bims-moremu 2022-05-15 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2022–05–15
thirty-six papers selected by
Anna Vainshtein, Craft Science Inc.

Defining the Skeletal Myogenic Lineage in Human Pluripotent Stem Cell-Derived Teratomas.
IL-6 Deficiency Attenuates Skeletal Muscle Atrophy by Inhibiting Mitochondrial ROS Production through the Upregulation of PGC-1α in Septic Mice.
Time course and fibre type-dependent nature of calcium-handling protein responses to sprint interval exercise in human skeletal muscle.
Notch, numb and numb-like responses to exercise-induced muscle damage in human skeletal muscle.
Time to Train: The Involvement of the Molecular Clock in Exercise Adaptation of Skeletal Muscle.
Generation of Skeletal Muscle Organoids from Human Pluripotent Stem Cells to Model Myogenesis and Muscle Regeneration.
Combinatorial therapies for rescuing myotonic dystrophy type 1 skeletal muscle defects.
The Role of Skeletal Muscle Intrinsic Clock in the Development and Progression of Cancer Cachexia.
The Heat Shock Connection: Skeletal Muscle Hypertrophy and Atrophy.
Characterization of the Skeletal Muscle Proteome in Undernourished Old Rats.
Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia.
Effect of Long-Term Supplementation with Acetic Acid on the Skeletal Muscle of Aging Sprague Dawley Rats.
Myofibrillar protein synthesis rates are increased in chronically exercised skeletal muscle despite decreased anabolic signaling.
CRediT author statement (Author contributions)Yoshifumi Tsuchiya: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing - original draft, Visualization, Supervision, Project administration, Funding acquisition. Monika Lucia Bayer: Investigation, Resources. Peter Schjerling: Investigation, Writing - review & editing. . Casper Soendenbroe: Validation, Writing - review & editing. Michael Kjaer: Writing - review & editing, Supervision, Project administration, Funding acquisition acquisition.Human derived tendon cells contribute to myotube formation in vitro.
Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance.
Linoleic Acid Attenuates Denervation-Induced Skeletal Muscle Atrophy in Mice through Regulation of Reactive Oxygen Species-Dependent Signaling.
CYB5R3 overexpression preserves skeletal muscle mitochondria and autophagic signaling in aged transgenic mice.
Impaired expression of BCAT1 relates to muscle atrophy of mouse model of sarcopenia.
Editorial: Modulators of Skeletal Muscle Hypertrophy: Mechanisms to Lifestyle Strategies.
Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy.
Lactococcus cremoris subsp. cremoris FC-fermented milk activates protein synthesis and increases skeletal muscle mass in middle-aged mice.
Cross-talk between TRPC-1, mTOR, PGC-1α and PPARδ in the dystrophic muscle cells treated with tempol.
Chronic Elevation of Skeletal Muscle [Ca2+]i Impairs Glucose Uptake. An in Vivo and in Vitro Study.
Identifying the challenges for successful pharmacotherapeutic management of sarcopenia.
Effects of obesity and acute resistance exercise on skeletal muscle angiogenic communication pathways.
Age Related Changes in Muscle Mass and Force Generation in the Triple Transgenic (3xTgAD) Mouse Model of Alzheimer's Disease.
Regulation of the evolutionarily conserved muscle myofibrillar matrix by cell type dependent and independent mechanisms.
Uncovering the effects of gender affirming hormone therapy on skeletal muscle and epigenetics: protocol for a prospective matched cohort study in transgender individuals (the GAME study).
Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations.
Regenerating Myofiber Directs Tregs and Th17 Responses in Inflamed Muscle through the Intrinsic TGF-β Signaling Mediated IL-6 Production.
Factors Regulating or Regulated by Myogenic Regulatory Factors in Skeletal Muscle Stem Cells.
Unraveling the Molecular Basis of the Dystrophic Process in Limb-Girdle Muscular Dystrophy LGMD-R12 by Differential Gene Expression Profiles in Diseased and Healthy Muscles.
Schwann Cells Promote Myogenic Differentiation of Myoblasts and Adipogenic Mesenchymal Stromal Cells on Poly-ɛ-Caprolactone-Collagen I-Nanofibers.
Molecular Mechanisms and Current Treatment Options for Cancer Cachexia.
Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle.
Combined effects of exercise training and D-allulose intake on endurance capacity in mice.

Cells. 2022 May 09. pii: 1589. [Epub ahead of print]11(9):

Defining the Skeletal Myogenic Lineage in Human Pluripotent Stem Cell-Derived Teratomas.

Matthew P Pappas, Ning Xie, Jacqueline S Penaloza, Sunny S K Chan.

  Skeletal muscle stem cells are essential to muscle homeostasis and regeneration after injury, and have emerged as a promising cell source for treating skeletal disorders. An attractive approach to obtain these cells utilizes differentiation of pluripotent stem cells (PSCs). We recently reported that teratomas derived from mouse PSCs are a rich source of skeletal muscle stem cells. Here, we showed that teratoma formation is also capable of producing skeletal myogenic progenitors from human PSCs. Using single-cell transcriptomics, we discovered several distinct skeletal myogenic subpopulations that represent progressive developmental stages of the skeletal myogenic lineage and recapitulate human embryonic skeletal myogenesis. We further discovered that ERBB3 and CD82 are effective surface markers for prospective isolation of the skeletal myogenic lineage in human PSC-derived teratomas. Therefore, teratoma formation provides an accessible model for obtaining human skeletal myogenic progenitors from PSCs.

Keywords:  muscle stem cells; myogenic development; pluripotent stem cells; satellite cells

DOI:  https://doi.org/10.3390/cells11091589
Oxid Med Cell Longev. 2022 ;2022 9148246

IL-6 Deficiency Attenuates Skeletal Muscle Atrophy by Inhibiting Mitochondrial ROS Production through the Upregulation of PGC-1α in Septic Mice.

Bo Yang, Xiaoming Yang, Xiangran Sun, Jiaofang Shi, Yi Shen, Ren Chen.

Current evidences indicate that both inflammation and oxidative stress contribute to the pathogenesis of sepsis-associated skeletal muscle atrophy. However, the interaction between inflammation and oxidative stress has not been completely understood in sepsis-associated skeletal muscle atrophy. Here in the present study, a murine model of sepsis has been established by cecal ligation and puncture (CLP) with wild-type and interleukin- (IL-) 6 knockout (KO) mice. Our results suggested that IL-6 KO largely attenuated skeletal muscle atrophy as reflected by reduced protein degradation, increased cross-sectional area (CSA) of myofibers, and improved muscle contractile function (all P < 0.05). In addition, we observed that IL-6 KO promoted the expression of peroxisome proliferator-activated receptor γ coactivator-1alpha (PGC-1α) and inhibited CLP-induced mitochondrial reactive oxygen species (ROS) production in skeletal muscles (all P < 0.05). However, the knockdown of PGC-1α abolished the protective effects of IL-6 KO in CLP-induced skeletal muscle atrophy and reversed the changes in mitochondrial ROS production (all P < 0.05). Ex vivo experiments found that exogenous IL-6 inhibited PGC-1α expression, promoted mitochondrial ROS production, and induced proteolysis in C2C12 cells (all P < 0.05). Together, these results suggested that IL-6 deficiency attenuated skeletal muscle atrophy by inhibiting mitochondrial ROS production through the upregulation of PGC-1α expression in septic mice.

DOI: https://doi.org/10.1155/2022/9148246
J Physiol. 2022 May 12.

Time course and fibre type-dependent nature of calcium-handling protein responses to sprint interval exercise in human skeletal muscle.

Thomas R Tripp, Barnaby P Frankish, Victor Lun, J Preston Wiley, Jane Shearer, Robyn M Murphy, Martin J MacInnis.

