bims-moremu 2024-10-06 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2024–10–06
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model.
Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.
Inhibition of MAT2A Impairs Skeletal Muscle Repair Function.
Aerobic Exercise Protects against Cardiotoxin-Induced Skeletal Muscle Injury in a DDAH1-Dependent Manner.
Beta2-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41.
Deubiquitinases in skeletal muscle - The Underappreciated Side of the Ubiquitination Coin.
Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.
The repeated bout effect evokes the training-induced skeletal muscle cellular memory.
Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.
Challenging Sarcopenia: Exploring AdipoRon in Aging Skeletal Muscle as a Healthspan-Extending Shield.
p38α kinase governs muscle strength through PGC1α in mice.
The MyoGravity project to study real microgravity effects on human muscle precursor cells and tissue.
Contribution of vascular endothelium to the regeneration of neuromuscular junctions after degenerative injury to adult skeletal muscle.
Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.
A Novel Assay Reveals the Early Setting-Up of Membrane Repair Machinery in Human Skeletal Muscle Cells.
Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.
Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.
Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection.
Does Vitamin B6 Act as an Exercise Mimetic in Skeletal Muscle?
Calpain-5 regulates muscle-specific protein expression and nuclear positioning during myoblast differentiation.
'Exerkines': A Comprehensive Term for the Factors Produced in Response to Exercise.
Muscle-fiber specific genetic manipulation of Drosophila sallimus severely impacts neuromuscular development, morphology, and physiology.
Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.
Skeletal Muscle Involvement in Friedreich Ataxia.
Therapeutic applications and challenges in myostatin inhibition for enhanced skeletal muscle mass and functions.
Profiling muscle transcriptome in mice exposed to microgravity using gene set enrichment analysis.
Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.
Submaximal eccentric resistance training increases serial sarcomere number and improves dynamic muscle performance in old rats.
Distinct Genomic Expression Signatures after Low-Force Electrically Induced Exercises in Persons with Spinal Cord Injury.
From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.
Exploring the Impact of Exercise-Derived Extracellular Vesicles in Cancer Biology.
Muscle loss: does one size fit all? A comment on Bozzetti's paper.
MicroRNAs as commonly expressed biomarkers for sarcopenia and frailty: A systematic review.
Association of Gut Microbiome with Muscle Mass, Muscle Strength, and Muscle Performance in Older Adults: A Systematic Review.

JCI Insight. 2024 Oct 01. pii: e174007. [Epub ahead of print]

Targeted Bmal1 restoration in muscle prolongs lifespan with systemic health effects in aging model.

Miguel A Gutierrez-Monreal, Christopher A Wolff, Eduardo E Rijos, Mark R Viggars, Collin M Douglas, Vishwajeeth Pagala, Junmin Peng, Liam C Hunt, Haocheng Ding, Fabio Demontis, Zhiguang Huo, Karyn A Esser.

  Disruption of the circadian clock in skeletal muscle worsens local and systemic health, leading to decreased muscle strength, metabolic dysfunction, and aging-like phenotypes. Whole-body knockout mice that lack Bmal1, a key component of the molecular clock, display premature aging. Here, by using adeno-associated viruses, we rescued Bmal1 expression specifically in the skeletal muscle fibers of Bmal1-KO mice and found that this engaged the circadian clock and clock output gene expression contributing to extended lifespan. Time course phenotypic analyses found that muscle strength, mobility, and glucose tolerance were improved with no effects on muscle mass, fiber size or type. A multi-omics approach at two ages further determined that restored muscle Bmal1 improved glucose handling pathways while concomitantly reducing lipid and protein metabolic pathways. The improved glucose tolerance and metabolic flexibility resulted in the systemic reduction of inflammatory signatures across peripheral tissues including liver, lung, and white adipose fat. Together, these findings highlight the critical role of muscle Bmal1 and downstream target genes for skeletal muscle homeostasis with considerable implications for systemic health.

Keywords:  Muscle biology; Skeletal muscle

DOI:  https://doi.org/10.1172/jci.insight.174007
Methods Mol Biol. 2025 ;2857 169-180

Characterization of Age-Dependent Changes in Skeletal Muscle Repair and Regeneration Using a Mouse Model of Acute Muscle Injury.

Faisal J Alibhai, Stephanie W Tobin.

  Acute skeletal muscle injury initiates a process of necrosis, debris clearance, and ultimately tissue regeneration via myogenesis. While skeletal muscle stem cells (MuSCs) are responsible for populating the proliferative myogenic progenitor pool to fuel muscle repair, recruited and resident immune cells have a central role in the regulation of muscle regeneration via the execution of phagocytosis and release of soluble factors that act directly on MuSCs to regulate myogenic differentiation. Therefore, the timing of MuSC proliferation and differentiation is closely linked to the populations and behaviors of immune cells present within skeletal muscle. This has important implications for aging and muscle repair, as systemic changes in immune system function contribute to a decline in muscle regenerative capacity. Here, we present adapted protocols for the isolation of mononuclear cells from skeletal muscles for the quantification of immune cell populations using flow cytometry. We also describe a cardiotoxin skeletal muscle injury protocol and detail the expected outcomes including immune cell infiltration to the injured sites and formation of new myocytes. As immune cell function is substantially influenced by aging, we extend these approaches and outcomes to aged mice.

