies the Glycan-Mediated Glycoprotein Interactors of Galectin-1 in Muscle Stem Cells.
  23. Age-related susceptibility to muscle damage following mechanotherapy in rats recovering from disuse atrophy.
  24. ACTN3 genotype influences skeletal muscle mass regulation and response to dexamethasone.
  25. Muscle Ionic Shifts During Exercise: Implications for Fatigue and Exercise Performance.
  26. Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy.
  27. A Muscle-Centric Perspective on Intermittent Fasting: A Suboptimal Dietary Strategy for Supporting Muscle Protein Remodeling and Muscle Mass?
  28. Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging-Related Muscle Weakness in Male Mice.
  29. Repeated bouts of resistance exercise in rats alter mTORC1 activity and ribosomal capacity but not muscle protein synthesis.
  30. Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing.
  31. Pathophysiology and mechanisms of primary sarcopenia (Review).
  32. Gene expression level of renalase in the skeletal muscles is increased with high-intensity exercise training in mice on a high-fat diet.
  33. Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy.
  34. Pathological features of reinnervated skeletal muscles following crush injury of the sciatic nerve in ob/ob mice.
  35. Editorial: Autophagy and Mitophagy in Skeletal Muscle Health and Disease.
  36. The effect of a chemotherapy drug cocktail on myotube morphology, myofibrillar protein abundance, and substrate availability.
  37. Identification of potential microRNAs and KEGG pathways in denervation muscle atrophy based on meta-analysis.
  38. Exercise and ribosome biogenesis in skeletal muscle hypertrophy: impact of genetic and epigenetic factors.
  39. Associations Between Measures of Physical Activity and Muscle Size and Strength: A Systematic Review.
  40. Exercise Training to Decrease Ectopic Intermuscular Adipose Tissue in Individuals with Chronic Diseases: A Systematic Review and Meta-Analysis.
  41. Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle.
  42. Genome-Wide Atlas of Promoter Expression Reveals Contribution of Transcribed Regulatory Elements to Genetic Control of Disuse-Mediated Atrophy of Skeletal Muscle.
  43. Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR.
  44. miR-194-Loaded Gelatin Nanospheres Target MEF2C to Suppress Muscle Atrophy in a Mechanical Unloading Model.
  45. Higher glucose availability augments the metabolic responses of the C2C12 myotubes to exercise-like electrical pulse stimulation.
  46. An integrative transcriptome study reveals Ddit4/Redd1 as a key regulator of cancer cachexia in rodent models.
  1. Cell Mol Life Sci. 2021 Jul 01.
    Targeting cancer via ribosome biogenesis: the cachexia perspective.
    Vandré Casagrande Figueiredo, John J McCarthy.
      Cancer cachexia afflicts many advanced cancer patients with many progressing to death. While there have been many advancements in understanding the molecular mechanisms that contribute to the development of cancer cachexia, substantial gaps still exist. Chemotherapy drugs often target ribosome biogenesis to slow or blunt tumor cell growth and proliferation. Some of the most frequent side-effects of chemotherapy are loss of skeletal muscle mass, muscular strength and an increase in fatigue. Given that ribosome biogenesis has emerged as a main mechanism regulating muscle hypertrophy, and more recently, also implicated in muscle atrophy, we propose that some chemotherapy drugs can cause further muscle wasting via its effect on skeletal muscle cells. Many chemotherapy drugs, including the most prescribed drugs such as doxorubicin and cisplatin, affect ribosomal DNA transcription, or other pathways related to ribosome biogenesis. Furthermore, middle-aged and older individuals are the most affected population with cancer, and advanced cancer patients often show reduced levels of physical inactivity. Thus, aging and inactivity can themselves affect muscle ribosome biogenesis, which can further worsen the effect of chemotherapy on skeletal muscle ribosome biogenesis and, ultimately, muscle mass and function. We propose that chemotherapy can accelerate the onset or worsen cancer cachexia via its inhibitory effects on skeletal muscle ribosome biogenesis. We end our review by providing recommendations that could be used to ameliorate the negative effects of chemotherapy on skeletal muscle ribosome biogenesis.
    Keywords:  Cachexia; Protein synthesis; Ribophagy; Ribosome biogenesis; Skeletal muscle
    DOI:  https://doi.org/10.1007/s00018-021-03888-6
  2. Compr Physiol. 2021 Jun 30. 11(3): 2249-2278
    Resistance Exercise, Aging, Disuse, and Muscle Protein Metabolism.
    James McKendry, Tanner Stokes, Jonathan C Mcleod, Stuart M Phillips.
      Skeletal muscle is the organ of locomotion, its optimal function is critical for athletic performance, and is also important for health due to its contribution to resting metabolic rate and as a site for glucose uptake and storage. Numerous endogenous and exogenous factors influence muscle mass. Much of what is currently known regarding muscle protein turnover is owed to the development and use of stable isotope tracers. Skeletal muscle mass is determined by the meal- and contraction-induced alterations of muscle protein synthesis and muscle protein breakdown. Increased loading as resistance training is the most potent nonpharmacological strategy by which skeletal muscle mass can be increased. Conversely, aging (sarcopenia) and muscle disuse lead to the development of anabolic resistance and contribute to the loss of skeletal muscle mass. Nascent omics-based technologies have significantly improved our understanding surrounding the regulation of skeletal muscle mass at the gene, transcript, and protein levels. Despite significant advances surrounding the mechanistic intricacies that underpin changes in skeletal muscle mass, these processes are complex, and more work is certainly needed. In this article, we provide an overview of the importance of skeletal muscle, describe the influence that resistance training, aging, and disuse exert on muscle protein turnover and the molecular regulatory processes that contribute to changes in muscle protein abundance. © 2021 American Physiological Society. Compr Physiol 11:2249-2278, 2021.
    DOI:  https://doi.org/10.1002/cphy.c200029
  3. Genomics. 2021 Jun 29. pii: S0888-7543(21)00252-4. [Epub ahead of print]
    Exercise-induced gene expression changes in skeletal muscle of old mice.
    Yori Endo, Yuteng Zhang, Shayan Olumi, Mehrean Karvar, Shailesh Argawal, Ronald L Neppl, Indranil Sinha.
      Exercise is believed to be beneficial for skeletal muscle functions across all ages. Regimented exercise is often prescribed as an effective treatment/prophylaxis for age-related loss of muscle mass and functions known as sarcopenia, and plays an important role in the maintenance of mobility and functional independence in the elderly. However, response to exercise changes with aging, with a shift from a predominantly anabolic response resulting in limited gain of muscle strength and endurance. These changes likely reflect age-dependent alterations in transcriptional response underlying the muscular adaptation to exercise. The exact changes in gene expression accompanying exercise, however, are largely unknown, and elucidating them is of a great clinical interest for understanding and optimizing the exercise-based therapies for sarcopenia. In order to characterize the exercise-induced transcriptomic changes in aged muscle, a paired-end RNA sequencing was performed on the rRNA-depleted total RNA extracted from the gastrocnemius muscles of 24 months-old mice after 8 weeks of regimented exercise (exercise group) or no formal exercise program (sedentary group). Differential gene expression analysis of aged skeletal muscle revealed upregulations in the group of genes involved in neurotransmission and neuroexcitation, as well as equally notable absence of anabolic gene upregulations in the exercised group. In particular, genes encoding the transporters and receptor components of glutaminergic transmission were significantly upregulated in exercised muscles, as exemplified by Gria 1, Gria 2 and Grin2c encoding glutamate receptor 1, 2 and 2C respectively, Grin1 and Grin2b encoding N-methyl-d-aspartate receptors (NMDARs), Nptx1 responsible for glutaminergic receptor clustering, and Slc1a2 and Slc17a7 regulating synaptic uptake of glutamate. These changes were accompanied by an increase in the post-synaptic density of NMDARs and acetylcholine receptors (AChRs), as well as their innervation at neuromuscular junctions (NMJs). These results suggest that neural responses predominate the adaptive response of aged skeletal muscle to exercise, and indicate a possibility that glutaminergic transmission at NMJs may be present and responsible for synaptic protection and neural remodeling accompanying the exercise-induced functional enhancement in aged skeletal muscle. In addition, the absence of upregulations in the anabolic pathways highlights them as the area of potential pharmacological targeting for optimizing exercise-led sarcopenia therapy.
    Keywords:  Aging; Differentially expressed genes; Exercise; Sarcopenia; Skeletal muscle
    DOI:  https://doi.org/10.1016/j.ygeno.2021.06.035
  4. JCSM Rapid Commun. 2021 Jan-Jun;4(1):4(1): 40-56
    Skeletal muscle-specific over-expression of the nuclear sirtuin SIRT6 blocks cancer-associated cachexia by regulating multiple targets.
    Sadhana A Samant, Vinodkumar B Pillai, Mahesh P Gupta.
       Background: During cancer cachexia, cytokines released from tumour cells can alter body's metabolism, which can lead to onset of this disease process. Biological basis of cachexia is multifactorial; hence, it is important to identify and modulate multiple targets to curtail the process of cachexia. Previously, we reported that the nuclear sirtuin, SIRT6, blocks expression of myostatin, a negative regulator of muscle growth, through modulation of the NF-κB signalling. This study was undertaken to test whether muscle-specific over-expression of SIRT6 can block the cancer-associated muscle wasting in vivo and to identify additional relevant targets of SIRT6, which can explain its ability to maintain muscle health.
    Methods: We generated a skeletal muscle-specific SIRT6 over-expressing transgenic mouse line (Sk.T6Tg) expressing SIRT6 at a moderate (two-fold to four-fold) level, compared with its control littermates. To generate a cancer-cachexia model, B16F10 mouse melanoma cells were injected subcutaneously in the flanks of mice. Gastrocnemius muscle tissues from non-tumour and tumour controls and Sk.T6Tg mice (n = 5-20) were analysed by histology, immunoblotting, and RT-qPCR. Plasma samples of mice were evaluated using cytokine arrays and ELISA in both non-tumour and tumour conditions.
    Results: Our results demonstrate dual benefits of muscle-specific moderate over-expression of SIRT6 in a mouse model of cancer-cachexia. In tumour-bearing mice, SIRT6 over-expression preserved muscle weight (P < 0.001) and fibre size (P < 0.005) as well as suppressed tumour growth (P < 0.05). SIRT6 over-expression significantly reduced myostatin expression and plasma free fatty acids levels but maintained plasma insulin levels in tumour-bearing mice. These positive effects of SIRT6 were associated with downregulation of the circulatory chemokine, CXCL10, and the myokine, WNT4. SIRT6 also upregulated expression of GLUT4, the major glucose transporter in the skeletal muscle. These results for the first time demonstrate that SIRT6 regulates multiple targets to limit tumour growth and cancer-associated muscle atrophy.
    Conclusion: Given the multifactorial nature of cachexia, SIRT6, which concurrently controls multiple pathways, can be a valuable therapeutic target to overcome this debilitating syndrome.
    Keywords:  Cachexia; Muscle wasting; SIRT6; Sirtuins; Skeletal muscle
    DOI:  https://doi.org/10.1002/rco2.27
  5. Biosci Rep. 2021 Jun 30. pii: BSR20210495. [Epub ahead of print]
    RNA Sequencing reveals potential interacting networks between the altered transcriptome and ncRNome in the skeletal muscle of diabetic mice.
    Devesh Kesharwani, Amit Kumar, Mukta Poojary, Vinod Scaria, Malabika Datta.