   KEY POINTS: Sprint interval training (SIT) has been shown to cause fragmentation of the sarcoplasmic reticulum calcium-release channel, ryanodine receptor 1 (RyR1) 24 hours post-exercise, which may act as a signal for mitochondrial biogenesis. In this study, we examined the time course of RyR1 fragmentation in human whole muscle and pooled type I and type II skeletal muscle fibres following a single session of SIT. Full-length RyR1 protein content was significantly lower than pre-exercise by 6 h post-SIT in whole muscle, and fragmentation was detectable in type II but not type I fibres, though to a lesser extent than in whole muscle. The peak in PGC1A mRNA expression occurred earlier than RyR1 fragmentation. The increased temporal resolution and fibre type-specific responses for RyR1 fragmentation provide insights into its importance to mitochondrial biogenesis in humans.
ABSTRACT: Sprint interval training (SIT) causes fragmentation of the skeletal muscle sarcoplasmic reticulum Ca2+ release channel, ryanodine receptor 1 (RyR1), 24h post-exercise, potentially signaling mitochondrial biogenesis by increasing cytosolic [Ca2+ ]. Yet, the time course and skeletal muscle fibre type-specific patterns of RyR1 fragmentation following a session of SIT remain unknown. Ten participants (n = 4 females; n = 6 males) performed a session of SIT (6 × 30 s "all-out" with 4.5 min rest after each sprint) with vastus lateralis muscle biopsy samples collected before and 3, 6, and 24h after exercise. In whole muscle, full-length RyR1 protein content was significantly reduced 6 h (mean [SD]; -38 [38]%; p<0.05) and 24 h post-SIT (-30 [48]%; p<0.05) compared to pre-exercise. Examining each participant's largest response in pooled samples, full-length RyR1 protein content was reduced in type II (-26 [30]%; p<0.05) but not type I fibres (-11 [40]%; p>0.05). 3h post-SIT, there was also a decrease in SERCA1 in type II fibres (-23 [17]%; p<0.05) and SERCA2a in type I fibres (-19 [21]%; p<0.05), despite no time effect for either protein in whole muscle samples (p>0.05). PGC1A mRNA content was elevated 3h and 6h post-SIT (5.3- and 3.7-fold change from pre, respectively; p<0.05 for both), but peak PGC1A mRNA expression was not significantly correlated with peak RyR1 fragmentation (r2 = 0.10; p>0.05). In summary, altered Ca2+ -handling protein expression, which occurs primarily in type II muscle fibres, may influence signals for mitochondrial biogenesis as early as 3-6 h post-SIT in humans. Abstract figure legend Western blotting was performed on whole muscle and pooled type I and II muscle fibre preparations derived from human vastus lateralis muscle biopsy samples collected before and after a single session of sprint interval training (SIT). Full-length ryanodine receptor 1 (RyR1) protein content was reduced 6 and 24 h post-exercise in whole muscle samples compared to baseline, despite a heterogeneous time course among individuals. This RyR1 fragmentation proceeded and outlasted the increase in peroxisome proliferator-activated γ receptor coactivator 1α (PGC1A) mRNA expression. When examining the time point of each individual's peak response, RyR1 fragmentation was evident in type II, but not type I, muscle fibres. These findings suggest that, in humans, mitochondrial biogenesis could be influenced by RyR1 fragmentation 3-6 h post-SIT in a fibre type-dependent manner. Created with BioRender.com. This article is protected by copyright. All rights reserved.

Keywords:  calcium regulation; exercise; gene expression; ryanodine receptor; skeletal muscle fibre

DOI:  https://doi.org/10.1113/JP282739
Exp Physiol. 2022 May 13.

Notch, numb and numb-like responses to exercise-induced muscle damage in human skeletal muscle.

Matthew P Bubak, Kevan Stout, Julia Tomtstik, Ethan Peterson, Christopher P Cardozo, Zachary A Graham, Phil Gallagher.

   NEW FINDINGS: What is the central question of this study? Do Notch, Numb, and Numb-Like expression change in human skeletal muscle after exercise-induced muscle damage? What is the main finding and its importance? We show Notch gene expression trends toward an increase in response to an acute bout of exercise-induced muscle damage, while Numb and Numb-Like expression does not change. These results suggest that human skeletal muscle response to exercise-induced muscle damage is dynamic and may differ from drosophila and rodent models. Furthermore, the timing of muscle biopsies, training status, and muscle damage protocols should be considered.
ABSTRACT: This investigation examined changes in the gene and protein expression of Notch, Numb, and Numb-like (Numbl) in human skeletal muscle after an acute bout of eccentric exercise-induced muscle damage. Twelve recreationally active male subjects participated in this study. These individuals completed 7 sets of 10 repetitions of eccentric leg extension at 120% of 1-repetition max with two minutes of rest period between sets. Four muscle biopsies of the vastus lateralis were collected: before exercise (Pre), and 3 Hr, 2 Days, and 5 Days post-muscle damage. Biopsy samples were used to probe Notch, Numb, and Numbl utilizing Western blot and RT-qPCR techniques. The results were analyzed using a one-way repeated-measures ANOVA. Notch1 mRNA expression trended toward a significant increase from Pre to 2 Days post-muscle damage from baseline measures (p = 0.087), while Numb (p = 0.804) and Numbl (p = 0.480) expression was unaltered post-muscle damage. There were no significant differences in protein expression post-muscle damage for any of the proteins. These results suggest that exercise-induced muscle damage, via eccentric exercise, slightly elevates Notch1 mRNA expression. This article is protected by copyright. All rights reserved.

Keywords:  eccentric; injury; satellite cells

DOI:  https://doi.org/10.1113/EP090364
Front Physiol. 2022 ;13 902031

Time to Train: The Involvement of the Molecular Clock in Exercise Adaptation of Skeletal Muscle.

Shivani Mansingh, Christoph Handschin.

  Circadian rhythms regulate a host of physiological processes in a time-dependent manner to maintain homeostasis in response to various environmental stimuli like day and night cycles, food intake, and physical activity. Disruptions in circadian rhythms due to genetic mutations, shift work, exposure to artificial light sources, aberrant eating habits, and abnormal sleep cycles can have dire consequences for health. Importantly, exercise training efficiently ameliorates many of these adverse effects and the role of skeletal muscle in mediating the benefits of exercise is a topic of great interest. However, the molecular and physiological interactions between the clock, skeletal muscle function and exercise are poorly understood, and are most likely a combination of molecular clock components directly acting in muscle as well as in concordance with other peripheral metabolic organ systems like the liver. This review aims to consolidate existing experimental evidence on the involvement of molecular clock factors in exercise adaptation of skeletal muscle and to highlight the existing gaps in knowledge that need to be investigated to develop therapeutic avenues for diseases that are associated with these systems.

Keywords:  PGC-1 alpha; REV-ERB; ROR alpha; bmal1; circadian clock; exercise; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.902031
Int J Mol Sci. 2022 May 04. pii: 5108. [Epub ahead of print]23(9):

Generation of Skeletal Muscle Organoids from Human Pluripotent Stem Cells to Model Myogenesis and Muscle Regeneration.

Min-Kyoung Shin, Jin Seok Bang, Jeoung Eun Lee, Hoang-Dai Tran, Genehong Park, Dong Ryul Lee, Junghyun Jo.

  In vitro organoids derived from human pluripotent stem cells (hPSCs) have been developed as essential tools to study the underlying mechanisms of human development and diseases owing to their structural and physiological similarity to corresponding organs. Despite recent advances, there are a few methodologies for three-dimensional (3D) skeletal muscle differentiation, which focus on the terminal differentiation into myofibers and investigate the potential of modeling neuromuscular disorders and muscular dystrophies. However, these methodologies cannot recapitulate the developmental processes and lack regenerative capacity. In this study, we developed a new method to differentiate hPSCs into a 3D human skeletal muscle organoid (hSkMO). This organoid model could recapitulate the myogenesis process and possesses regenerative capacities of sustainable satellite cells (SCs), which are adult muscle stem/progenitor cells capable of self-renewal and myogenic differentiation. Our 3D model demonstrated myogenesis through the sequential occurrence of multiple myogenic cell types from SCs to myocytes. Notably, we detected quiescent, non-dividing SCs throughout the hSkMO differentiation in long-term culture. They were activated and differentiated to reconstitute muscle tissue upon damage. Thus, hSkMOs can recapitulate human skeletal muscle development and regeneration and may provide a new model for studying human skeletal muscles and related diseases.

Keywords:  human pluripotent stem cells; myogenesis; regeneration; satellite cells; skeletal muscle organoids

DOI:  https://doi.org/10.3390/ijms23095108
Trends Mol Med. 2022 May 07. pii: S1471-4914(22)00082-X. [Epub ahead of print]

Combinatorial therapies for rescuing myotonic dystrophy type 1 skeletal muscle defects.

Aymeric Ravel-Chapuis, Bernard J Jasmin.

  Myotonic dystrophy type 1 (DM1) is a multisystemic disorder for which there is no cure. In recent years, progress has been made in defining disease mechanisms and in developing novel therapies, especially for skeletal muscle defects. Here, we highlight the potential of activating AMP-activated protein kinase (AMPK) with different approaches in combinatorial therapies.

Keywords:  AMP-activated protein kinase; combinatorial therapy; exercise; myotonic dystrophy; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmed.2022.04.004
FASEB J. 2022 May;36 Suppl 1

The Role of Skeletal Muscle Intrinsic Clock in the Development and Progression of Cancer Cachexia.

Jason Lin, Brittany Counts-Franch, Zereque Powell, Chidambaram Ramanathan, James Carson, Melissa Puppa.