Keywords:  Aging; Flow cytometry; Inflammation; Muscle regeneration

DOI:  https://doi.org/10.1007/978-1-0716-4128-6_16
Biomolecules. 2024 Sep 02. pii: 1098. [Epub ahead of print]14(9):

Inhibition of MAT2A Impairs Skeletal Muscle Repair Function.

Wanli Xiao, Tian-E Huang, Jing Zhou, Benhui Wang, Xiang Wang, Weirong Zeng, Qiquan Wang, Xinqiang Lan, Yang Xiang.

  The regenerative capacity of muscle, which primarily relies on anabolic processes, diminishes with age, thereby reducing the effectiveness of therapeutic interventions aimed at treating age-related muscle atrophy. In this study, we observed a decline in the expression of methionine adenosine transferase 2A (MAT2A), which synthesizes S-adenosylmethionine (SAM), in the muscle tissues of both aged humans and mice. Considering MAT2A's critical role in anabolism, we hypothesized that its reduced expression contributes to the impaired regenerative capacity of aging skeletal muscle. Mimicking this age-related reduction in the MAT2A level, either by reducing gene expression or inhibiting enzymatic activity, led to inhibiting their differentiation into myotubes. In vivo, inhibiting MAT2A activity aggravated BaCl2-induced skeletal muscle damage and decreased the number of satellite cells, whereas supplementation with SAM improved these effects. RNA-sequencing analysis further revealed that the Fas cell surface death receptor (Fas) gene was upregulated in Mat2a-knockdown C2C12 cells. Suppressing MAT2A expression or activity elevated Fas protein levels and increased the proportion of apoptotic cells. Additionally, inhibition of MAT2A expression or activity increased p53 expression. In conclusion, our findings demonstrated that impaired MAT2A expression or activity compromised the regeneration and repair capabilities of skeletal muscle, partially through p53-Fas-mediated apoptosis.

Keywords:  C2C12; Fas; Mat2a; regeneration; skeletal muscle

DOI:  https://doi.org/10.3390/biom14091098
Antioxidants (Basel). 2024 Sep 01. pii: 1069. [Epub ahead of print]13(9):

Aerobic Exercise Protects against Cardiotoxin-Induced Skeletal Muscle Injury in a DDAH1-Dependent Manner.

Fei Feng, Kai Luo, Xinyi Yuan, Ting Lan, Siyu Wang, Xin Xu, Zhongbing Lu.

  Dimethylarginine dimethylaminohydrolase 1 (DDAH1) is a critical enzyme that regulates nitric oxide (NO) signaling through the degradation of asymmetric dimethylarginine (ADMA). Previous studies have revealed a link between the beneficial effects of aerobic exercise and the upregulation of DDAH1 in bones and hearts. We previously reported that skeletal muscle DDAH1 plays a protective role in cardiotoxin (CTX)-induced skeletal muscle injury and regeneration. To determine the effects of aerobic exercise on CTX-induced skeletal muscle injury and the role of DDAH1 in this process, wild-type (WT) mice and skeletal muscle-specific Ddah1-knockout (Ddah1MKO) mice were subjected to swimming training for 8 weeks and then injected with CTX. In WT mice, swimming training for 8 weeks significantly promoted skeletal muscle regeneration and attenuated inflammation, oxidative stress, and apoptosis in the gastrocnemius (GA) muscle after CTX injection. These phenomena were associated with increases in the protein expression of PAX7, myogenin, MEF2A, eNOS, SOD2, and peroxiredoxin 5 and decreases in iNOS expression in GA muscles. Swimming training also decreased serum ADMA levels and increased serum nitrate/nitrite (NOx) levels and skeletal muscle DDAH1 expression. Interestingly, swimming training in Ddah1MKO mice had no obvious effect on CTX-induced skeletal muscle injury or regeneration and did not repress the CTX-induced inflammatory response, superoxide generation, or apoptosis. In summary, our data suggest that DDAH1 is important for the protective effect of aerobic exercise on skeletal muscle injury and regeneration.

Keywords:  DDAH1; cardiotoxin; exercise; oxidative stress; skeletal muscle regeneration

DOI:  https://doi.org/10.3390/antiox13091069
Scand J Med Sci Sports. 2024 Oct;34(10): e14736

Beta2-Adrenergic Stimulation Induces Resistance Training-Like Adaptations in Human Skeletal Muscle: Potential Role of KLHL41.

Søren Jessen, Júlia Prats Quesada, Andrea Di Credico, Roger Moreno-Justicia, Richard Wilson, Glenn Jacobson, Jens Bangsbo, Atul S Deshmukh, Morten Hostrup.