      For a global epidemic like Type 2 diabetes mellitus (T2DM), while impaired gene regulation is identified as a primary cause of aberrant cellular physiology; in the past few years, non-coding RNAs (ncRNAs) have emerged as important regulators of cellular metabolism. However, there are no reports of comprehensive in-depth crosstalk between these regulatory elements and the potential consequences in the skeletal muscle during diabetes. Here, using RNA sequencing, we identified 465 mRNAs and 12 lncRNAs (long non-coding RNAs), to be differentially regulated in the skeletal muscle of diabetic mice and pathway enrichment analysis of these altered transcripts revealed pathways of insulin, FOXO and AMPK signaling to be majorly over-represented. Construction of networks showed that these pathways significantly interact with each other that might underlie aberrant skeletal muscle metabolism during diabetes. Gene-gene interaction network depicted strong interactions among several differentially expressed genes namely, Prkab2, Irs1, Pfkfb3, Socs2, etc. Seven altered lncRNAs depicted multiple interactions with the altered transcripts, suggesting possible regulatory roles of these lncRNAs. Inverse patterns of expression were observed between several of the deregulated microRNAs and the differentially expressed transcripts in the tissues. Towards validation, overexpression of miR-381-3p and miR-539-5p in skeletal muscle C2C12 cells significantly decreased the transcript levels of their targets, Nfkbia, Pik3r1 and Pi3kr1, Cdkn2d, respectively. Collectively, the findings provide a comprehensive understanding of the interactions and cross-talk between the ncRNome and transcriptome in the skeletal muscle during diabetes and put forth potential therapeutic options for improving insulin sensitivity.
    Keywords:  RNA sequencing; diabetes; ncRNA; skeletal muscle
    DOI:  https://doi.org/10.1042/BSR20210495
  6. Metabolites. 2021 Jun 28. pii: 424. [Epub ahead of print]11(7):
    Altered Ca2+ Handling and Oxidative Stress Underlie Mitochondrial Damage and Skeletal Muscle Dysfunction in Aging and Disease.
    Antonio Michelucci, Chen Liang, Feliciano Protasi, Robert T Dirksen.
      Skeletal muscle contraction relies on both high-fidelity calcium (Ca2+) signals and robust capacity for adenosine triphosphate (ATP) generation. Ca2+ release units (CRUs) are highly organized junctions between the terminal cisternae of the sarcoplasmic reticulum (SR) and the transverse tubule (T-tubule). CRUs provide the structural framework for rapid elevations in myoplasmic Ca2+ during excitation-contraction (EC) coupling, the process whereby depolarization of the T-tubule membrane triggers SR Ca2+ release through ryanodine receptor-1 (RyR1) channels. Under conditions of local or global depletion of SR Ca2+ stores, store-operated Ca2+ entry (SOCE) provides an additional source of Ca2+ that originates from the extracellular space. In addition to Ca2+, skeletal muscle also requires ATP to both produce force and to replenish SR Ca2+ stores. Mitochondria are the principal intracellular organelles responsible for ATP production via aerobic respiration. This review provides a broad overview of the literature supporting a role for impaired Ca2+ handling, dysfunctional Ca2+-dependent production of reactive oxygen/nitrogen species (ROS/RNS), and structural/functional alterations in CRUs and mitochondria in the loss of muscle mass, reduction in muscle contractility, and increase in muscle damage in sarcopenia and a wide range of muscle disorders including muscular dystrophy, rhabdomyolysis, central core disease, and disuse atrophy. Understanding the impact of these processes on normal muscle function will provide important insights into potential therapeutic targets designed to prevent or reverse muscle dysfunction during aging and disease.
    Keywords:  Ca2+ signaling; atrophy; mitochondria; oxidative stress; sarcopenia; skeletal muscle disease
    DOI:  https://doi.org/10.3390/metabo11070424
  7. Function (Oxf). 2021 ;2(4): zqab029
    Identification of the MuRF1 Skeletal Muscle Ubiquitylome Through Quantitative Proteomics.
    Leslie M Baehr, David C Hughes, Sarah A Lynch, Delphi Van Haver, Teresa Mendes Maia, Andrea G Marshall, Lilliana Radoshevich, Francis Impens, David S Waddell, Sue C Bodine.
      MuRF1 (TRIM63) is a muscle-specific E3 ubiquitin ligase and component of the ubiquitin proteasome system. MuRF1 is transcriptionally upregulated under conditions that cause muscle loss, in both rodents and humans, and is a recognized marker of muscle atrophy. In this study, we used in vivo electroporation to determine whether MuRF1 overexpression alone can cause muscle atrophy and, in combination with ubiquitin proteomics, identify the endogenous MuRF1 substrates in skeletal muscle. Overexpression of MuRF1 in adult mice increases ubiquitination of myofibrillar and sarcoplasmic proteins, increases expression of genes associated with neuromuscular junction instability, and causes muscle atrophy. A total of 169 ubiquitination sites on 56 proteins were found to be regulated by MuRF1. MuRF1-mediated ubiquitination targeted both thick and thin filament contractile proteins, as well as, glycolytic enzymes, deubiquitinases, p62, and VCP. These data reveal a potential role for MuRF1 in not only the breakdown of the sarcomere but also the regulation of metabolism and other proteolytic pathways in skeletal muscle.
    Keywords:  MuRF1; electroporation; muscle atrophy; protein degradation; ubiquitin proteomics
    DOI:  https://doi.org/10.1093/function/zqab029
  8. J Orthop Res. 2021 Jun 29.
    MuRF1 Deficiency Prevents Age-Related Fat Weight Gain, Possibly Through Accumulation of PDK4 in Skeletal Muscle Mitochondria in Older Mice.
    Kosuke Sugiura, Katsuya Hirasaka, Tasuku Maeda, Takayuki Uchida, Koji Kishimoto, Motoko Oarada, Siegfried Labeit, Anayt Ulla, Iori Sakakibara, Reiko Nakao, Koichi Sairyo, Takeshi Nikawa.
      Recent studies show that muscle mass and metabolic function are interlinked. Muscle RING finger 1 (MuRF1) is a critical muscle-specific ubiquitin ligase associated with muscle atrophy. Yet, the molecular target of MuRF1 in atrophy and aging remains unclear. We examined the role of MuRF1 in aging, using MuRF1-deficient (MuRF1-/- ) mice in vivo, and MuRF1-overexpressing cell in vitro. MuRF1 deficiency partially prevents age-induced skeletal muscle loss in mice. Interestingly, body weight and fat mass of >7-month-old MuRF1-/- mice were lower than in MuRF1+/+ mice. Serum and muscle metabolic parameters and results of indirect calorimetry suggest significantly higher energy expenditure and enhanced lipid metabolism in 3-month-old MuRF1-/- mice than in MuRF1+/+ mice, resulting in suppressed adipose tissue gain during aging. Pyruvate dehydrogenase kinase 4 (PDK4) is crucial for a switch from glucose to lipid metabolism, and the interaction between MuRF1 and PDK4 was examined. PDK4 protein levels were elevated in mitochondria from the skeletal muscle in MuRF1-/- mice. In vitro, MuRF1 interacted with PDK4 but did not induce degradation through ubiquitination. Instead, SUMOylation of PDK4 was detected in MuRF1-overexpressing cells, in contrast to cells without the RING domain of MuRF1. MuRF1 deficiency enhances lipid metabolism possibly by upregulating PDK4 localization into mitochondrial through prevention of SUMOylation. Inhibition of MuRF1-mediated PDK4 SUMOylation is a potential therapeutic target for age-related dysfunction of lipid metabolism and muscle atrophy. This article is protected by copyright. All rights reserved.
    Keywords:  Muscle RING finger 1 (MuRF1); Muscle atrophy; Pyruvate dehydrogenase kinase 4 (PDK4); SUMO modification; lipid metabolism
    DOI:  https://doi.org/10.1002/jor.25131
  9. J Cachexia Sarcopenia Muscle. 2021 Jul 01.
    Age-related decline in murine heart and skeletal muscle performance is attenuated by reduced Ahnak1 expression.
    Shokoufeh Mahmoodzadeh, Katharina Koch, Cindy Schriever, Jingman Xu, Maria Steinecker, Joachim Leber, Elke Dworatzek, Bettina Purfürst, Severine Kunz, Deborah Recchia, Monica Canepari, Arnd Heuser, Silvia Di Francescantonio, Ingo Morano.
       BACKGROUND: Aging is associated with a progressive reduction in cellular function leading to poor health and loss of physical performance. Mitochondrial dysfunction is one of the hallmarks of aging; hence, interventions targeting mitochondrial dysfunction have the potential to provide preventive and therapeutic benefits to elderly individuals. Meta-analyses of age-related gene expression profiles showed that the expression of Ahnak1, a protein regulating several signal-transduction pathways including metabolic homeostasis, is increased with age, which is associated with low VO2MAX and poor muscle fitness. However, the role of Ahnak1 in the aging process remained unknown. Here, we investigated the age-related role of Ahnak1 in murine exercise capacity, mitochondrial function, and contractile function of cardiac and skeletal muscles.
    METHODS: We employed 15- to 16-month-old female and male Ahnak1-knockout (Ahnak1-KO) and wild-type (WT) mice and performed morphometric, biochemical, and bioenergetics assays to evaluate the effects of Ahnak1 on exercise capacity and mitochondrial morphology and function in cardiomyocytes and tibialis anterior (TA) muscle. A human left ventricular (LV) cardiomyocyte cell line (AC16) was used to investigate the direct role of Ahnak1 in cardiomyocytes.
    RESULTS: We found that the level of Ahnak1 protein is significantly up-regulated with age in the murine LV (1.9-fold) and TA (1.8-fold) tissues. The suppression of Ahnak1 was associated with improved exercise tolerance, as all aged adult Ahnak1-KO mice (100%) successfully completed the running programme, whereas approximately 31% male and 8% female WT mice could maintain the required running speed and distance. Transmission electron microscopic studies showed that LV and TA tissue specimens of aged adult Ahnak1-KO of both sexes have significantly more enlarged/elongated mitochondria and less small mitochondria compared with WT littermates (P < 0.01 and P < 0.001, respectively) at basal level. Further, we observed a shift in mitochondrial fission/fusion balance towards fusion in cardiomyocytes and TA muscle from aged adult Ahnak1-KO mice. The maximal and reserve respiratory capacities were significantly higher in cardiomyocytes from aged adult Ahnak1-KO mice compared with the WT counterparts (P < 0.05 and P < 0.01, respectively). Cardiomyocyte contractility and fatigue resistance of TA muscles were significantly increased in Ahnak1-KO mice of both sexes, compared with the WT groups. In vitro studies using AC16 cells have confirmed that the alteration of mitochondrial function is indeed a direct effect of Ahnak1. Finally, we presented Ahnak1 as a novel cardiac mitochondrial membrane-associated protein.
    CONCLUSIONS: Our data suggest that Ahnak1 is involved in age-related cardiac and skeletal muscle dysfunction and could therefore serve as a promising therapeutical target.
    Keywords:  Age-related mitochondrial dysfunction; Ahnak1; Heart; Physical performance; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.12749
  10. Proteomes. 2021 Jun 08. pii: 28. [Epub ahead of print]9(2):
    Advanced Fiber Type-Specific Protein Profiles Derived from Adult Murine Skeletal Muscle.
    Britta Eggers, Karin Schork, Michael Turewicz, Katalin Barkovits, Martin Eisenacher, Rolf Schröder, Christoph S Clemen, Katrin Marcus.