Cancer cachexia is a chronic wasting disorder characterized by severe loss of skeletal muscle that affects approximately 80% of cancer patients, accounting for about 20 - 30% of cancer-related deaths. Altered rest-activity is a hallmark of circadian disruption and is often seen in cachectic patients. Additionally, loss of skeletal muscle-specific clock gene results in muscle atrophy similar to that seen in cancer cachexia. However, it is unknown how skeletal muscle clock gene expression is altered with the progression of cachexia. Therefore, we investigated skeletal muscle clock gene expression during cachexia. ApcMin/+ mice (MIN) were harvested in the morning and evening and were analyzed for clock gene expression. There was no effect of cancer on muscle Bmal1 (p = 0.55) and Clock (p = 0.59) expression. Cry1 expression showed no significant difference compared to BL - 6 mice (p = 0.24). Per 2 (p = 0.07) and Per 3 (p = 0.02) increased expression in the evening; however there was no difference between MIN and BL - 6 (Per 2 p=0.97, Per 3 p=0.87). Rev-ERBα showed decreased expression in BL - 6 mice in the evening (p<0.001). However, there was no difference between the morning and evening MIN mice (p=0.31). RORα showed increased expression in BL - 6 mice in the evening (p = 0.03). Additionally, BL - 6 evening was significantly higher compared to MIN evening (p=0.01). However, there was no difference between the morning and evening MIN RORα expression (p>0.99). In LLC conditioned media treated myotubes, myotube diameter was decreased (p<0.001), and Bmal1 expression was decreased after 4 days in LLC conditioned media. In conclusion, the data suggest circadian clock expression is altered in a cachectic environment. Addition research is needed to understand the influence of these changes on the progression of cancer cachexia. Understanding the role of muscle-specific circadian clock could lead to potential therapeutic interventions to attenuate cancer cachexia.

DOI: https://doi.org/10.1096/fasebj.2022.36.S1.R5190
Am J Physiol Regul Integr Comp Physiol. 2022 May 10.

The Heat Shock Connection: Skeletal Muscle Hypertrophy and Atrophy.

Zachary James Fennel, Fabiano Trigueiro Amorim, Michael R Deyhle, Paul Samuel Hafen, Christine M Mermier.

  Skeletal muscle is an integral tissue system that plays a crucial role in the physical function of all vertebrates and is a key target for maintaining or improving health and performance across the lifespan. Based largely on cellular and animal models, there is some evidence that various forms of heat stress with or without resistance exercise may enhance skeletal muscle growth or reduce its loss. It is not clear whether these stimuli are similarly effective in humans or meaningful in comparison to exercise alone across various heating methodologies. Furthermore, the magnitude by which heat stress may influence whole body thermoregulatory responses and the connection to skeletal muscle adaptation remains ambiguous. Finally, the underlying mechanisms, which may include interaction between relevant heat shock proteins and intracellular hypertrophy and atrophy related factors, remain unclear. In this narrative mini-review we examine the relevant literature regarding heat stress alone or in combination with resistance exercise emphasizing skeletal muscle hypertrophy and atrophy across cellular and animal models, as well as human investigations. Additionally, we present working mechanistic theories for heat shock protein mediated signaling effects regarding hypertrophy and atrophy related signaling processes. Importantly, continued research is necessary to determine the practical effects and mechanisms of heat stress with and without resistance exercise on skeletal muscle function via growth and maintenance.

Keywords:  Atrophy; Heat Shock Proteins; Heat Stress; Hypertrophy; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpregu.00048.2022
Int J Mol Sci. 2022 Apr 26. pii: 4762. [Epub ahead of print]23(9):

Characterization of the Skeletal Muscle Proteome in Undernourished Old Rats.

Caroline Barbé, Jérôme Salles, Christophe Chambon, Christophe Giraudet, Phelipe Sanchez, Véronique Patrac, Philippe Denis, Yves Boirie, Stéphane Walrand, Marine Gueugneau.

  Aging is associated with a progressive loss of skeletal muscle mass and function termed sarcopenia. Various metabolic alterations that occur with aging also increase the risk of undernutrition, which can worsen age-related sarcopenia. However, the impact of undernutrition on aged skeletal muscle remains largely under-researched. To build a deeper understanding of the cellular and molecular mechanisms underlying age-related sarcopenia, we characterized the undernutrition-induced changes in the skeletal muscle proteome in old rats. For this study, 20-month-old male rats were fed 50% or 100% of their spontaneous intake for 12 weeks, and proteomic analysis was performed on both slow- and fast-twitch muscles. Proteomic profiling of undernourished aged skeletal muscle revealed that undernutrition has profound effects on muscle proteome independently of its effect on muscle mass. Undernutrition-induced changes in muscle proteome appear to be muscle-type-specific: slow-twitch muscle showed a broad pattern of differential expression in proteins important for energy metabolism, whereas fast-twitch muscle mainly showed changes in protein turnover between undernourished and control rats. This first proteomic analysis of undernourished aged skeletal muscle provides new molecular-level insight to explain phenotypic changes in undernourished aged muscle. We anticipate this work as a starting point to define new biomarkers associated with undernutrition-induced muscle loss in the elderly.

Keywords:  aging; proteome; sarcopenia; skeletal muscle; undernutrition

DOI:  https://doi.org/10.3390/ijms23094762
Cells. 2022 Apr 21. pii: 1406. [Epub ahead of print]11(9):

Physiactisome: A New Nanovesicle Drug Containing Heat Shock Protein 60 for Treating Muscle Wasting and Cachexia.

Valentina Di Felice, Rosario Barone, Eleonora Trovato, Daniela D'Amico, Filippo Macaluso, Claudia Campanella, Antonella Marino Gammazza, Vera Muccilli, Vincenzo Cunsolo, Patrizia Cancemi, Gabriele Multhoff, Dario Coletti, Sergio Adamo, Felicia Farina, Francesco Cappello.

  Currently, no commercially available drugs have the ability to reverse cachexia or counteract muscle wasting and the loss of lean mass. Here, we report the methodology used to develop Physiactisome-a conditioned medium released by heat shock protein 60 (Hsp60)-overexpressing C2C12 cell lines enriched with small and large extracellular vesicles. We also present evidence supporting its use in the treatment of cachexia. Briefly, we obtain a nanovesicle-based secretion by genetically modifying C2C12 cell lines with an Hsp60-overexpressing plasmid. The secretion is used to treat naïve C2C12 cell lines. Physiactisome activates the expression of PGC-1α isoform 1, which is directly involved in mitochondrial biogenesis and muscle atrophy suppression, in naïve C2C12 cell lines. Proteomic analyses show Hsp60 localisation inside isolated nanovesicles and the localisation of several apocrine and merocrine molecules, with potential benefits for severe forms of muscle atrophy. Considering that Physiactisome can be easily obtained following tissue biopsy and can be applied to autologous muscle stem cells, we propose a potential nanovesicle-based anti-cachexia drug that could mimic the beneficial effects of exercise. Thus, Physiactisome may improve patient survival and quality of life. Furthermore, the method used to add Hsp60 into nanovesicles can be used to deliver other drugs or active proteins to vesicles.

Keywords:  cachexia; exercise; exosome; muscle atrophy; muscle wasting; sarcopenia

DOI:  https://doi.org/10.3390/cells11091406
Int J Mol Sci. 2022 Apr 23. pii: 4691. [Epub ahead of print]23(9):

Effect of Long-Term Supplementation with Acetic Acid on the Skeletal Muscle of Aging Sprague Dawley Rats.

Hitomi Maruta, Reina Abe, Hiromi Yamashita.

  Mitochondrial function in skeletal muscle, which plays an essential role in oxidative capacity and physical activity, declines with aging. Acetic acid activates AMP-activated protein kinase (AMPK), which plays a key role in the regulation of whole-body energy by phosphorylating key metabolic enzymes in both biosynthetic and oxidative pathways and stimulates gene expression associated with slow-twitch fibers and mitochondria in skeletal muscle cells. In this study, we investigate whether long-term supplementation with acetic acid improves age-related changes in the skeletal muscle of aging rats in association with the activation of AMPK. Male Sprague Dawley (SD) rats were administered acetic acid orally from 37 to 56 weeks of age. Long-term supplementation with acetic acid decreased the expression of atrophy-related genes, such as atrogin-1, muscle RING-finger protein-1 (MuRF1), and transforming growth factor beta (TGF-β), activated AMPK, and affected the proliferation of mitochondria and type I fiber-related molecules in muscles. The findings suggest that acetic acid exhibits an anti-aging function in the skeletal muscles of aging rats.

Keywords:  AMPK; acetic acid; aging; mitochondria; skeletal muscle; type I fiber

DOI:  https://doi.org/10.3390/ijms23094691
Sci Rep. 2022 May 09. 12(1): 7553

Myofibrillar protein synthesis rates are increased in chronically exercised skeletal muscle despite decreased anabolic signaling.

Henning T Langer, Daniel West, Joan Senden, Simone Spuler, Luc J C van Loon, Keith Baar.

The molecular responses to acute resistance exercise are well characterized. However, how cellular signals change over time to modulate chronic adaptations to more prolonged exercise training is less well understood. We investigated anabolic signaling and muscle protein synthesis rates at several time points after acute and chronic eccentric loading. Adult rat tibialis anterior muscle was stimulated for six sets of ten repetitions, and the muscle was collected at 0 h, 6 h, 18 h and 48 h. In the last group of animals, 48 h after the first exercise bout a second bout was conducted, and the muscle was collected 6 h later (54 h total). In a second experiment, rats were exposed to four exercise sessions over the course of 2 weeks. Anabolic signaling increased robustly 6 h after the first bout returning to baseline between 18 and 48 h. Interestingly, 6 h after the second bout mTORC1 activity was significantly lower than following the first bout. In the chronically exercised rats, we found baseline anabolic signaling was decreased, whereas myofibrillar protein synthesis (MPS) was substantially increased, 48 h after the last bout of exercise. The increase in MPS occurred in the absence of changes to muscle fiber size or mass. In conclusion, we find that anabolic signaling is already diminished after the second bout of acute resistance type exercise. Further, chronic exposure to resistance type exercise training results in decreased basal anabolic signaling but increased overall MPS rates.

DOI: https://doi.org/10.1038/s41598-022-11621-x
Exp Cell Res. 2022 May 05. pii: S0014-4827(22)00157-4. [Epub ahead of print] 113164

CRediT author statement (Author contributions)Yoshifumi Tsuchiya: Conceptualization, Methodology, Validation, Formal analysis, Investigation, Resources, Writing - original draft, Visualization, Supervision, Project administration, Funding acquisition. Monika Lucia Bayer: Investigation, Resources. Peter Schjerling: Investigation, Writing - review & editing. . Casper Soendenbroe: Validation, Writing - review & editing. Michael Kjaer: Writing - review & editing, Supervision, Project administration, Funding acquisition acquisition.Human derived tendon cells contribute to myotube formation in vitro.

Yoshifumi Tsuchiya, Monika Lucia Bayer, Peter Schjerling, Casper Soendenbroe, Michael Kjaer.

  Skeletal muscle possesses remarkable adaptability to mechanical loading and regenerative potential following muscle injury primarily due to satellite cell activity. Although the roles of several types of interstitial cells in skeletal muscle have been documented, the signaling interplay between the skeletal muscle and the adjacent tendon tissue has not been elucidated. Here, we tested whether human tendon derived cells (tenocytes) could induce human myogenic cells (myoblasts) proliferation and differentiation in vitro using co-culture experiments that allowed us to investigate the effect of tenocytes secretion upon myogenic progression. This was done in vitro by introducing insert wells with either myoblasts, tenocytes, or no cells (control) into a myoblast containing well (co-culture). Immunofluorescence analysis revealed a higher fusion index (≥5 nuclei within one Desmin + myotube) and a higher myotube diameter in co-cultures with tenocytes compared to myoblasts condition. Correspondingly, MHC-IIX gene expression was up-regulated when co-cultured with tenocytes. However, the proliferation of myoblasts (either Ki67 or BrdU + cells) was not enhanced under the presence of tenocytes. These findings show that tenocytes influence myotube formation upon human primary cells in vitro and contribute to understanding the role of tendon derived cells in skeletal muscle during development and regeneration.

Keywords:  Cell communication; Muscle regeneration; Myoblasts; Myogenesis; Myotube formation; Satellite cells; Skeletal muscle; Tendon; Tendon fibroblasts; Tenocytes

DOI:  https://doi.org/10.1016/j.yexcr.2022.113164
Int J Mol Sci. 2022 Apr 22. pii: 4636. [Epub ahead of print]23(9):

Mechanisms by Which Skeletal Muscle Myokines Ameliorate Insulin Resistance.

Rekha Balakrishnan, Debbie C Thurmond.

  The skeletal muscle is the largest organ in the body and secretes circulating factors, including myokines, which are involved in various cellular signaling processes. Skeletal muscle is vital for metabolism and physiology and plays a crucial role in insulin-mediated glucose disposal. Myokines have autocrine, paracrine, and endocrine functions, serving as critical regulators of myogenic differentiation, fiber-type switching, and maintaining muscle mass. Myokines have profound effects on energy metabolism and inflammation, contributing to the pathophysiology of type 2 diabetes (T2D) and other metabolic diseases. Myokines have been shown to increase insulin sensitivity, thereby improving glucose disposal and regulating glucose and lipid metabolism. Many myokines have now been identified, and research on myokine signaling mechanisms and functions is rapidly emerging. This review summarizes the current state of the field regarding the role of myokines in tissue cross-talk, including their molecular mechanisms, and their potential as therapeutic targets for T2D.

Keywords:  insulin resistance; inter-organ cross-talk; metabolic disorder; myokines; type 2 diabetes

DOI:  https://doi.org/10.3390/ijms23094636
Int J Mol Sci. 2022 Apr 26. pii: 4778. [Epub ahead of print]23(9):

Linoleic Acid Attenuates Denervation-Induced Skeletal Muscle Atrophy in Mice through Regulation of Reactive Oxygen Species-Dependent Signaling.

Myung-Hun Lee, Jin-Ho Lee, Wan-Joong Kim, Seo Ho Kim, Sun-Young Kim, Han Sung Kim, Tack-Joong Kim.

  Muscle atrophy is a major muscle disease, the symptoms of which include decreased muscle volume leading to insufficient muscular support during exercise. One cause of muscle atrophy is the induction of oxidative stress by reactive oxygen species (ROS). This study aimed to identify the antioxidant mechanism of linoleic acid (LA) in muscle atrophy caused by oxidative stress. H2O2 has been used to induce oxidative stress in myoblasts in vitro. C2C12 myoblasts treated with H2O2 exhibited decreased viability and increased ROS synthesis. However, with LA treatment, the cells tended to recover from oxidative effects similar to those of the control groups. At the molecular level, the expression of superoxide dismutase 1 (SOD1), Bax, heat shock protein 70 (HSP70), and phosphorylated forkhead box protein O1 was increased by oxidative stress, causing apoptosis. LA treatment suppressed these changes. In addition, the expression of MuRF1 and Atrogin-1/MAFbx mRNA increased under oxidative stress but not in the LA-treated group. Sciatic denervation of C57BL/6 mice manifested as atrophy of the skeletal muscle in micro-computed tomography (micro-CT). The protein expression levels of SOD1, HSP70, and MuRF1 did not differ between the atrophied muscle tissues and C2C12 myoblasts under oxidative stress. With LA treatment, muscle atrophy recovered and protein expression was restored to levels similar to those in the control. Therefore, this study suggests that LA may be a candidate substance for preventing muscle atrophy.

Keywords:  antioxidant; linoleic acid; muscle atrophy; oxidative stress; sciatic denervation

DOI:  https://doi.org/10.3390/ijms23094778
Geroscience. 2022 May 09.

CYB5R3 overexpression preserves skeletal muscle mitochondria and autophagic signaling in aged transgenic mice.

Sara López-Bellón, Sandra Rodríguez-López, José A González-Reyes, M Isabel Burón, Rafael de Cabo, José M Villalba.

  Cytochrome b5 reductase 3 (CYB5R3) overexpression activates respiratory metabolism and exerts prolongevity effects in transgenic mice, mimicking some of the salutary effects of calorie restriction. The aim of our study was to understand how CYB5R3 overexpression targets key pathways that modulate the rate of aging in skeletal muscle, a postmitotic tissue with a greater contribution to resting energy expenditure. Mitochondrial function, autophagy and mitophagy markers were evaluated in mouse hind limb skeletal muscles from young-adult (7 months old) and old (24 months old) males of wild-type and CYB5R3-overexpressing genotypes. Ultrastructure of subsarcolemmal and intermyofibrillar mitochondria was studied by electron microscopy in red gastrocnemius. CYB5R3, which was efficiently overexpressed and targeted to skeletal muscle mitochondria regardless of age, increased the abundance of complexes I, II, and IV in old mice and prevented the age-related decrease of complexes I, III, IV, and V and the mitofusin MFN-2. ATP was significantly decreased by aging, which was prevented by CYB5R3 overexpression. Coenzyme Q and the mitochondrial biogenesis markers TFAM and NRF-1 were also significantly diminished by aging, but CYB5R3 overexpression did not protect against these declines. Both aging and CYB5R3 overexpression upregulated SIRT3 and the mitochondrial fission markers FIS1 and DRP-1, although with different outcomes on mitochondrial ultrastructure: old wild-type mice exhibited mitochondrial fragmentation whereas CYB5R3 overexpression increased mitochondrial size in old transgenic mice concomitant with an improvement of autophagic recycling. Interventions aimed at stimulating CYB5R3 could represent a valuable strategy to counteract the deleterious effects of aging in skeletal muscle.