      Skeletal muscle is a heterogeneous tissue consisting of blood vessels, connective tissue, and muscle fibers. The last are highly adaptive and can change their molecular composition depending on external and internal factors, such as exercise, age, and disease. Thus, examination of the skeletal muscles at the fiber type level is essential to detect potential alterations. Therefore, we established a protocol in which myosin heavy chain isoform immunolabeled muscle fibers were laser microdissected and separately investigated by mass spectrometry to develop advanced proteomic profiles of all murine skeletal muscle fiber types. All data are available via ProteomeXchange with the identifier PXD025359. Our in-depth mass spectrometric analysis revealed unique fiber type protein profiles, confirming fiber type-specific metabolic properties and revealing a more versatile function of type IIx fibers. Furthermore, we found that multiple myopathy-associated proteins were enriched in type I and IIa fibers. To further optimize the assignment of fiber types based on the protein profile, we developed a hypothesis-free machine-learning approach, identified a discriminative peptide panel, and confirmed our panel using a public data set.
    Keywords:  fiber types; laser microdissection; neuromuscular disorders; proteomics; skeletal muscle
    DOI:  https://doi.org/10.3390/proteomes9020028
  11. J Physiol. 2021 Jun 27.
    Beta-catenin is required for optimal exercise and contraction stimulated skeletal muscle glucose uptake.
    Stewart W C Masson, Jonathan S T Woodhead, Randall F D'Souza, Sophie C Broome, Caitlin MacRae, Hyun C Cho, Robert D Atiola, Tumanu Futi, Jessica R Dent, Peter R Shepherd, Troy L Merry.
       KEY POINTS: Loss of β-catenin impairs in vivo and isolated muscle exercise/contraction stimulated glucose uptake β-catenin is required for exercise-induced skeletal muscle actin cytoskeleton remodelling β-catenin675 phosphorylation during exercise may intensity dependent ABSTRACT: The conserved structural protein β-catenin is an emerging regulator of vesicle trafficking in multiple tissues and supports insulin-stimulated GLUT4 translocation in skeletal muscle by facilitating cortical actin remodelling. Actin remodelling may be a convergence point between insulin and exercise/contraction stimulated glucose uptake. Here we investigated whether β-catenin is involved in regulating exercise/contraction-stimulated glucose uptake. We report that the muscle specific deletion of β-catenin induced in adult mice (BCAT-mKO) impairs both exercise and contraction (isolated muscle) induced glucose uptake without affecting running performance or canonical exercise signalling pathways. Furthermore, high intensity exercise in mice, and contraction of myotubes and isolated muscles led to the phosphorylation of β-cateninS675 , and this was impaired by Rac1 inhibition. Whereas moderate intensity exercise in control and Rac1 muscle specific knockout mice did not induce muscle β-cateninS675 phosphorylation suggesting exercise-intensity dependent regulation of β-cateninS675 . Introduction of a non-phosphorylatable S675A mutant of β-catenin into myoblasts impaired carbachol, a Rac1 and RhoA activator, stimulated GLUT4 translocation and actin remodelling in myoblasts, and exercise-induced increases in cross-sectional phalloidin staining (F-actin marker) of gastrocnemius muscle was impaired in muscle from BCAT-mKO. Collectively our findings suggest that β-catenin is required for optimal glucose transport in muscle during exercise/contraction, potentially via facilitating actin cytoskeleton remodelling. This article is protected by copyright. All rights reserved.
    Keywords:  GLUT4; Rac1; actin; glucose transport; insulin
    DOI:  https://doi.org/10.1113/JP281352
  12. Biology (Basel). 2021 Jun 16. pii: 539. [Epub ahead of print]10(6):
    Transdifferentiation of Human Fibroblasts into Skeletal Muscle Cells: Optimization and Assembly into Engineered Tissue Constructs through Biological Ligands.
    Khaled M A Abdel-Raouf, Rachid Rezgui, Cesare Stefanini, Jeremy C M Teo, Nicolas Christoforou.
      The development of robust skeletal muscle models has been challenging due to the partial recapitulation of human physiology and architecture. Reliable and innovative 3D skeletal muscle models recently described offer an alternative that more accurately captures the in vivo environment but require an abundant cell source. Direct reprogramming or transdifferentiation has been considered as an alternative. Recent reports have provided evidence for significant improvements in the efficiency of derivation of human skeletal myotubes from human fibroblasts. Herein we aimed at improving the transdifferentiation process of human fibroblasts (tHFs), in addition to the differentiation of murine skeletal myoblasts (C2C12), and the differentiation of primary human skeletal myoblasts (HSkM). Differentiating or transdifferentiating cells were exposed to single or combinations of biological ligands, including Follistatin, GDF8, FGF2, GDF11, GDF15, hGH, TMSB4X, BMP4, BMP7, IL6, and TNF-α. These were selected for their critical roles in myogenesis and regeneration. C2C12 and tHFs displayed significant differentiation deficits when exposed to FGF2, BMP4, BMP7, and TNF-α, while proliferation was significantly enhanced by FGF2. When exposed to combinations of ligands, we observed consistent deficit differentiation when TNF-α was included. Finally, our direct reprogramming technique allowed for the assembly of elongated, cross-striated, and aligned tHFs within tissue-engineered 3D skeletal muscle constructs. In conclusion, we describe an efficient system to transdifferentiate human fibroblasts into myogenic cells and a platform for the generation of tissue-engineered constructs. Future directions will involve the evaluation of the functional characteristics of these engineered tissues.
    Keywords:  3D engineered human skeletal muscle; biological ligands; direct reprogramming; skeletal muscle differentiation; transdifferentiation
    DOI:  https://doi.org/10.3390/biology10060539
  13. Eur J Appl Physiol. 2021 Jul 01.
    The effects of acute aerobic and resistance exercise on mTOR signaling and autophagy markers in untrained human skeletal muscle.
    Corey E Mazo, Andrew C D'Lugos, Kaylin R Sweeney, Jacob M Haus, Siddhartha S Angadi, Chad C Carroll, Jared M Dickinson.
       PURPOSE: Aerobic (AE) and resistance (RE) exercise elicit unique adaptations in skeletal muscle. The purpose here was to compare the post-exercise response of mTOR signaling and select autophagy markers in skeletal muscle to acute AE and RE.
    METHODS: In a randomized, cross-over design, six untrained men (27 ± 3 years) completed acute AE (40 min cycling, 70% HRmax) and RE (8 sets, 10 repetitions, 65% 1RM). Muscle biopsies were taken at baseline, and at 1 h and 4 h following each exercise. Western blot analyses were performed to examine total and phosphorylated protein levels. Upstream regulator analyses of skeletal muscle transcriptomics were performed to discern the predicted activation states of mTOR and FOXO3.
    RESULTS: Compared to AE, acute RE resulted in greater phosphorylation (P < 0.05) of mTORSer2448 at 4 h, S6K1Thr389 at 1 h, and 4E- BP1Thr37/46 during the post-exercise period. However, both AE and RE increased mTORSer2448 and S6K1Thr389 phosphorylation at 4 h (P < 0.05). Upstream regulator analyses revealed the activation state of mTOR was increased for both AE (z score, 2.617) and RE (z score, 2.789). No changes in LC3BI protein were observed following AE or RE (P > 0.05), however, LC3BII protein was decreased after both AE and RE at 1 h and 4 h (P < 0.05). p62 protein content was also decreased at 4 h following AE and RE (P < 0.05).
    CONCLUSION: Both acute AE and RE stimulate mTOR signaling and similarly impact select markers of autophagy. These findings indicate the early adaptive response of untrained human skeletal muscle to divergent exercise modes is not likely mediated through large differences in mTOR signaling or autophagy.
    Keywords:  Anabolic; Catabolic; Cell signaling; Endurance; Hypertrophy; Weightlifting
    DOI:  https://doi.org/10.1007/s00421-021-04758-6
  14. Cancers (Basel). 2021 Jun 30. pii: 3285. [Epub ahead of print]13(13):
    Control of Skeletal Muscle Atrophy Associated to Cancer or Corticosteroids by Ceramide Kinase.
    Federica Pierucci, Alessia Frati, Chiara Battistini, Fabio Penna, Paola Costelli, Elisabetta Meacci.
      Apart from cytokines and chemokines, sphingolipid mediators, particularly sphingosine-1-phosphate (S1P) and ceramide 1-phosphate (C1P), contribute to cancer and inflammation. Cancer, as well as other inflammatory conditions, are associated with skeletal muscle (SkM) atrophy, which is characterized by the unbalance between protein synthesis and degradation. Although the signaling pathways involved in SkM mass wasting are multiple, the regulatory role of simple sphingolipids is limited. Here, we report the impairment of ceramide kinase (CerK), the enzyme responsible for the phosphorylation of ceramide to C1P, associated with the accomplishment of atrophic phenotype in various experimental models of SkM atrophy: in vivo animal model bearing the C26 adenocarcinoma or Lewis lung carcinoma tumors, in human and murine SkM cells treated with the conditioned medium obtained from cancer cells or with the glucocorticoid dexamethasone. Notably, we demonstrate in all the three experimental approaches a drastic decrease of CerK expression. Gene silencing of CerK promotes the up-regulation of atrogin-1/MAFbx expression, which was also observed after cell treatment with C8-ceramide, a biologically active ceramide analogue. Conversely, C1P treatment significantly reduced the corticosteroid's effects. Altogether, these findings provide evidence that CerK, acting as a molecular modulator, may be a new possible target for SkM mass regulation associated with cancer or corticosteroids.
    Keywords:  C2C12 skeletal muscle cells; atrogin-1/MAFbx; cachexia; ceramide; ceramide kinase; glucocorticoids; skeletal muscle mass wasting; sphingolipids
    DOI:  https://doi.org/10.3390/cancers13133285
  15. Nutrients. 2021 Jun 24. pii: 2169. [Epub ahead of print]13(7):
    Magnesium Deficiency Alters Expression of Genes Critical for Muscle Magnesium Homeostasis and Physiology in Mice.
    Dominique Bayle, Cécile Coudy-Gandilhon, Marine Gueugneau, Sara Castiglioni, Monica Zocchi, Magdalena Maj-Zurawska, Adriana Palinska-Saadi, André Mazur, Daniel Béchet, Jeanette A Maier.
      Chronic Mg2+ deficiency is the underlying cause of a broad range of health dysfunctions. As 25% of body Mg2+ is located in the skeletal muscle, Mg2+ transport and homeostasis systems (MgTHs) in the muscle are critical for whole-body Mg2+ homeostasis. In the present study, we assessed whether Mg2+ deficiency alters muscle fiber characteristics and major pathways regulating muscle physiology. C57BL/6J mice received either a control, mildly, or severely Mg2+-deficient diet (0.1%; 0.01%; and 0.003% Mg2+ wt/wt, respectively) for 14 days. Mg2+ deficiency slightly decreased body weight gain and muscle Mg2+ concentrations but was not associated with detectable variations in gastrocnemius muscle weight, fiber morphometry, and capillarization. Nonetheless, muscles exhibited decreased expression of several MgTHs (MagT1, CNNM2, CNNM4, and TRPM6). Moreover, TaqMan low-density array (TLDA) analyses further revealed that, before the emergence of major muscle dysfunctions, even a mild Mg2+ deficiency was sufficient to alter the expression of genes critical for muscle physiology, including energy metabolism, muscle regeneration, proteostasis, mitochondrial dynamics, and excitation-contraction coupling.
    Keywords:  magnesium; magnesium transporters; skeletal muscle; transcriptome
    DOI:  https://doi.org/10.3390/nu13072169
  16. Int J Mol Sci. 2021 Jun 22. pii: 6669. [Epub ahead of print]22(13):
    Emerin Represses STAT3 Signaling through Nuclear Membrane-Based Spatial Control.
    Byongsun Lee, Seungjae Lee, Younggwang Lee, Yongjin Park, Jaekyung Shim.
      Emerin is the inner nuclear membrane protein involved in maintaining the mechanical integrity of the nuclear membrane. Mutations in EMD encoding emerin cause Emery-Dreifuss muscular dystrophy (EDMD). Evidence is accumulating that emerin regulation of specific gene expression is associated with this disease, but the exact function of emerin has not been fully elucidated. Here, we show that emerin downregulates Signal transducer and activators of transcription 3 (STAT3) signaling, activated exclusively by Janus kinase (JAK). Deletion mutation experiments show that the lamin-binding domain of emerin is essential for the inhibition of STAT3 signaling. Emerin interacts directly and co-localizes with STAT3 in the nuclear membrane. Emerin knockdown induces STAT3 target genes Bcl2 and Survivin to increase cell survival signals and suppress hydrogen peroxide-induced cell death in HeLa cells. Specifically, downregulation of BAF or lamin A/C increases STAT3 signaling, suggesting that correct-localized emerin, by assembling with BAF and lamin A/C, acts as an intrinsic inhibitor against STAT3 signaling. In C2C12 cells, emerin knockdown induces STAT3 target gene, Pax7, and activated abnormal myoblast proliferation associated with muscle wasting in skeletal muscle homeostasis. Our results indicate that emerin downregulates STAT3 signaling by inducing retention of STAT3 and delaying STAT3 signaling in the nuclear membrane. This mechanism provides clues to the etiology of emerin-related muscular dystrophy and may be a new therapeutic target for treatment.
    Keywords:  JAK; STAT3; emerin; muscular dystrophy
    DOI:  https://doi.org/10.3390/ijms22136669
  17. Am J Physiol Cell Physiol. 2021 06 30.
    Skeletal Muscle progenitors are sensitive to collagen architectural features of fibril size and crosslinking.
    Lin-Ya Hu, Cassidy Jane Mileti, Taryn Loomis, Sarah E Brashear, Sarah Ahmad, Rosemary R Chellakudam, Ross P Wohlgemuth, Marissa A Gionet-Gonzales, J Kent Leach, Lucas R Smith.
      Muscle stem cells (MuSCs) are essential for the robust regenerative capacity of skeletal muscle. However, in fibrotic environments marked by abundant collagen and altered collagen organization, the regenerative capability of MuSCs is diminished. MuSCs are sensitive to their extracellular matrix environment, but their response to collagen architecture is largely unknown. The present study aimed to systematically test the effect of underlying collagen structures on MuSC functions. Collagen hydrogels were engineered with varied architectures: collagen concentration, crosslinking, fibril size, and fibril alignment, and the changes were validated with second harmonic generation imaging and rheology. Proliferation and differentiation responses of primary mouse MuSCs and immortal myoblasts (C2C12s) were assessed using EdU assays and immunolabeling skeletal muscle myosin expression, respectively. Changing collagen concentration and the corresponding hydrogel stiffness did not have a significant influence on MuSC proliferation or differentiation. However, MuSC differentiation on atelocollagen gels, which do not form mature pyridinoline crosslinks, was increased compared to the crosslinked control. In addition, MuSCs and C2C12 myoblasts showed greater differentiation on gels with smaller collagen fibrils. Proliferation rates of C2C12 myoblasts were also higher on gels with smaller collagen fibrils, while MuSCs did not show a significant difference. Surprisingly, collagen alignment did not have significant effects on muscle progenitor function. This study demonstrates that MuSCs are capable of sensing their underlying ECM structures and enhancing differentiation on substrates with less collagen crosslinking or smaller collagen fibrils. Thus, in fibrotic muscle, targeting crosslinking and fibril size rather than collagen expression may more effectively support MuSC-based regeneration.
    Keywords:  Collagen architecture; extracellular matrix; muscle differentiation; satellite cell; stem cell
    DOI:  https://doi.org/10.1152/ajpcell.00065.2021
  18. Am J Physiol Cell Physiol. 2021 06 30.
    Dystrophin deficiency disrupts muscle clock expression and mitochondrial quality control in mdx mice.
    Justin P Hardee, Marissa K Caldow, Audrey S M Chan, Stuart K Plenderleith, Jennifer Trieu, Rene Koopman, Gordon S Lynch.
      Impaired oxidative capacity and mitochondrial function contribute to the dystrophic pathology in muscles of Duchenne muscular dystrophy (DMD) patients and in relevant mouse models of the disease. Emerging evidence suggests an association between disrupted core clock expression and mitochondrial quality control, but this has not been established in muscles lacking dystrophin. We examined the diurnal regulation of muscle core clock and mitochondrial quality control expression in dystrophin-deficient C57BL/10ScSn-Dmdmdx (mdx) mice, an established model of DMD. Male C57BL/10 (BL/10; n=18) and mdx mice (n=18) were examined every 4 hours beginning at the dark cycle. Throughout the entire light-dark cycle, extensor digitorum longus (EDL) muscles from mdx mice had decreased core clock mRNA expression (Arntl, Cry1, Cry2, Nr1d2; p<0.05) and disrupted mitochondrial quality control mRNA expression related to biogenesis (decreased; Ppargc1a, Esrra; p<0.05), fission (increased; Dnm1l; p<0.01), fusion (decreased; Opa1, Mfn1; p<0.05) and autophagy/mitophagy (decreased: Bnip3; p<0.05; increased: Becn1; p<0.05). Cosinor analysis revealed a decrease in the rhythmicity parameters mesor and amplitude for Arntl, Cry1, Cry2, Per2, and Nr1d1 (p<0.001) in mdx mice. Diurnal oscillations in Esrra, Sirt1, Map1lc3b and Sqstm1 were absent in mdx mice, along with decreased mesor and amplitude of Ppargc1a mRNA expression (p<0.01). The expression of proteins involved in mitochondrial biogenesis (decreased: PPARGC1A, p<0.05) and autophagy/mitophagy (increased: MAP1LC3BII, SQSTM1, BNIP3; p<0.05) were also dysregulated in tibialis anterior muscles of mdx mice. These findings suggest that dystrophin deficiency in mdx mice impairs the regulation of the core clock and mitochondrial quality control, with relevance to DMD and related disorders.
    Keywords:  diurnal variation; dystrophin; mitochondria; muscular dystrophy
    DOI:  https://doi.org/10.1152/ajpcell.00188.2021
  19. Cells. 2021 Jun 30. pii: 1649. [Epub ahead of print]10(7):
    Inhibition of the Combinatorial Signaling of Transforming Growth Factor-Beta and NOTCH Promotes Myotube Formation of Human Pluripotent Stem Cell-Derived Skeletal Muscle Progenitor Cells.
    In Young Choi, Ho Tae Lim, Young Hyun Che, Gabsang Lee, Yong Jun Kim.
      Understanding the signaling pathways that regulate the final differentiation of human myoblasts is essential for successful cell transplantation and drug screening for the treatment of muscular dystrophy. In an effort to improve myotube formation from hiPSC-derived myoblasts, we validated a collection of 13 small molecules in a newly established in vitro screening platform for the assessment of myotube formation. The analysis of myotube formation as measured by the fusion index showed that the combinational inhibition of the TGFβ signaling with NOTCH signaling enhances the ability of multi-nucleated myotube production. Combinational treatment of inhibitors for TGFβ and NOTCH signaling pathways improved myotube formation in a dose-dependent manner. This effect was achieved by inhibiting the combinatorial mechanism of signaling. The combination treatment of small molecules effective in inducing multinucleated myotubes was validated in healthy human primary myoblasts. In addition, it was also applied to DMD patient iPSC-derived myoblasts to enhance the generation of multinucleated myotubes.
    Keywords:  Duchenne muscular dystrophy; human pluripotent stem cell-derived skeletal muscle; in vitro drug screening platform
    DOI:  https://doi.org/10.3390/cells10071649
  20. J Oleo Sci. 2021 ;70(7): 937-946
    Lipid Dynamics due to Muscle Atrophy Induced by Immobilization.
    Keisuke Kimura, Mizuki Morisasa, Takafumi Mizushige, Rikuo Karasawa, Chinatsu Kanamaru, Yukihito Kabuyama, Takahiro Hayasaka, Tsukasa Mori, Naoko Goto-Inoue.
      Muscle atrophy refers to skeletal muscle loss and dysfunction that affects glucose and lipid metabolism. Moreover, muscle atrophy is manifested in cancer, diabetes, and obesity. In this study, we focused on lipid metabolism during muscle atrophy. We observed that the gastrocnemius muscle was associated with significant atrophy with 8 days of immobilization of hind limb joints and that muscle atrophy occurred regardless of the muscle fiber type. Further, we performed lipid analyses using thin layer chromatography, liquid chromatography-mass spectrometry, and mass spectrometry imaging. Total amounts of triacylglycerol, phosphatidylserine, and sphingomyelin were found to be increased in the immobilized muscle. Additionally, we found that specific molecular species of phosphatidylserine, phosphatidylcholine, and sphingomyelin were increased by immobilization. Furthermore, the expression of adipose triglyceride lipase and the activity of cyclooxygenase-2 were significantly reduced by atrophy. From these results, it was revealed that lipid accumulation and metabolic changes in specific fatty acids occur during disuse muscle atrophy. The present study holds implications in validating preventive treatment strategies for muscle atrophy.
    Keywords:  fatty acid; immobilization; lipid; muscle atrophy
    DOI:  https://doi.org/10.5650/jos.ess21045
  21. J Appl Physiol (1985). 2021 07 01.
    Skeletal Muscle Specific Calpastatin Overexpression Mitigates Muscle Weakness in Aging and Extends Lifespan.
    Elizabeth A Schroder, Lin Wang, Yuan Wen, Leigh Ann P Callahan, Gerald S Supinski.
      Calpain activation has been postulated as a potential contributor to the loss of muscle mass and function associated with both aging and disease but limitations of previous experimental approaches have failed to completely examine this issue. We hypothesized that mice overexpressing calpastatin, an endogenous inhibitor of calpain (CalpOX), solely in skeletal muscle would show an amelioration of the aging muscle phenotype. We assessed 4 groups of mice (age in months): (1) young wild type (5.71±0.43) (WT); (2) young CalpOX (5.6±0.5); (3) old WT (25.81±0.56); and (4) old CalpOX (25.91±0.60) for diaphragm and limb muscle (extensor digitorum longus, EDL) force frequency relations. Aging significantly reduced diaphragm and EDL peak force in old WT mice, and decreased the force-time integral during a fatiguing protocol by 48% and 23% in aged WT diaphragm and EDL, respectively. In contrast, we found that CalpOX mice had significantly increased diaphragm and EDL peak force in old mice, similar to that observed in young mice. The impact of aging on the force-time integral during a fatiguing protocol was abolished in the diaphragm and EDL of old CalpOX animals. Surprisingly, we found that CalpOX had a significant impact on longevity, increasing median survival from 20.55 months in WT mice to 24 months in CalpOX mice (p = 0.0006).
    Keywords:  aging; calpain; calpastatin; force; muscle
    DOI:  https://doi.org/10.1152/japplphysiol.00883.2020
  22. ACS Chem Biol. 2021 Jun 28.
    Proximity Tagging Identifies the Glycan-Mediated Glycoprotein Interactors of Galectin-1 in Muscle Stem Cells.
    Zak Vilen, Eugene Joeh, Meg Critcher, Christopher G Parker, Mia L Huang.