Keywords:  Aging; Autophagy; Cytochrome b 5 reductase; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-022-00574-8
BMC Musculoskelet Disord. 2022 May 13. 23(1): 450

Impaired expression of BCAT1 relates to muscle atrophy of mouse model of sarcopenia.

Hui Ouyang, Xuguang Gao, Jun Zhang.

   BACKGROUND: The underlying mechanism of muscle atrophy in sarcopenia is still not fully understood; branched chain aminotransferase 1(BCAT1) isocitrate dehydrogenase-1 encodes an evolutionarily conserved cytoplasmic aminotransferase for glutamate and branched-chain amino acids (BCAAs), thus constituting a regulatory component of cytoplasmic amino and keto acid metabolism. In human gliomas carrying wild-type isocitrate dehydrogenase-1, BCAT1 promotes cell proliferation through amino acid catabolism. Hence, the goals of this study were to unravel the potential role of BCAT1 expression in muscle atrophy and to explore the mechanisms underlying this process.
METHODS: We first measured Bcat1 expression by RT-qPCR and western blotting in murine and cellular models of muscle atrophy. To understand how the Bcat1-driven changes sustained muscle cell growth, we analyzed reactive oxygen species (ROS) levels and activation of the mTORC1/S6K1 pathway in muscle cells. Furthermore, we performed Cell Counting Kit-8(CCK8) assays and fluorescence staining to evaluate growth rate of cells and ROS levels. Finally, we verified that depletion of Bcat1 impairs the growth rate of muscle cells and increases ROS levels, indicating that muscle atrophy resulted from the downregulation of the mTORC1/S6K1 pathway. Data were analyzed by two-tailed unpaired Student's t-test or Mann-Whitney U test for two groups to determine statistical significance. Statistical analyses were performed using GraphPad Prism version 6.0 and SPSS 16.0 software.
RESULTS: Bcat1 expression level in skeletal muscles was lower in murine and cellular models of sarcopenia than in the control groups. Bcat1 knockdown not only suppressed the growth of muscle cells but also increased the production of ROS. Impaired cell growth and increased ROS production was rescued by co-introduction of an shRNA-resistant Bcat1 cDNA or addition of the mTORC1 stimulator MYH1485. Muscle cells with Bcat1 knockdown featured lower mTORC1 and S6K1 phosphorylation (pS6K1) than NT muscle cells. Addition of either shRNA-resistant Bcat1 cDNA or MYH1485 rescued the suppression of cell growth, increase in ROS production, and decrease in pS6K1.
CONCLUSIONS: The branched chain amino acids catabolic enzyme BCAT1 is essential for the growth of muscle cells. BCAT1 expression contributes to sustained growth of muscle cells by activating mTOR signaling and reducing ROS production.

Keywords:  BCAT1; Muscle; Muscle atrophy; Sarcopenia; mTORC1

DOI:  https://doi.org/10.1186/s12891-022-05332-7
Front Physiol. 2022 ;13 893698

Editorial: Modulators of Skeletal Muscle Hypertrophy: Mechanisms to Lifestyle Strategies.

Vandré C Figueiredo, Llion A Roberts, David Cameron-Smith, James F Markworth.



Keywords:  atrophy; hypertrophy; protein degradation; protein synthesis; satellite cell; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.893698
Cells. 2022 Apr 22. pii: 1417. [Epub ahead of print]11(9):

Reduced Sarcolemmal Membrane Repair Exacerbates Striated Muscle Pathology in a Mouse Model of Duchenne Muscular Dystrophy.

Brian J Paleo, Kevin E McElhanon, Hannah R Bulgart, Kassidy K Banford, Eric X Beck, Kristina M Sattler, Briana N Goines, Shelby L Ratcliff, Kelly E Crowe, Noah Weisleder.

  Duchenne muscular dystrophy (DMD) is a common X-linked degenerative muscle disorder that involves mutations in the DMD gene that frequently reduce the expression of the dystrophin protein, compromising the structural integrity of the sarcolemmal membrane and leaving it vulnerable to injury during cycles of muscle contraction and relaxation. This results in an increased frequency of sarcolemma disruptions that can compromise the barrier function of the membrane and lead to death of the myocyte. Sarcolemmal membrane repair processes can potentially compensate for increased membrane disruptions in DMD myocytes. Previous studies demonstrated that TRIM72, a muscle-enriched tripartite motif (TRIM) family protein also known as mitsugumin 53 (MG53), is a component of the cell membrane repair machinery in striated muscle. To test the importance of membrane repair in striated muscle in compensating for the membrane fragility in DMD, we crossed TRIM72/MG53 knockout mice into the mdx mouse model of DMD. These double knockout (DKO) mice showed compromised sarcolemmal membrane integrity compared to mdx mice, as measured by immunoglobulin G staining and ex vivo muscle laser microscopy wounding assays. We also found a significant decrease in muscle ex vivo contractile function as compared to mdx mice at both 6 weeks and 1.5 years of age. As the DKO mice aged, they developed more extensive fibrosis in skeletal muscles compared to mdx. Our findings indicate that TRIM72/MG53-mediated membrane repair can partially compensate for the sarcolemmal fragility associated with DMD and that the loss of membrane repair results in increased pathology in the DKO mice.

Keywords:  dystrophy; fibrosis; membrane repair; muscle; sarcolemma

DOI:  https://doi.org/10.3390/cells11091417
Biochem Biophys Res Commun. 2022 Apr 25. pii: S0006-291X(22)00639-8. [Epub ahead of print]612 176-180

Lactococcus cremoris subsp. cremoris FC-fermented milk activates protein synthesis and increases skeletal muscle mass in middle-aged mice.

Wataru Aoi, Masayo Iwasa, Chisato Aiso, Yoshiyuki Tabata, Yayoi Gotoh, Hideki Kosaka, Toshio Suzuki.

  Age-related muscle atrophy is associated with decreased protein anabolic capacity. Dietary intervention is an important strategy for the treatment of age-related muscle atrophy. This study examined the effect of Lactococcus cremoris subsp. cremoris FC-fermented milk on muscle mass and protein anabolic signaling in middle-aged mice. Male C57BL/6J mice (18-month-old) were divided into the control and Lactococcus cremoris subsp. cremoris FC-fermented milk supplementation groups. Mice were administered unfermented or fermented milk (300 μL/day) by gavage every alternate day for 8 weeks; thereafter, muscle weight, protein metabolic signaling factors, and inflammatory factors were investigated. Soleus muscle weight was higher in the fermented milk group than in the control group. Expression of insulin growth factor-1, a typical anabolic factor, and phosphorylation levels of anabolic signaling factors (mTOR and p70S6K) were higher after fermented milk supplementation. Levels of tumor necrosis factor-α, an inhibitor of protein anabolism, were lower in the fermented milk group. These data suggest that the daily intake of Lactococcus cremoris subsp. cremoris FC-fermented milk increased skeletal muscle mass as well as protein synthesis in the middle-aged mice, which may be mediated by reduction in the levels of inflammatory factors. Therefore, accelerated protein synthesis, induced by the consumption of fermented milk, has a potential role in counteracting muscle atrophy.

Keywords:  Anabolic resistance; Growth factor; Muscle atrophy; Sarcopenia; Soleus muscle

DOI:  https://doi.org/10.1016/j.bbrc.2022.04.097
Free Radic Res. 2022 May 12. 1-13

Cross-talk between TRPC-1, mTOR, PGC-1α and PPARδ in the dystrophic muscle cells treated with tempol.

Guilherme Luiz da Rocha, Ian Feller Rupcic, Daniela Sayuri Mizobuti, Túlio de Almeida Hermes, Caroline Covatti, Heloina Nathalliê Mariano da Silva, Hygor Nunes Araujo, Caroline Caramano de Lourenço, Leonardo Dos Reis Silveira, Elaine Cristina Leite Pereira, Elaine Minatel.

  Background Ca2+ dysregulation and oxidative damage appear to have a central role in Duchenne muscular dystrophy (DMD) progression. The current study provides muscle cell-specific insights into the effect of Tempol on the TRPC 1 channel; on the positive and negative regulators of muscle cell differentiation; on the antioxidant enzymatic system; on the activators of mitochondrial biogenesis; and on the inflammatory process in the dystrophic primary muscle cells in culture.
METHODS: Mdx myotubes were treated with Tempol (5 mM) for 24 h. Untreated mdx myotubes and C57BL/10 myotubes were used as controls.
RESULTS: The Trypan Blue, MTT and Live/Dead Cell assays showed that Tempol (5 mM) presented no cytotoxic effect on the dystrophic muscle cells. The Tempol treated-mdx muscle cells showed significantly lower levels in the fluorescence intensity of intracellular calcium; TRPC-1 channel; MyoD; H2O2 and O2•- production; 4-HNE levels; SOD2, CAT and GPx levels; and TNF levels. On the other hand, SOD, CAT and GR mRNA relative expression were significantly higher in Tempol treated-mdx muscle cells. In addition, higher levels of Myogenin, MHC-Slow, mTOR, PGC-1α and PPARδ were also observed in Tempol treated-mdx muscle cells.
CONCLUSION: Our findings demonstrated that Tempol decreased intracellular calcium and oxidative stress in primary dystrophic muscle cells, promoting a cross-talk between TRPC-1, mTOR, PGC-1α and PPARδ.