      Myogenic differentiation, the irreversible developmental process where precursor myoblast muscle stem cells become contractile myotubes, is heavily regulated by glycosylation and glycan-protein interactions at the cell surface and the extracellular matrix. The glycan-binding protein galectin-1 has been found to be a potent activator of myogenic differentiation. While it is being explored as a potential therapeutic for muscle repair, a precise understanding of its glycoprotein interactors is lacking. These gaps are due in part to the difficulties of capturing glycan-protein interactions in live cells. Here, we demonstrate the use of a proximity tagging strategy coupled with quantitative mass-spectrometry-based proteomics to capture, enrich, and identify the glycan-mediated glycoprotein interactors of galectin-1 in cultured live mouse myoblasts. Our interactome dataset can serve as a resource to aid the determination of mechanisms through which galectin-1 promotes myogenic differentiation. Moreover, it can also facilitate the determination of the physiological glycoprotein counter-receptors of galectin-1. Indeed, we identify several known and novel glycan-mediated ligands of galectin-1 as well as validate that galectin-1 binds the native CD44 glycoprotein in a glycan-mediated manner.
    DOI:  https://doi.org/10.1021/acschembio.1c00313
  23. J Gerontol A Biol Sci Med Sci. 2021 Jun 28. pii: glab186. [Epub ahead of print]
    Age-related susceptibility to muscle damage following mechanotherapy in rats recovering from disuse atrophy.
    Zachary R Hettinger, Kyoko Hamagata, Amy L Confides, Marcus M Lawrence, Benjamin F Miller, Timothy A Butterfield, Esther E Dupont-Versteegden.
      The inability to fully recover lost muscle mass following periods of disuse atrophy predisposes older adults to lost independence and poor quality of life. We have previously shown that mechanotherapy at a moderate load (4.5 N) enhances muscle mass recovery following atrophy in adult, but not older adult rats. We propose that elevated transverse stiffness in aged muscle inhibits the growth response to mechanotherapy and hypothesize that a higher load (7.6 N) will overcome this resistance to mechanical stimuli. F344/BN adult and older adult male rats underwent 14-days of hindlimb suspension, followed by 7-days of recovery with (RE+M) or without (RE) mechanotherapy at 7.6 N on gastrocnemius muscle. The 7.6 N load was determined by measuring transverse passive stiffness and linearly scaling up from 4.5 N. No differences in protein turnover or mean fiber cross sectional area were observed between RE and RE+M for older adult rats or adult rats at 7.6 N. However, there was a higher number of small muscle fibers present in older adult, but not adult rats, which was explained by a 16-fold increase in the frequency of small fibers expressing embryonic myosin heavy chain. Elevated central nucleation, satellite cell abundance, and dystrophin -/laminin + fibers were present in older adult rats only following 7.6 N, while 4.5 N did not induce damage at either age. We conclude that age is an important variable when considering load used during mechanotherapy and age-related transverse stiffness may predispose older adults to damage during the recovery period following disuse atrophy.
    Keywords:  Skeletal muscle; aging; disuse atrophy; extracellular matrix; mechanotherapy
    DOI:  https://doi.org/10.1093/gerona/glab186
  24. Sci Adv. 2021 Jul;pii: eabg0088. [Epub ahead of print]7(27):
    ACTN3 genotype influences skeletal muscle mass regulation and response to dexamethasone.
    Jane T Seto, Kelly N Roeszler, Lyra R Meehan, Harrison D Wood, Chrystal Tiong, Lucinda Bek, Siaw F Lee, Manan Shah, Kate G R Quinlan, Paul Gregorevic, Peter J Houweling, Kathryn N North.
      Homozygosity for the common ACTN3 null polymorphism (ACTN3 577X) results in α-actinin-3 deficiency in ~20% of humans worldwide and is linked to reduced sprint and power performance in both elite athletes and the general population. α-Actinin-3 deficiency is also associated with reduced muscle mass, increased risk of sarcopenia, and altered muscle wasting response induced by denervation and immobilization. Here, we show that α-actinin-3 plays a key role in the regulation of protein synthesis and breakdown signaling in skeletal muscle and influences muscle mass from early postnatal development. We also show that α-actinin-3 deficiency reduces the atrophic and anti-inflammatory response to the glucocorticoid dexamethasone in muscle and protects against dexamethasone-induced muscle wasting in female but not male mice. The effects of α-actinin-3 deficiency on muscle mass regulation and response to muscle wasting provide an additional mechanistic explanation for the positive selection of the ACTN3 577X allele in recent human history.
    DOI:  https://doi.org/10.1126/sciadv.abg0088
  25. Compr Physiol. 2021 Jun 30. 11(3): 1895-1959
    Muscle Ionic Shifts During Exercise: Implications for Fatigue and Exercise Performance.
    Morten Hostrup, Simeon Peter Cairns, Jens Bangsbo.
      Exercise causes major shifts in multiple ions (e.g., K+ , Na+ , H+ , lactate- , Ca2+ , and Cl- ) during muscle activity that contributes to development of muscle fatigue. Sarcolemmal processes can be impaired by the trans-sarcolemmal rundown of ion gradients for K+ , Na+ , and Ca2+ during fatiguing exercise, while changes in gradients for Cl- and Cl- conductance may exert either protective or detrimental effects on fatigue. Myocellular H+ accumulation may also contribute to fatigue development by lowering glycolytic rate and has been shown to act synergistically with inorganic phosphate (Pi) to compromise cross-bridge function. In addition, sarcoplasmic reticulum Ca2+ release function is severely affected by fatiguing exercise. Skeletal muscle has a multitude of ion transport systems that counter exercise-related ionic shifts of which the Na+ /K+ -ATPase is of major importance. Metabolic perturbations occurring during exercise can exacerbate trans-sarcolemmal ionic shifts, in particular for K+ and Cl- , respectively via metabolic regulation of the ATP-sensitive K+ channel (KATP ) and the chloride channel isoform 1 (ClC-1). Ion transport systems are highly adaptable to exercise training resulting in an enhanced ability to counter ionic disturbances to delay fatigue and improve exercise performance. In this article, we discuss (i) the ionic shifts occurring during exercise, (ii) the role of ion transport systems in skeletal muscle for ionic regulation, (iii) how ionic disturbances affect sarcolemmal processes and muscle fatigue, (iv) how metabolic perturbations exacerbate ionic shifts during exercise, and (v) how pharmacological manipulation and exercise training regulate ion transport systems to influence exercise performance in humans. © 2021 American Physiological Society. Compr Physiol 11:1895-1959, 2021.
    DOI:  https://doi.org/10.1002/cphy.c190024
  26. Pharmacol Res. 2021 Jun 29. pii: S1043-6618(21)00334-0. [Epub ahead of print] 105750
    Targeting HDAC8 to ameliorate skeletal muscle differentiation in Duchenne muscular dystrophy.
    Marco Spreafico, Marco Cafora, Cinzia Bragato, Daniele Capitanio, Federica Marasca, Beatrice Bodega, Clara De Palma, Marina Mora, Cecilia Gelfi, Anna Marozzi, Anna Pistocchi.
      Duchenne muscular dystrophy (DMD) causes progressive skeletal muscle degeneration and currently there are few therapeutic options. The identification of new drug targets and their validation in model systems of DMD could be a promising approach to make progress in finding new treatments for this lethal disease. Histone deacetylases (HDACs) play key roles in myogenesis and the therapeutic approach targeting HDACs in DMD is in an advanced phase of clinical trial. Here, we show that the expression of HDAC8, one of the members of the HDAC family, is increased in DMD patients and dystrophic zebrafish. The selective inhibition of HDAC8 with the PCI-34051 inhibitor rescues skeletal muscle defects, similarly to the treatment with the pan-HDAC inhibitor Givinostat. Through acetylation profile of zebrafish with HDAC8 dysregulation, we identified new HDAC8 targets involved in cytoskeleton organization such as tubulin that, when acetylated, is a marker of stable microtubules. Our work provides evidence of HDAC8 overexpression in DMD patients and zebrafish and support its specific inhibition as a new valuable therapeutic approach in the treatment of this pathology.
    Keywords:  Duchenne muscular dystrophy; Givinostat; Givinostat Hydrochloride Hydrate (PubChem CID: 9804991); HDAC8; PCI-34051; PCI-34051 (PubChem CID:24753719); zebrafish
    DOI:  https://doi.org/10.1016/j.phrs.2021.105750
  27. Front Nutr. 2021 ;8 640621
    A Muscle-Centric Perspective on Intermittent Fasting: A Suboptimal Dietary Strategy for Supporting Muscle Protein Remodeling and Muscle Mass?
    Eric Williamson, Daniel R Moore.
      Muscle protein is constantly "turning over" through the breakdown of old/damaged proteins and the resynthesis of new functional proteins, the algebraic difference determining net muscle gain, maintenance, or loss. This turnover, which is sensitive to the nutritional environment, ultimately determines the mass, quality, and health of skeletal muscle over time. Intermittent fasting has become a topic of interest in the health community as an avenue to improve health and body composition primarily via caloric deficiency as well as enhanced lipolysis and fat oxidation secondary to attenuated daily insulin response. However, this approach belies the established anti-catabolic effect of insulin on skeletal muscle. More importantly, muscle protein synthesis, which is the primary regulated turnover variable in healthy humans, is stimulated by the consumption of dietary amino acids, a process that is saturated at a moderate protein intake. While limited research has explored the effect of intermittent fasting on muscle-related outcomes, we propose that infrequent meal feeding and periods of prolonged fasting characteristic of models of intermittent fasting may be counter-productive to optimizing muscle protein turnover and net muscle protein balance. The present commentary will discuss the regulation of muscle protein turnover across fasted and fed cycles and contrast it with studies exploring how dietary manipulation alters the partitioning of fat and lean body mass. It is our position that intermittent fasting likely represents a suboptimal dietary approach to remodel skeletal muscle, which could impact the ability to maintain or enhance muscle mass and quality, especially during periods of reduced energy availability.
    Keywords:  dietary protein; intermittent fasting; lean body mass; muscle mass; muscle protein metabolism; muscle protein synthesis/breakdown; time-restricted eating; weight loss
    DOI:  https://doi.org/10.3389/fnut.2021.640621
  28. J Am Heart Assoc. 2021 Jul 02. e021030
    Double Deletion of Angiotensin II Type 2 and Mas Receptors Accelerates Aging-Related Muscle Weakness in Male Mice.
    Hikari Takeshita, Koichi Yamamoto, Masaki Mogi, Yu Wang, Yoichi Nozato, Taku Fujimoto, Serina Yokoyama, Kazuhiro Hongyo, Futoshi Nakagami, Hiroshi Akasaka, Yoichi Takami, Yasushi Takeya, Ken Sugimoto, Masatsugu Horiuchi, Hiromi Rakugi.
      Background The activation of AT2 (angiotensin II type 2 receptor ) and Mas receptor by angiotensin II and angiotensin-(1-7), respectively, is the primary process that counteracts activation of the canonical renin-angiotensin system (RAS). Although inhibition of canonical RAS could delay the progression of physiological aging, we recently reported that deletion of Mas had no impact on the aging process in mice. Here, we used male mice with a deletion of only AT2 or a double deletion of AT2 and Mas to clarify whether these receptors contribute to the aging process in a complementary manner, primarily by focusing on aging-related muscle weakness. Methods and Results Serial changes in grip strength of these mice up to 24 months of age showed that AT2/Mas knockout mice, but not AT2 knockout mice, had significantly weaker grip strength than wild-type mice from the age of 18 months. AT2/Mas knockout mice exhibited larger sizes, but smaller numbers and increased frequency of central nucleation (a marker of aged muscle) of single skeletal muscle fibers than AT2 knockout mice. Canonical RAS-associated genes, inflammation-associated genes, and senescence-associated genes were highly expressed in skeletal muscles of AT2/Mas knockout mice. Muscle angiotensin II content increased in AT2/Mas knockout mice. Conclusions Double deletion of AT2 and Mas in mice exaggerated aging-associated muscle weakness, accompanied by signatures of activated RAS, inflammation, and aging in skeletal muscles. Because aging-associated phenotypes were absent in single deletions of the receptors, AT2 and Mas could complement each other in preventing local activation of RAS during aging.