Keywords:  Dystrophic muscle cells; calcium channels; mitochondrial biogenesis; muscle cell differentiation; tempol

DOI:  https://doi.org/10.1080/10715762.2022.2074842
Front Physiol. 2022 ;13 872624

Chronic Elevation of Skeletal Muscle [Ca2+]i Impairs Glucose Uptake. An in Vivo and in Vitro Study.

Arkady Uryash, Alfredo Mijares, Carlos E Lopez, Jose A Adams, Jose R Lopez.

  Skeletal muscle is the primary site of insulin-mediated glucose uptake through the body and, therefore, an essential contributor to glucose homeostasis maintenance. We have recently provided evidence that chronic elevated intracellular Ca2+ concentration at rest [(Ca2+)i] compromises glucose homeostasis in malignant hyperthermia muscle cells. To further investigate how chronic elevated muscle [Ca2+]i modifies insulin-mediated glucose homeostasis, we measured [Ca2+]i and glucose uptake in vivo and in vitro in intact polarized muscle cells from glucose-intolerant RYR1-p.R163C and db/db mice. Glucose-intolerant RYR1-p.R163C and db/db mice have significantly elevated muscle [Ca2+]i and reduced muscle glucose uptake compared to WT muscle cells. Dantrolene treatment (1.5 mg/kg IP injection for 2 weeks) caused a significant reduction in fasting blood glucose levels and muscle [Ca2+]i and increased muscle glucose uptake compared to untreated RYR1-p.R163C and db/db mice. Furthermore, RYR1-p.R163C and db/db mice had abnormal basal insulin levels and response to glucose-stimulated insulin secretion. In vitro experiments conducted on single muscle fibers, dantrolene improved insulin-mediated glucose uptake in RYR1-p.R163C and db/db muscle fibers without affecting WT muscle fibers. In muscle cells with chronic elevated [Ca2+]i, GLUT4 expression was significantly lower, and the subcellular fraction (plasma membrane/cytoplasmic) was abnormal compared to WT. The results of this study suggest that i) Chronic elevated muscle [Ca2+]i decreases insulin-stimulated glucose uptake and consequently causes hyperglycemia; ii) Reduced muscle [Ca2+]i by dantrolene improves muscle glucose uptake and subsequent hyperglycemia; iii) The mechanism by which chronic high levels of [Ca2+]i interfere with insulin action appears to involve the expression of GLUT4 and its subcellular fractionation.

Keywords:  GLUT4; calcium; dantrolene; diabetes; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2022.872624
Expert Opin Pharmacother. 2022 May 13.

Identifying the challenges for successful pharmacotherapeutic management of sarcopenia.

Gordon S Lynch.



Keywords:  Aging; dystrophin; exercise; healthspan; hormone; longevity; metabolism; muscle wasting; muscle weakness; neuromuscular; nutrition; physiology; sarcopenia; strength

DOI:  https://doi.org/10.1080/14656566.2022.2076593
Exp Physiol. 2022 May 13.

Effects of obesity and acute resistance exercise on skeletal muscle angiogenic communication pathways.

Ron T Garner, Jessica A Weiss, Yaohui Nie, Brian P Sullivan, Christopher K Kargl, Cathal J Drohan, Shihuan Kuang, Julianne Stout, Timothy P Gavin.

   NEW FINDINGS: What are the central questions of this study? Do obesity and acute resistance exercise alter the regulation of muscle intercellular communication pathways consistent with inadequate compensatory angiogenesis in response to muscle loading present in individuals with obesity? What is the main finding and its importance? Obesity is associated with differences in both pro- and anti-angiogenic signaling consistent with lower muscle capillarization. Acute resistance exercise increases the release of skeletal muscle small extracellular vesicles independent of body mass. These results identify novel cellular factors associated with impaired angiogenesis in obesity and the positive effects of acute resistance exercise in lean and obese skeletal muscle.
ABSTRACT: Introduction Obesity (OB) impairs cell-to-cell communication signaling. Small extracellular vesicles (EVs), which includes exosomes, are released by skeletal muscle and participate in cell-to-cell communications including the regulation of angiogenesis. Resistance exercise (REx) increases muscle fiber size and capillarization. However, while obesity increases muscle fiber size, there is an inadequate increase in capillarization such that capillary density is reduced. It was hypothesized that REx induced angiogenic signaling and EV biogenesis would be lower with obesity. Methods Sedentary lean (LN) and individuals with obesity (OB) (n = 8/group) performed three sets of single leg, knee extension REx at 80% of maximum. Muscle biopsies were obtained at rest, 15 min, and 3 hr post-exercise and analyzed for angiogenic and EV biogenesis mRNA and protein. Results In OB, muscle fiber size was ∼20% greater and capillary density with type II fibers was ∼25% lower compared to LN (p<0.001) . In response to REx, increased vascular endothelial growth factor (VEGF) mRNA (pro-angiogenic) was similar (3-fold) between groups, while thrombospondin-1 (TSP-1) mRNA (anti-angiogenic) increased ∼2.5-fold in OB only (p = 0.010). miR-130a (pro-angiogenic) was ∼1.4-fold (p = 0.011) and miR-503 (anti-angiogenic) was ∼1.8-fold (p = 0.017) greater in OB compared to LN across all time points. In both groups acute REx decreased the EV surface protein Alix ∼50% consistent with the release of exosomes (p = 0.016). Conclusion Acute resistance exercise appears to induce the release of skeletal muscle small EVs independent of body mass. However, with obesity there is predominantly impaired angiogenic signaling consistent with inadequate angiogenesis in response to basal muscle hypertrophy. This article is protected by copyright. All rights reserved.

Keywords:  MVB; angiogenesis; exosomes

DOI:  https://doi.org/10.1113/EP090152
Front Aging Neurosci. 2022 ;14 876816

Age Related Changes in Muscle Mass and Force Generation in the Triple Transgenic (3xTgAD) Mouse Model of Alzheimer's Disease.

Hongyang Xu, Shylesh Bhaskaran, Katarzyna M Piekarz, Rojina Ranjit, Jan Bian, Parker Kneis, Aubrey Ellis, Suyesha Bhandari, Heather C Rice, Holly Van Remmen.

  Emerging evidence suggests that patients with Alzheimer's disease (AD) may show accelerated sarcopenia phenotypes. To investigate whether pathological changes associated with neuronal death and cognitive dysfunction also occur in peripheral motor neurons and muscle as a function of age, we used the triple transgenic mouse model of AD (3xTgAD mice) that carries transgenes for mutant forms of APP, Tau, and presenilin proteins that are associated with AD pathology. We measured changes in motor neurons and skeletal muscle function and metabolism in young (2 to 4 month) female control and 3xTgAD mice and in older (18-20 month) control and 3xTgAD female mice. In older 3xTgAD mice, we observed a number of sarcopenia-related phenotypes, including significantly fragmented and denervated neuromuscular junctions (NMJs) associated with a 17% reduction in sciatic nerve induced vs. direct muscle stimulation induced contractile force production, and a 30% decrease in gastrocnemius muscle mass. On the contrary, none of these outcomes were found in young 3xTgAD mice. We also measured an accumulation of amyloid-β (Aβ) in both skeletal muscle and neuronal tissue in old 3xTgAD mice that may potentially contribute to muscle atrophy and NMJ disruption in the older 3xTgAD mice. Furthermore, the TGF-β mediated atrophy signaling pathway is activated in old 3xTgAD mice and is a potential contributing factor in the muscle atrophy that occurs in this group. Perhaps surprisingly, mitochondrial oxygen consumption and reactive oxygen species (ROS) production are not elevated in skeletal muscle from old 3xTgAD mice. Together, these results provide new insights into the effect of AD pathological mechanisms on peripheral changes in skeletal muscle.

Keywords:  Alzheimer’s disease; amyloid-β (Aβ); neuromuscular junction (NMJ); sarcopenia; triple transgenic mice

DOI:  https://doi.org/10.3389/fnagi.2022.876816
Nat Commun. 2022 May 13. 13(1): 2661

Regulation of the evolutionarily conserved muscle myofibrillar matrix by cell type dependent and independent mechanisms.

Peter T Ajayi, Prasanna Katti, Yingfan Zhang, T Bradley Willingham, Ye Sun, Christopher K E Bleck, Brian Glancy.