    Keywords:  Mas receptor; aging; angiotensin II type 2 receptor; muscle; renin‐angiotensin system
    DOI:  https://doi.org/10.1161/JAHA.120.021030
  29. Exp Physiol. 2021 Jul 01.
    Repeated bouts of resistance exercise in rats alter mTORC1 activity and ribosomal capacity but not muscle protein synthesis.
    Takaya Kotani, Junya Takegaki, Yuki Tamura, Karina Kouzaki, Koichi Nakazato, Naokata Ishii.
       NEW FINDINGS: What is the central question of this study? Is muscle protein synthesis (MPS) additionally activated following exercise when ribosomal capacity is increased after repeated bouts of resistance exercise (RE)? What is the main finding and its importance? Skeletal muscles with increased ribosome content by repeated RE bouts showed sufficient activation of MPS with lower mTORC1 signaling. Thus, repeated bouts of RE possibly change the translational capacity and efficiency to optimize translation activation following RE.
    ABSTRACT: Resistance exercise (RE) activates ribosome biogenesis and increases ribosome content in skeletal muscles. However, it is unclear whether the increase in ribosome content subsequently causes an increase in RE-induced muscle protein synthesis (MPS) activation. Thus, this study aimed to investigate the relationship between ribosome content and MPS after exercise using a rat RE model. Male Sprague-Dawley rats were categorized into three groups (n = 6 for each group): sedentary (SED), RE trained with one bout (1B) and three bouts (3B). The RE stimulus was applied to the right gastrocnemius muscle by transcutaneous electric stimulation under isoflurane anaesthesia. The 3B group underwent stimulation every other day. Our results revealed that 6 h after the last bout of RE, muscles in the 3B group showed an increase in total RNA and 18S + 28S rRNA content per muscle weight than in the SED and 1B groups. In both the 1B and 3B groups, MPS, estimated by puromycin incorporation in proteins, was higher than that in the SED group 6 h after exercise; however, no significant difference was observed between the 1B and 3B groups. In the 1B and 3B groups, phosphorylated p70S6K at Thr-389 increased, indicating mTORC1 activity. p70S6K phosphorylation level was lower in the 3B group than in the 1B group. Lastly, protein synthesis per ribosome (indicator of translation efficiency) was lower in the 3B group than in the 1B group. Thus, three bouts of RE changed the ribosome content and mTORC1 activation, however, not the degree of RE-induced global MPS activation. This article is protected by copyright. All rights reserved.
    Keywords:  mTORC1, SUnSET; translation efficiency, translation capacity, rRNA
    DOI:  https://doi.org/10.1113/EP089699
  30. Int J Mol Sci. 2021 Jun 08. pii: 6195. [Epub ahead of print]22(12):
    Improper Remodeling of Organelles Deputed to Ca2+ Handling and Aerobic ATP Production Underlies Muscle Dysfunction in Ageing.
    Feliciano Protasi, Laura Pietrangelo, Simona Boncompagni.
      Proper skeletal muscle function is controlled by intracellular Ca2+ concentration and by efficient production of energy (ATP), which, in turn, depend on: (a) the release and re-uptake of Ca2+ from sarcoplasmic-reticulum (SR) during excitation-contraction (EC) coupling, which controls the contraction and relaxation of sarcomeres; (b) the uptake of Ca2+ into the mitochondrial matrix, which stimulates aerobic ATP production; and finally (c) the entry of Ca2+ from the extracellular space via store-operated Ca2+ entry (SOCE), a mechanism that is important to limit/delay muscle fatigue. Abnormalities in Ca2+ handling underlie many physio-pathological conditions, including dysfunction in ageing. The specific focus of this review is to discuss the importance of the proper architecture of organelles and membrane systems involved in the mechanisms introduced above for the correct skeletal muscle function. We reviewed the existing literature about EC coupling, mitochondrial Ca2+ uptake, SOCE and about the structural membranes and organelles deputed to those functions and finally, we summarized the data collected in different, but complementary, projects studying changes caused by denervation and ageing to the structure and positioning of those organelles: a. denervation of muscle fibers-an event that contributes, to some degree, to muscle loss in ageing (known as sarcopenia)-causes misplacement and damage: (i) of membrane structures involved in EC coupling (calcium release units, CRUs) and (ii) of the mitochondrial network; b. sedentary ageing causes partial disarray/damage of CRUs and of calcium entry units (CEUs, structures involved in SOCE) and loss/misplacement of mitochondria; c. functional electrical stimulation (FES) and regular exercise promote the rescue/maintenance of the proper architecture of CRUs, CEUs, and of mitochondria in both denervation and ageing. All these structural changes were accompanied by related functional changes, i.e., loss/decay in function caused by denervation and ageing, and improved function following FES or exercise. These data suggest that the integrity and proper disposition of intracellular organelles deputed to Ca2+ handling and aerobic generation of ATP is challenged by inactivity (or reduced activity); modifications in the architecture of these intracellular membrane systems may contribute to muscle dysfunction in ageing and sarcopenia.
    Keywords:  Ca2+ entry unit (CEU); Ca2+ release unit (CRU); excitation–contraction (EC) coupling; mitochondria; sarcoplasmic-reticulum (SR); store-operated Ca2+ entry (SOCE); transverse tubule (TT)
    DOI:  https://doi.org/10.3390/ijms22126195
  31. Int J Mol Med. 2021 Aug;pii: 156. [Epub ahead of print]48(2):
    Pathophysiology and mechanisms of primary sarcopenia (Review).
    Hiroki Nishikawa, Shinya Fukunishi, Akira Asai, Keisuke Yokohama, Shuhei Nishiguchi, Kazuhide Higuchi.
      Aging causes skeletal muscle atrophy, and myofiber loss can be a critical component of this process. In 1989, Rosenberg emphasized the importance of the loss of skeletal muscle mass that occurs with aging and coined the term 'sarcopenia'. Since then, sarcopenia has attracted considerable attention due to the aging population in developed countries. The presence of sarcopenia is closely related to staggering, falls and even frailty in the elderly, which in turn leads to the need for nursing care. Sarcopenia is often associated with a poor prognosis in the elderly. Therefore, it is crucial to investigate the causes and pathogenesis of sarcopenia, and to develop and introduce interventional strategies in line with these causes and pathogenesis. Sarcopenia can be a primary component of physical frailty. The association between sarcopenia, frailty and locomotive syndrome is complex; however, sarcopenia is a muscle‑specific concept that is relatively easy to approach in research. In the elderly, a lack of exercise, malnutrition and hormonal changes lead to neuromuscular junction insufficiency, impaired capillary blood flow, reduced repair and regeneration capacity due to a decrease in the number of muscle satellite cells, the infiltration of inflammatory cells and oxidative stress, resulting in muscle protein degradation exceeding synthesis. In addition, mitochondrial dysfunction causes metabolic abnormalities, such as insulin resistance, which may lead to quantitative and qualitative abnormalities in skeletal muscle, resulting in sarcopenia. The present review article focuses on age‑related primary sarcopenia and outlines its pathogenesis and mechanisms.
    Keywords:  mechanism; myofiber; myokine; primary sarcopenia; satellite cell
    DOI:  https://doi.org/10.3892/ijmm.2021.4989
  32. Physiol Int. 2021 Jun 29.
    Gene expression level of renalase in the skeletal muscles is increased with high-intensity exercise training in mice on a high-fat diet.
    Katsuyuki Tokinoya, Seiko Ono, Kai Aoki, Koki Yanazawa, Yasuhiro Shishikura, Takehito Sugasawa, Kazuhiro Takekoshi.
       Introduction: Exercise training is beneficial for reducing obesity. In particular, exercise training can lower the catecholamine concentration in circulation. Renalase, whose expression was first confirmed in the kidneys, is a physiologically active substance that decomposes circulating catecholamines; additionally, it has been reported to be present in the skeletal muscles. The aim of this study was to clarify the expression of renalase in the skeletal muscles and kidneys after high-intensity exercise training in obese mice.
    Material and methods: The mice were divided into four groups: normal diet and sedentary, normal diet and exercise training, high-fat diet and sedentary, and high-fat diet and exercise training, and the test was performed for 8 weeks.
    Results: Body weight and skeletal muscle wet weight were reduced by high-fat diet intake but were rescued by training. Skeletal muscle renalase gene expression was significantly increased by exercise training. However, in the kidneys the gene expression of renalase was significantly increased by high-fat diet intake and exercise training. No significant changes were observed in the gene expression of catecholamine-degrading enzymes, catechol-O-methyltransferase and monoamine oxidase A and B.
    Conclusion: We demonstrated that exercise training increased the gene expression of renalase in the skeletal muscles and kidneys, thus lowering circulating catecholamine levels. This may lead to amelioration of obesity as catecholamines are lipolytic.
    Keywords:  blood pressure; catecholamine; kidney; obesity; skeletal muscle
    DOI:  https://doi.org/10.1556/2060.2021.00147
  33. Cells. 2021 Jun 16. pii: 1521. [Epub ahead of print]10(6):
    Ion Channel Gene Mutations Causing Skeletal Muscle Disorders: Pathomechanisms and Opportunities for Therapy.
    Lorenzo Maggi, Silvia Bonanno, Concetta Altamura, Jean-François Desaphy.
      Skeletal muscle ion channelopathies (SMICs) are a large heterogeneous group of rare genetic disorders caused by mutations in genes encoding ion channel subunits in the skeletal muscle mainly characterized by myotonia or periodic paralysis, potentially resulting in long-term disabilities. However, with the development of new molecular technologies, new genes and new phenotypes, including progressive myopathies, have been recently discovered, markedly increasing the complexity in the field. In this regard, new advances in SMICs show a less conventional role of ion channels in muscle cell division, proliferation, differentiation, and survival. Hence, SMICs represent an expanding and exciting field. Here, we review current knowledge of SMICs, with a description of their clinical phenotypes, cellular and molecular pathomechanisms, and available treatments.
    Keywords:  CACNA1S; CLCN1; KCNJ2; SCN4A; ion channels; myopathies; myotonia; periodic paralysis
    DOI:  https://doi.org/10.3390/cells10061521
  34. Muscle Nerve. 2021 Jul 01.
    Pathological features of reinnervated skeletal muscles following crush injury of the sciatic nerve in ob/ob mice.
    Takahiro Asano, Masaya Tsujii, Takahiro Iino, Kazuya Odake, Akihiro Sudo.
       INTRODUCTION: Obesity is a factor contributing to suboptimal improvement of motor function in peripheral nerve disorders. We aimed to evaluate the skeletal muscles during denervation and re-innervation following nerve crush injury in leptin-deficient (ob/ob) mice.
    METHODS: Experiments were performed on the skeletal muscles of the hindlimbs in 20 male ob/ob mice and controls. Characteristics of the gastrocnemius muscles were evaluated by histological analysis, immunohistological analysis, and Sircol-collagen assay after measurement of body weight and wet weight of the skeletal muscles, and by walking track analysis. Then, the sciatic nerve was denervated by crushing with smooth forceps and reinnervation was evaluated.