Skeletal muscles play a central role in human movement through forces transmitted by contraction of the sarcomere. We recently showed that mammalian sarcomeres are connected through frequent branches forming a singular, mesh-like myofibrillar matrix. However, the extent to which myofibrillar connectivity is evolutionarily conserved as well as mechanisms which regulate the specific architecture of sarcomere branching remain unclear. Here, we demonstrate the presence of a myofibrillar matrix in the tubular, but not indirect flight (IF) muscles within Drosophila melanogaster. Moreover, we find that loss of transcription factor H15 increases sarcomere branching frequency in the tubular jump muscles, and we show that sarcomere branching can be turned on in IF muscles by salm-mediated conversion to tubular muscles. Finally, we demonstrate that neurochondrin misexpression results in myofibrillar connectivity in IF muscles without conversion to tubular muscles. These data indicate an evolutionarily conserved myofibrillar matrix regulated by both cell-type dependent and independent mechanisms.

DOI: https://doi.org/10.1038/s41467-022-30401-9
BMJ Open. 2022 May 11. 12(5): e060869

Uncovering the effects of gender affirming hormone therapy on skeletal muscle and epigenetics: protocol for a prospective matched cohort study in transgender individuals (the GAME study).

Patrice R Jones, Sarah Voisin, Brendan J Nolan, Shanie Landen, Macsue Jacques, Beau Newell, Sav Zwickl, Teddy Cook, Alex Wong, Ariel Ginger, Andrew Palmer, Andrew Garnham, Javier Alvarez-Romero, Namitha Mohandas, Kirsten Seale, Ada Cheung, Nir Eynon.

   INTRODUCTION: Gender affirming hormone therapy (GAHT) is increasingly used by transgender individuals and leads to shifts in sex hormone levels. Skeletal muscle is highly responsive to hormone activity, with limited data on the effects of GAHT on different human tissues. Here, we present the protocol for the GAME study (the effects of Gender Affirming hormone therapy on skeletal Muscle training and Epigenetics), which aims to uncover the effects of GAHT on skeletal muscle 'omic' profiles (methylomics, transcriptomics, proteomics, metabolomics) and markers of skeletal muscle health and fitness.
METHODS AND ANALYSIS: This study is a prospective age-matched cohort study in transgender adults commencing GAHT (n=80) and age-matched individuals not commencing GAHT (n=80), conducted at Austin Health and Victoria University in Victoria, Australia. Assessments will take place prior to beginning GAHT and 6 and 12 months into therapies in adults commencing GAHT. Age-matched individuals will be assessed at the same time points. Assessments will be divided over three examination days, involving (1) aerobic fitness tests, (2) muscle strength assessments and (3) collection of blood and muscle samples, as well as body composition measurements. Standardised diets, fitness watches and questionnaires will be used to control for key confounders in analyses. Primary outcomes are changes in aerobic fitness and muscle strength, as well as changes in skeletal muscle DNA methylation and gene expression profiles. Secondary outcomes include changes in skeletal muscle characteristics, proteomics, body composition and blood markers. Linear mixed models will be used to assess changes in outcomes, while accounting for repeated measures within participants and adjusting for known confounders.
ETHICS AND DISSEMINATION: The Austin Health Human Research Ethics Committee (HREC) and Victoria University HREC granted approval for this study (HREC/77146/Austin-2021). Findings from this project will be published in open-access, peer-reviewed journals and presented to scientific and public audiences.
TRIAL REGISTRATION NUMBER: ACTRN12621001415897; Pre-results.

Keywords:  CLINICAL PHYSIOLOGY; GENETICS; MOLECULAR BIOLOGY; SPORTS MEDICINE; Sex steroids & HRT

DOI:  https://doi.org/10.1136/bmjopen-2022-060869
Cell Rep. 2022 May 10. pii: S2211-1247(22)00552-6. [Epub ahead of print]39(6): 110785

Identification of distinct non-myogenic skeletal-muscle-resident mesenchymal cell populations.

Abigail P Leinroth, Anthony J Mirando, Douglas Rouse, Yoshihiko Kobayahsi, Purushothama Rao Tata, Helen E Rueckert, Yihan Liao, Jason T Long, Joe V Chakkalakal, Matthew J Hilton.

  Mesenchymal progenitors of the lateral plate mesoderm give rise to various cell fates within limbs, including a heterogeneous group of muscle-resident mesenchymal cells. Often described as fibro-adipogenic progenitors, these cells are key players in muscle development, disease, and regeneration. To further define this cell population(s), we perform lineage/reporter analysis, flow cytometry, single-cell RNA sequencing, immunofluorescent staining, and differentiation assays on normal and injured murine muscles. Here we identify six distinct Pdgfra+ non-myogenic muscle-resident mesenchymal cell populations that fit within a bipartite differentiation trajectory from a common progenitor. One branch of the trajectory gives rise to two populations of immune-responsive mesenchymal cells with strong adipogenic potential and the capability to respond to acute and chronic muscle injury, whereas the alternative branch contains two cell populations with limited adipogenic capacity and inherent mineralizing capabilities; one of the populations displays a unique neuromuscular junction association and an ability to respond to nerve injury.

Keywords:  CP: Developmental biology; FAPs; fibro-adipogenic progenitors; non-myogenic mesenchymal cells; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2022.110785
Am J Physiol Endocrinol Metab. 2022 May 09.

Regenerating Myofiber Directs Tregs and Th17 Responses in Inflamed Muscle through the Intrinsic TGF-β Signaling Mediated IL-6 Production.

Tao Huang, Jingwen Huang, Zhaohong Liao, Haiqiang Lan, Xiaoting Jian, Ruicai Gu, Jun Ouyang, Jijie Hu, Hua Liao.

  TGF-β is considered to be an important immuno regulatory cytokine. However, it remains unknown whether and how the muscle fiber specific-TGF-β signaling is directly involved in intramuscular inflammatory regulation by affecting T cells. Here, we addressed these in a mouse tibialis anterior muscle Cardiotoxin injection-induced injury repair model in MCK-Cre control or transgenic mice with TGF-β receptor II (TGF-βr2) being specifically deleted in muscle cells (SM TGF-βr2-/-). In control mice, TGF-β2 and TGF-βr2 were found significantly up-regulated in muscle after the acute injury. In mutant mice, deficiency of TGF-β signaling in muscle cells caused more serious muscle inflammation, with the increased infiltration of macrophages and CD4+ T cells at the degeneration stage (D4) and the early stage of regeneration (D7) after myoinjury. Notably, the loss of TGF-β signaling in myofibers dramatically affected on CD4+ T cell function and delayed T cells withdrawal at the later stage of muscle regeneration (D10 and D15), marked by the elevated Th17, but the impaired Tregs response. Furthermore, in vivo and in vitro, the intrinsic TGF-β signaling affected on immune behaviors of muscle cells, and directed CD4+ T cells differentiation by impairing IL-6 production and release. It suggests that local muscle inflammation can be inhibited potentially by directly activating the TGF-β signaling pathway in muscle cells to suppress Th17, but induce Tregs responses. Thus, according to the results of this study, we found a new idea for the control of local acute inflammation in skeletal muscle.

Keywords:  IL-6; T cell; TGF-β; myoinjury; myokines

DOI:  https://doi.org/10.1152/ajpendo.00247.2021
Cells. 2022 Apr 29. pii: 1493. [Epub ahead of print]11(9):

Factors Regulating or Regulated by Myogenic Regulatory Factors in Skeletal Muscle Stem Cells.

Tomohiko Shirakawa, Takashi Toyono, Asako Inoue, Takuma Matsubara, Tatsuo Kawamoto, Shoichiro Kokabu.

  MyoD, Myf5, myogenin, and MRF4 (also known as Myf6 or herculin) are myogenic regulatory factors (MRFs). MRFs are regarded as master transcription factors that are upregulated during myogenesis and influence stem cells to differentiate into myogenic lineage cells. In this review, we summarize MRFs, their regulatory factors, such as TLE3, NF-κB, and MRF target genes, including non-myogenic genes such as taste receptors. Understanding the function of MRFs and the physiology or pathology of satellite cells will contribute to the development of cell therapy and drug discovery for muscle-related diseases.

Keywords:  MyoD; NF-κB; TLE3; myogenesis; p65; satellite cell; taste receptor

DOI:  https://doi.org/10.3390/cells11091493
Cells. 2022 Apr 30. pii: 1508. [Epub ahead of print]11(9):

Unraveling the Molecular Basis of the Dystrophic Process in Limb-Girdle Muscular Dystrophy LGMD-R12 by Differential Gene Expression Profiles in Diseased and Healthy Muscles.

Christophe E Depuydt, Veerle Goosens, Rekin's Janky, Ann D'Hondt, Jan L De Bleecker, Nathalie Noppe, Stefaan Derveaux, Dietmar R Thal, Kristl G Claeys.