    RESULTS: Gastrocnemius wet weight was significantly lower in the ob/ob mice than in control mice. A smaller cross-sectional area of type II fibers and increase of type I fiber grouping of the skeletal muscles was demonstrated in the ob/ob mice. Following nerve injury, motor function recovery was equal between both groups but the cross-sectional area of type II fibers was significantly smaller in ob/ob mice than control mice at 4 weeks. The denervated muscles showed an increase in collagen deposition in the interstitial space; predominant in the ob/ob mice after nerve injury.
    DISCUSSION: The results of this study suggest that fibrosis in the skeletal muscle of obese patients after nerve injury is prominent, which may impair improvement of muscle function after treatment of peripheral nerve disorders.
    Keywords:  motor function; ob/ob mice; obesity; peripheral nerve disorder; skeletal muscle
    DOI:  https://doi.org/10.1002/mus.27365
  35. Front Physiol. 2021 ;12 703458
    Editorial: Autophagy and Mitophagy in Skeletal Muscle Health and Disease.
    Sabah N A Hussain, Marco Sandri, Gilles Gouspillou.
      
    Keywords:  atrophy; autophagy; mitophagy; proteolysis; skeletal muscles; sympathethic nervous system
    DOI:  https://doi.org/10.3389/fphys.2021.703458
  36. Physiol Rep. 2021 Jul;9(13): e14927
    The effect of a chemotherapy drug cocktail on myotube morphology, myofibrillar protein abundance, and substrate availability.
    Stephen Mora, Olasunkanmi A J Adegoke.
      Cachexia, a condition prevalent in many chronically ill patients, is characterized by weight loss, fatigue, and decreases in muscle mass and function. Cachexia is associated with tumor burden and disease-related malnutrition, but other studies implicate chemotherapy as being causative. We investigated the effects of a chemotherapy drug cocktail on myofibrillar protein abundance and synthesis, anabolic signaling mechanisms, and substrate availability. On day 4 of differentiation, L6 myotubes were treated with vehicle (1.4 μl/ml DMSO) or a chemotherapy drug cocktail (a mixture of cisplatin [20 μg/ml], leucovorin [10 μg/ml], and 5-fluorouracil [5-FLU; 50 μg/ml]) for 24-72 h. Compared to myotubes treated with vehicle, those treated with the drug cocktail showed 50%-80% reductions in the abundance of myofibrillar proteins, including myosin heavy chain-1, troponin, and tropomyosin (p < 0.05). Cells treated with only a mixture of cisplatin and 5-FLU had identical reductions in myofibrillar protein abundance. Myotubes treated with the drug cocktail also showed >50% reductions in the phosphorylation of AKTSer473 and of mTORC1 substrates ribosomal protein S6Ser235/236 , its kinase S6K1Thr389 and eukaryotic translation initiation factor 4E-binding protein 1 (all p < 0.05). Drug treatment impaired peptide chain initiation in myofibrillar protein fractions and insulin-stimulated glucose uptake (p = 0.06) but increased the expression of autophagy markers beclin-1 and microtubule-associated proteins 1A/1B light chain 3B (p < 0.05), and of apoptotic marker, cleaved caspase 3 (p < 0.05). Drug treatment reduced the expression of mitochondrial markers cytochrome oxidase and succinate dehydrogenase (p < 0.05). The observed profound negative effects of this chemotherapy drug cocktail on myotubes underlie a need for approaches that can reduce the negative effects of these drugs on muscle metabolism.
    Keywords:  cachexia; chemotherapy; protein synthesis; skeletal muscle
    DOI:  https://doi.org/10.14814/phy2.14927
  37. Sci Rep. 2021 Jun 30. 11(1): 13560
    Identification of potential microRNAs and KEGG pathways in denervation muscle atrophy based on meta-analysis.
    Xinyi Gu, Bo Jin, Zhidan Qi, Xiaofeng Yin.
      The molecular mechanism of muscle atrophy has been studied a lot, but there is no comprehensive analysis focusing on the denervated muscle atrophy. The gene network that controls the development of denervated muscle atrophy needs further elucidation. We examined differentially expressed genes (DEGs) from five denervated muscle atrophy microarray datasets and predicted microRNAs that target these DEGs. We also included the differentially expressed microRNAs datasets of denervated muscle atrophy in previous studies as background information to identify potential key microRNAs. Finally, we compared denervated muscle atrophy with disuse muscle atrophy caused by other reasons, and obtained the Den-genes which only differentially expressed in denervated muscle atrophy. In this meta-analysis, we obtained 429 up-regulated genes, 525 down-regulated genes and a batch of key microRNAs in denervated muscle atrophy. We found eight important microRNA-mRNA interactions (miR-1/Jun, miR-1/Vegfa, miR-497/Vegfa, miR-23a/Vegfa, miR-206/Vegfa, miR-497/Suclg1, miR-27a/Suclg1, miR-27a/Mapk14). The top five KEGG pathways enriched by Den-genes are Insulin signaling pathway, T cell receptor signaling pathway, MAPK signaling pathway, Toll-like receptor signaling pathway and B cell receptor signaling pathway. Our research has delineated the RNA regulatory network of denervated muscle atrophy, and uncovered the specific genes and terms in denervated muscle atrophy.
    DOI:  https://doi.org/10.1038/s41598-021-92489-1
  38. J Physiol. 2021 Jul 01.
    Exercise and ribosome biogenesis in skeletal muscle hypertrophy: impact of genetic and epigenetic factors.
    Robert Solsona, Anthony M J Sanchez.
      
    Keywords:  DNA methylation; resistance exercise; ribosomal DNA
    DOI:  https://doi.org/10.1113/JP281984
  39. Arch Rehabil Res Clin Transl. 2021 Jun;3(2): 100124
    Associations Between Measures of Physical Activity and Muscle Size and Strength: A Systematic Review.
    Zachary P Rostron, Rodney A Green, Michael Kingsley, Anita Zacharias.
       Objective: To determine whether physical activity is associated with lower limb muscle size and strength within the general population.
    Data Sources: Six databases were systematically searched from inception using 3 main constructs: lower extremity, muscle volume, and muscle strength.
    Study Selection: Studies that measured physical activity (using either objective or subjective measurements), lower limb muscle size, and strength were included. Available discrete group data were standardized using previously published age- and sex-specific normative values prior to analysis.
    Data Extraction: The final analysis included 47 studies from an initial yield of 5402 studies. Standardized scores for outcome measures were calculated for 97 discrete groups.
    Data Synthesis: As anticipated, lower limb muscle size was positively correlated with lower limb muscle strength (r=0.26, P<.01; n=4812). Objectively measured physical activity (ie, accelerometry, pedometry) (n=1944) was positively correlated with both lower limb muscle size (r=0.30, P<.01; n=1626) and lower limb strength (r=0.24, P<.01; n=1869). However, subjectively measured physical activity (ie, questionnaires) (n=3949) was negatively associated with lower limb muscle size (r=-0.59, P<.01; n=3243) and lower limb muscle strength (r=-0.48, P<. 01; n=3882).
    Conclusions: This review identified that objective measures of physical activity are moderately associated with lower limb muscle size and muscle strength and can, therefore, be used to predict muscle changes within the lower limbs associated with exercise-based rehabilitation programs.
    Keywords:  1RM, 1 repetition maximum; BMI, body mass index; CSA, cross-sectional area; Exercise; IPAQ, international physical activity questionnaire; MRI, magnetic resonance imaging; MVPA, moderate to vigorous physical activity; Muscle, skeletal; Rehabilitation; Surveys and questionnaires
    DOI:  https://doi.org/10.1016/j.arrct.2021.100124
  40. Phys Ther. 2021 Jun 25. pii: pzab162. [Epub ahead of print]
    Exercise Training to Decrease Ectopic Intermuscular Adipose Tissue in Individuals with Chronic Diseases: A Systematic Review and Meta-Analysis.
    Mauro Tuñón-Suárez, Alvaro Reyes-Ponce, Rodrigo Godoy-Órdenes, Nicolás Quezada, Marcelo Flores-Opazo.
       OBJECTIVE: The purpose of this study was to evaluate the effect of exercise training on ectopic fat within skeletal muscle (intermuscular adipose tissue [IMAT]) in adult populations with chronic diseases.
    METHODS: A literature search was conducted in relevant databases to identify randomized controlled trials (RCTs) from inception. Selected studies examined the effect of aerobic training (AET), resistance training (RT), or combined training (COM) on IMAT as assessed by noninvasive magnetic resonance (MRI) or computed tomography (CT). Eligibility was determined using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses). Data extraction was performed using the population (P), intervention (I), comparison (C), outcome (O), timing (T), and settings (S) approach. Methodological quality was analyzed by the Cochrane risk of bias assessment. Standardized effect sizes (ES) with 95% Cis were calculated. Heterogeneity among studies was quantified using I2 statistics. Subgroup and meta-regression analyses were included. Risk of publication bias was examined by the Egger regression test.
    RESULTS: Nineteen RCTs included 962 adults (628 women; age range = 34.8-93.4 y) with different chronic conditions that participated in 10 AET, 12 RT, and 5 COM interventions. The quality of studies was deemed moderate. Overall, the effect of exercise on IMAT was small (ES = 0.24; 95% CI = 0.10-0.37; heterogeneity I2 = 0.0%) compared with no exercise or control interventions. Moderate intensity AET and COM had larger ES compared with RT regardless of intensity. This effect was associated with exercise-induced body weight and fat mass losses. Subgroup analysis revealed larger ES in studies assessing IMAT by MRI compared with CT, in adults and middle-aged individuals compared with older adults, and in participants who were HIV+ compared with other diagnoses.
    CONCLUSION: AET and COM of moderate intensity reduce IMAT in individuals from 18 to 65 years of age who are affected by chronic diseases. This effect is associated with exercise-induced body weight and fat mass losses. In older individuals who are frail and patients at an advanced disease stage, exercise may result in a paradoxical IMAT accumulation.
    IMPACT: In people affected by chronic conditions, IMAT accumulation induces muscle mass and strength losses, decline in physical performance, inflammation, and metabolic alterations. The present study shows that moderate intensity AET or COM prevent or reduce IMAT in these conditions. Thus, the deleterious effect of IMAT on skeletal muscle homeostasis may be reverted by a properly prescribed exercise regime. Findings of the present systematic review are critical for physical therapists and health care professionals as they emphasize the therapeutic role of exercise and provide recommendations for exercise prescription that ultimately may have a positive impact on the course of disease, recovery of functionality, and independence.
    LAY SUMMARY: Aerobic exercise (eg, walking/jogging, cycling) alone or combined with resistance exercise (strength training with free-weights, kettle bells, or gym equipment) is effective in reducing fat streaks that infiltrate muscles and impair muscle function and growth, particularly in adults affected by chronic diseases.
    Keywords:  Chronic Disease; Exercise Physiology; Exercise Therapy; Intermuscular Adipose Tissue; Noninvasive Imaging; Sarcopenia
    DOI:  https://doi.org/10.1093/ptj/pzab162
  41. J Cachexia Sarcopenia Muscle. 2021 Jun 30.
    Meta-analysis of genome-wide DNA methylation and integrative omics of age in human skeletal muscle.
    Sarah Voisin, Macsue Jacques, Shanie Landen, Nicholas R Harvey, Larisa M Haupt, Lyn R Griffiths, Sofiya Gancheva, Meriem Ouni, Markus Jähnert, Kevin J Ashton, Vernon G Coffey, Jamie-Lee M Thompson, Thomas M Doering, Anne Gabory, Claudine Junien, Robert Caiazzo, Hélène Verkindt, Violetta Raverdy, François Pattou, Philippe Froguel, Jeffrey M Craig, Sara Blocquiaux, Martine Thomis, Adam P Sharples, Annette Schürmann, Michael Roden, Steve Horvath, Nir Eynon.
       BACKGROUND: Knowledge of age-related DNA methylation changes in skeletal muscle is limited, yet this tissue is severely affected by ageing in humans.
    METHODS: We conducted a large-scale epigenome-wide association study meta-analysis of age in human skeletal muscle from 10 studies (total n = 908 muscle methylomes from men and women aged 18-89 years old). We explored the genomic context of age-related DNA methylation changes in chromatin states, CpG islands, and transcription factor binding sites and performed gene set enrichment analysis. We then integrated the DNA methylation data with known transcriptomic and proteomic age-related changes in skeletal muscle. Finally, we updated our recently developed muscle epigenetic clock (https://bioconductor.org/packages/release/bioc/html/MEAT.html).
    RESULTS: We identified 6710 differentially methylated regions at a stringent false discovery rate <0.005, spanning 6367 unique genes, many of which related to skeletal muscle structure and development. We found a strong increase in DNA methylation at Polycomb target genes and bivalent chromatin domains and a concomitant decrease in DNA methylation at enhancers. Most differentially methylated genes were not altered at the mRNA or protein level, but they were nonetheless strongly enriched for genes showing age-related differential mRNA and protein expression. After adding a substantial number of samples from five datasets (+371), the updated version of the muscle clock (MEAT 2.0, total n = 1053 samples) performed similarly to the original version of the muscle clock (median of 4.4 vs. 4.6 years in age prediction error), suggesting that the original version of the muscle clock was very accurate.
    CONCLUSIONS: We provide here the most comprehensive picture of DNA methylation ageing in human skeletal muscle and reveal widespread alterations of genes involved in skeletal muscle structure, development, and differentiation. We have made our results available as an open-access, user-friendly, web-based tool called MetaMeth (https://sarah-voisin.shinyapps.io/MetaMeth/).
    Keywords:  Ageing; DNA methylation; Epigenetic clock; Epigenetics; Meta-analysis; Omics; Skeletal muscle
    DOI:  https://doi.org/10.1002/jcsm.12741
  42. Biology (Basel). 2021 Jun 20. pii: 557. [Epub ahead of print]10(6):
    Genome-Wide Atlas of Promoter Expression Reveals Contribution of Transcribed Regulatory Elements to Genetic Control of Disuse-Mediated Atrophy of Skeletal Muscle.
    Sergey S Pintus, Ilya R Akberdin, Ivan Yevshin, Pavel Makhnovskii, Oksana Tyapkina, Islam Nigmetzyanov, Leniz Nurullin, Ruslan Devyatiyarov, Elena Shagimardanova, Daniil Popov, Fedor A Kolpakov, Oleg Gusev, Guzel R Gazizova.
      The prevention of muscle atrophy carries with it clinical significance for the control of increased morbidity and mortality following physical inactivity. While major transcriptional events associated with muscle atrophy-recovery processes are the subject of active research on the gene level, the contribution of non-coding regulatory elements and alternative promoter usage is a major source for both the production of alternative protein products and new insights into the activity of transcription factors. We used the cap-analysis of gene expression (CAGE) to create a genome-wide atlas of promoter-level transcription in fast (m. EDL) and slow (m. soleus) muscles in rats that were subjected to hindlimb unloading and subsequent recovery. We found that the genetic regulation of the atrophy-recovery cycle in two types of muscle is mediated by different pathways, including a unique set of non-coding transcribed regulatory elements. We showed that the activation of "shadow" enhancers is tightly linked to specific stages of atrophy and recovery dynamics, with the largest number of specific regulatory elements being transcriptionally active in the muscles on the first day of recovery after a week of disuse. The developed comprehensive database of transcription of regulatory elements will further stimulate research on the gene regulation of muscle homeostasis in mammals.
    Keywords:  RNA transcription; atrophy; cis-regulatory elements; disuse; enhancers; promoters; rat; skeletal muscles; transcribed non-coding elements of genome; transcriptomics
    DOI:  https://doi.org/10.3390/biology10060557
  43. Biology (Basel). 2021 Jun 17. pii: 543. [Epub ahead of print]10(6):
    Female Mice Are Protected from Metabolic Decline Associated with Lack of Skeletal Muscle HuR.
    Allison C Stone, Robert C Noland, Randall L Mynatt, Samuel E Velasquez, David S Bayless, Eric Ravussin, Jaycob D Warfel.
      Male mice lacking HuR in skeletal muscle (HuRm-/-) have been shown to have decreased gastrocnemius lipid oxidation and increased adiposity and insulin resistance. The same consequences have not been documented in female HuRm-/- mice. Here we examine this sexually dimorphic phenotype. HuRm-/- mice have an increased fat mass to lean mass ratio (FM/LM) relative to controls where food intake is similar. Increased body weight for male mice correlates with increased blood glucose during glucose tolerance tests (GTT), suggesting increased fat mass in male HuRm-/- mice as a driver of decreased glucose clearance. However, HuRm-/- female mice show decreased blood glucose levels during GTT relative to controls. HuRm-/- mice display decreased palmitate oxidation in skeletal muscle relative to controls. This difference is more robust for male HuRm-/- mice and more exaggerated for both sexes at high dietary fat. A high-fat diet stimulates expression of Pgc1α in HuRm-/- male skeletal muscle, but not in females. However, the lipid oxidation Pparα pathway remains decreased in HuRm-/- male mice relative to controls regardless of diet. This pathway is only decreased in female HuRm-/- mice fed high fat diet. A decreased capacity for lipid oxidation in skeletal muscle in the absence of HuR may thus be linked to decreased glucose clearance in male but not female mice.
    Keywords:  HuR; insulin resistance; lipid oxidation; metabolic flexibility; sexual dimorphism; skeletal muscle
    DOI:  https://doi.org/10.3390/biology10060543
  44. Mol Pharm. 2021 Jun 30.
    miR-194-Loaded Gelatin Nanospheres Target MEF2C to Suppress Muscle Atrophy in a Mechanical Unloading Model.
    Chen-Yan Zhang, Chang-Qing Yang, Qiang Chen, Jie Liu, Ge Zhang, Chen Dong, Xin-Li Liu, Hafiz Muhammad Umer Farooq, Shi-Qi Zhao, Li-Heng Luo, Shan-Feng Jiang, Yin-Bo Niu, Da-Chuan Yin.
      Muscle atrophy usually occurs under mechanical unloading, which increases the risk of injury to reduce the functionality of the moving system, while there is still no effective therapy until now. It was found that miR-194 was significantly downregulated in a muscle atrophy model, and its target protein was the myocyte enhancer factor 2C (MEF2C). miR-194 could promote muscle differentiation and also inhibit ubiquitin ligases, thus miR-194 could be used as a nucleic acid drug to treat muscle atrophy, whereas miRNA was unstable in vivo, limiting its application as a therapeutic drug. A gelatin nanosphere (GN) delivery system was applied for the first time to load exogenous miRNA here. Exogenous miR-194 was loaded in GNs and injected into the muscle atrophy model. It demonstrated that the muscle fiber cross-sectional area, in situ muscle contractile properties, and myogenic markers were increased significantly after treatment. It proposed miR-194 loaded in GNs as an effective treatment for muscle atrophy by promoting muscle differentiation and inhibiting ubiquitin ligase activity. Moreover, the developed miRNA delivery system, taking advantage of its tunable composition, degradation rate, and capacity to load various drug molecules with high dosage, is considered a promising platform to achieve precise treatment of muscle atrophy-related diseases.
    Keywords:  MEF2C; drug delivery; mechanical unloading environment; miR-194; muscle atrophy
    DOI:  https://doi.org/10.1021/acs.molpharmaceut.1c00121
  45. Am J Physiol Endocrinol Metab. 2021 06 28.
    Higher glucose availability augments the metabolic responses of the C2C12 myotubes to exercise-like electrical pulse stimulation.
    Juulia H Lautaoja, Thomas O'Connell, Sakari Mäntyselkä, Juuli Peräkylä, Heikki Kainulainen, Satu Pekkala, Perttu Permi, Juha J Hulmi.
      The application of exercise-like electrical pulse simulation (EL-EPS) has become a widely used exercise mimetic in vitro. EL-EPS produces similar physiological responses as in vivo exercise, while less is known about the detailed metabolic effects. Routinely the C2C12 myotubes are cultured in high glucose medium (4.5 g/l), which may alter EL-EPS responses. In this study, we evaluate the metabolic effects of EL-EPS under the high and low glucose (1.0 g/l) conditions to understand how substrate availability affects the myotube response to EL-EPS.The C2C12 myotube, media and cell-free media metabolites were analyzed using untargeted nuclear magnetic resonance (NMR)-based metabolomics. Further, translational and metabolic changes and possible exerkine effects were analyzed. EL-EPS enhanced substrate utilization as well as production and secretion of lactate, acetate, 3-hydroxybutyrate and branched chain fatty acids (BCFAs). The increase in BCFAs correlated with branched chain amino acids (BCAAs) and BCFAs were strongly decreased when myotubes were cultured without BCAAs suggesting the action of acyl-CoA thioesterases on BCAA catabolites. Notably, not all EL-EPS responses were augmented by high glucose because EL-EPS increased phosphorylated c-Jun N-terminal kinase and interleukin-6 secretion independent of glucose availability. Administration of acetate and EL-EPS conditioned media on HepG2 hepatocytes had no adverse effects on lipolysis or triacylglycerol content.Our results demonstrate that unlike in cell-free media, the C2C12 myotube and media metabolites were affected by EL-EPS, particularly under high glucose condition suggesting that media composition should be considered in future EL-EPS studies. Further, acetate and BCFAs were identified as putative exerkines warranting more research.
    Keywords:  acetate; branched chain fatty acids; exerkine; metabolomics; skeletal muscle
    DOI:  https://doi.org/10.1152/ajpendo.00133.2021
  46. Cell Death Dis. 2021 Jun 26. 12(7): 652
    An integrative transcriptome study reveals Ddit4/Redd1 as a key regulator of cancer cachexia in rodent models.
    Mengyuan Niu, Li Li, Zhonglan Su, Lulu Wei, Wenyuan Pu, Chen Zhao, Yibing Ding, Junaid Wazir, Wangsen Cao, Shiyu Song, Qian Gao, Hongwei Wang.
      Cancer cachexia is a multifactorial metabolic syndrome that causes up to 20% of cancer-related deaths. Muscle atrophy, the hallmark of cancer cachexia, strongly impairs the quality of life of cancer patients; however, the underlying pathological process is still poorly understood. Investigation of the disease pathogenesis largely relies on cachectic mouse models. In our study, the transcriptome of the cachectic gastrocnemius muscle in the C26 xenograft model was integrated and compared with that of 5 more different datasets. The bioinformatic analysis revealed pivotal gene ontology (GO) terms and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways of the disease, and the key genes were validated. Construction of the protein-protein interaction network and the comparison of pathways enriched in cancer cachexia with 5 other muscle atrophy models revealed Ddit4 (DNA damage-inducible transcript 4), as a key protein in cancer cachexia. The higher expression of Ddit4 in cachectic muscle was further validated in animal models and cachectic cancer patients. Further study revealed that p38 induced the expression of Ddit4, which in turn inhibited the mTOR pathway in atrophic cells.
    DOI:  https://doi.org/10.1038/s41419-021-03932-0
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