  Limb-girdle muscular dystrophy R12 (LGMD-R12) is caused by two mutations in anoctamin-5 (ANO5). Our aim was to identify genes and pathways that underlie LGMD-R12 and explain differences in the molecular predisposition and susceptibility between three thigh muscles that are severely (semimembranosus), moderately (vastus lateralis) or mildly (rectus femoris) affected in this disease. We performed transcriptomics on these three muscles in 16 male LGMD-R12 patients and 15 age-matched male controls. Our results showed that LGMD-R12 dystrophic muscle is associated with the expression of genes indicative of fibroblast and adipocyte replacement, such as fibroadipogenic progenitors and immune cell infiltration, while muscle protein synthesis and metabolism were downregulated. Muscle degeneration was associated with an increase in genes involved in muscle injury and inflammation, and muscle repair/regeneration. Baseline differences between muscles in healthy individuals indicated that muscles that are the most affected by LGMD-R12 have the lowest expression of transcription factor networks involved in muscle (re)generation and satellite stem cell activation. Instead, they show relative high levels of fetal/embryonic myosins, all together indicating that muscles differ in their baseline regenerative potential. To conclude, we profiled the gene expression landscape in LGMD-R12, identified baseline differences in expression levels between differently affected muscles and characterized disease-associated changes.

Keywords:  ANO5; LGMD2L; RNA-seq; anoctamin-5; fibroadipogenic progenitors; gene signatures; muscle biopsy; muscle dystrophy; selective muscle involvement; transcriptomics

DOI:  https://doi.org/10.3390/cells11091508
Cells. 2022 Apr 24. pii: 1436. [Epub ahead of print]11(9):

Schwann Cells Promote Myogenic Differentiation of Myoblasts and Adipogenic Mesenchymal Stromal Cells on Poly-ɛ-Caprolactone-Collagen I-Nanofibers.

Aijia Cai, Zeng-Ming Zheng, Marcus Himmler, Dirk W Schubert, Thomas A Fuchsluger, Volker Weisbach, Raymund E Horch, Andreas Arkudas.

  For the purpose of skeletal muscle tissue engineering, different cell types have been investigated regarding their myogenic differentiation potential, including co-cultured myoblasts and adipogenic mesenchymal stromal cells (Mb/ADSC). As neural cells enhance synaptic junction formation, the aim of this study was to co-culture Schwann cells (SCs) with Mb/ADSC on biocompatible electrospun aligned poly-ε-polycaprolacton (PCL)-collagen I-nanofibers. It was hypothesized that SCs, as part of the peripheral nervous system, promote the myogenic differentiation of Mb/ADSC co-cultures. Mb/ADSC were compared to Mb/ADSC/SC regarding their capacity for myogenic differentiation via immunofluorescent staining and gene expression of myogenic markers. Mb/ADSC/SC showed more myotubes after 28 days of differentiation (p ≤ 0.05). After 28 days of differentiation on electrospun aligned PCL-collagen I-nanofibers, gene expression of myosin heavy chains (MYH2) and myogenin (MYOG) was upregulated in Mb/ADSC/SC compared to Mb/ADSC (p ≤ 0.01 and p ≤ 0.05, respectively). Immunofluorescent staining for MHC showed highly aligned multinucleated cells as possible myotube formation in Mb/ADSC/SC. In conclusion, SCs promote myogenic differentiation of Mb/ADSC. The co-culture of primary Mb/ADSC/SC on PCL-collagen I-nanofibers serves as a physiological model for skeletal muscle tissue engineering, applicable to future clinical applications.

Keywords:  ADSC; Schwann cells; mesenchymal stem cells; myoblasts; myogenic differentiation; nanofibers

DOI:  https://doi.org/10.3390/cells11091436
Cancers (Basel). 2022 Apr 23. pii: 2107. [Epub ahead of print]14(9):

Molecular Mechanisms and Current Treatment Options for Cancer Cachexia.

Syed Sayeed Ahmad, Khurshid Ahmad, Sibhghatulla Shaikh, Hye Jin You, Eun-Young Lee, Shahid Ali, Eun Ju Lee, Inho Choi.

  Cancer cachexia is a condition marked by functional, metabolic, and immunological dysfunctions associated with skeletal muscle (SM) atrophy, adipose tissue loss, fat reduction, systemic inflammation, and anorexia. Generally, the condition is caused by a variety of mediators produced by cancer cells and cells in tumor microenvironments. Myostatin and activin signaling, IGF-1/PI3K/AKT signaling, and JAK-STAT signaling are known to play roles in cachexia, and thus, these pathways are considered potential therapeutic targets. This review discusses the current state of knowledge of the molecular mechanisms underlying cachexia and the available therapeutic options and was undertaken to increase understanding of the various factors/pathways/mediators involved and to identify potential treatment options.

Keywords:  cancer cachexia; inhibitors; myostatin; natural compounds; skeletal muscle

DOI:  https://doi.org/10.3390/cancers14092107
JCI Insight. 2022 May 09. pii: e155201. [Epub ahead of print]7(9):

Frataxin deficiency lowers lean mass and triggers the integrated stress response in skeletal muscle.

César Vásquez-Trincado, Julia Dunn, Ji In Han, Briyanna Hymms, Jaclyn Tamaroff, Monika Patel, Sara Nguyen, Anna Dedio, Kristin Wade, Chinazo Enigwe, Zuzana Nichtova, David R Lynch, Gyorgy Csordas, Shana E McCormack, Erin L Seifert.

  Friedreich's ataxia (FRDA) is an inherited disorder caused by reduced levels of frataxin (FXN), which is required for iron-sulfur cluster biogenesis. Neurological and cardiac comorbidities are prominent and have been a major focus of study. Skeletal muscle has received less attention despite indications that FXN loss affects it. Here, we show that lean mass is lower, whereas body mass index is unaltered, in separate cohorts of adults and children with FRDA. In adults, lower lean mass correlated with disease severity. To further investigate FXN loss in skeletal muscle, we used a transgenic mouse model of whole-body inducible and progressive FXN depletion. There was little impact of FXN loss when FXN was approximately 20% of control levels. When residual FXN was approximately 5% of control levels, muscle mass was lower along with absolute grip strength. When we examined mechanisms that can affect muscle mass, only global protein translation was lower, accompanied by integrated stress response (ISR) activation. Also in mice, aerobic exercise training, initiated prior to the muscle mass difference, improved running capacity, yet, muscle mass and the ISR remained as in untrained mice. Thus, FXN loss can lead to lower lean mass, with ISR activation, both of which are insensitive to exercise training.

Keywords:  Cell stress; Mitochondria; Muscle Biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.155201
Physiol Rep. 2022 May;10(9): e15297

Combined effects of exercise training and D-allulose intake on endurance capacity in mice.

Takamasa Tsuzuki, Ryo Suzuki, Risa Kajun, Takako Yamada, Tetsuo Iida, Bingyang Liu, Teruhiko Koike, Yukiyasu Toyoda, Takayuki Negishi, Kazunori Yukawa.

  This study investigated the combined effects of exercise training and D-allulose intake on endurance capacity in mice. Male C57BL/6J mice were fed either a control diet (Con) or a 3% D-allulose diet (Allu) and further divided into the sedentary (Sed) or exercise training (Ex) groups (Con-Sed, Con-Ex, Allu-Sed, Allu-Ex, respectively; n = 6-7/group). The mice in the Ex groups were trained on a motor-driven treadmill 5 days/week for 4 weeks (15-18 m/min, 60 min). After the exercise training period, all mice underwent an exhaustive running test to assess their endurance capacity. At 48 h after the running test, the mice in the Ex groups were subjected to run at 18 m/min for 60 min again. Then the gastrocnemius muscle and liver were sampled immediately after the exercise bout. The running time until exhaustion tended to be higher in the Allu-Ex than in the Con-Ex group (p = 0.08). The muscle glycogen content was significantly lower in the Con-Ex than in the Con-Sed group and was significantly higher in the Allu-Ex than in the Con-Ex group (p < 0.05). Moreover, exercise training increased the phosphorylation levels of adenosine monophosphate-activated protein kinase (AMPK) in the muscle and liver. The phosphorylation levels of acetyl coenzyme A carboxylase (ACC), a downstream of AMPK, in the muscle and liver were significantly higher in the Allu-Ex than in the Con-Sed group (p < 0.05), suggesting that the combination of exercise training and D-allulose might have activated the AMPK-ACC signaling pathway, which is associated with fatty acid oxidation in the muscle and liver. Taken together, our data suggested the combination of exercise training and D-allulose intake as an effective strategy to upregulate endurance capacity in mice. This may be associated with sparing glycogen content and enhancing activation of AMPK-ACC signaling in the skeletal muscle.

Keywords:  endurance capacity; exercise training; glycogen; rare sugar

DOI:  https://doi.org/10.14814/phy2.15297