  Skeletal muscle mass plays a pivotal role in metabolic function, but conditions such as bed rest or injury often render resistance training impractical. The beta2-adrenergic receptor has been highlighted as a potential target to promote muscle hypertrophy and treat atrophic conditions. Here, we investigate the proteomic changes associated with beta2-adrenergic-mediated muscle hypertrophy, using resistance training as a hypertrophic comparator. We utilize MS-based proteomics to map skeletal muscle proteome remodeling in response to beta2-adrenergic stimulation or resistance training as well as cell model validation. We report that beta2-adrenergic stimulation mimics multiple features of resistance training in proteome-wide remodeling, comprising systematic upregulation of ribosomal subunits and concomitant downregulation of mitochondrial proteins. Approximately 20% of proteins were regulated in both conditions, comprising proteins involved in steroid metabolism (AKR1C1, AKR1C2, AKRC1C3), protein-folding (SERPINB1), and extracellular matrix organization (COL1A1, COL1A2). Among overall most significantly upregulated proteins were kelch-like family members (KLHL) 40 and 41. In follow-up experiments, we identify KLHL41 as having novel implications for beta2-adrenergic-mediated muscle hypertrophy. Treating C2C12 cells with beta2-agonist for 96 h increased myotube diameter by 48% (p < 0.001). This anabolic effect was abolished by prior knockdown of KLHL41. Using siRNA, KLHL41 abundance was decreased by 60%, and the anabolic response to beta2-agonist was diminished (+ 15%, i.e., greater in the presence of KLHL41, knock-down × treatment: p = 0.004). In conclusion, protein-wide remodeling induced by beta2-adrenergic stimulation mimics multiple features of resistance training, and thus the beta2-adrenergic receptor may be a target with therapeutic potential in the treatment of muscle wasting conditions without imposing mechanical load.

Keywords:  atrophy; kelch‐like; muscle hypertrophy; strength training; target

DOI:  https://doi.org/10.1111/sms.14736
Am J Physiol Cell Physiol. 2024 Sep 30.

Deubiquitinases in skeletal muscle - The Underappreciated Side of the Ubiquitination Coin.

Wayne X Du, Craig A Goodman, Paul Gregorevic.

  Ubiquitination is a post-translational modification that plays important roles in regulating protein stability, function, localization, and protein-protein interactions. Proteins are ubiquitinated via a process involving specific E1 activating enzymes, E2 conjugating enzymes, and E3 ligases. Simultaneously, protein ubiquitination is opposed by deubiquitinating enzymes (DUBs). DUB-mediated deubiquitination can change protein function or fate and recycle ubiquitin to maintain the free ubiquitin pool. Approximately 100 DUBs have been identified in the mammalian genome, and characterized into seven classes (USP, OTU, UCH, MJD, JAMM, MINDY and ZUP classes). Of these 100 DUBs, there has only been relatively limited investigation of 19 specifically in skeletal muscle cells, in vitro or in vivo, using overexpression, knockdown, and knockout models. To date, evidence indicates roles for individual DUBs in regulating aspects of myogenesis, protein turnover, muscle mass, and muscle metabolism. However, the exact mechanism by which these DUBs act (i.e. the specific targets of these DUBs and the type of ubiquitin chains they target) is still largely unknown, underscoring how little we know about DUBs in skeletal muscle. This review endeavors to comprehensively summarize the current state of knowledge of the function of DUBs in skeletal muscle and highlight the opportunities for gaining a greater understanding through further research into this important area of skeletal muscle and ubiquitin biology.

Keywords:  Deubiquitinase; Ubiquitin; Ubiquitin Proteasome System; post-translation modeifications; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00553.2024
Int J Mol Sci. 2024 Sep 13. pii: 9892. [Epub ahead of print]25(18):

Reduction of Mitochondrial Calcium Overload via MKT077-Induced Inhibition of Glucose-Regulated Protein 75 Alleviates Skeletal Muscle Pathology in Dystrophin-Deficient mdx Mice.

Mikhail V Dubinin, Anastasia E Stepanova, Irina B Mikheeva, Anastasia D Igoshkina, Alena A Cherepanova, Eugeny Yu Talanov, Ekaterina I Khoroshavina, Konstantin N Belosludtsev.

  Duchenne muscular dystrophy is secondarily accompanied by Ca2+ excess in muscle fibers. Part of the Ca2+ accumulates in the mitochondria, contributing to the development of mitochondrial dysfunction and degeneration of muscles. In this work, we assessed the effect of intraperitoneal administration of rhodacyanine MKT077 (5 mg/kg/day), which is able to suppress glucose-regulated protein 75 (GRP75)-mediated Ca2+ transfer from the sarcoplasmic reticulum (SR) to mitochondria, on the Ca2+ overload of skeletal muscle mitochondria in dystrophin-deficient mdx mice and the concomitant mitochondrial dysfunction contributing to muscle pathology. MKT077 prevented Ca2+ overload of quadriceps mitochondria in mdx mice, reduced the intensity of oxidative stress, and improved mitochondrial ultrastructure, but had no effect on impaired oxidative phosphorylation. MKT077 eliminated quadriceps calcification and reduced the intensity of muscle fiber degeneration, fibrosis level, and normalized grip strength in mdx mice. However, we noted a negative effect of MKT077 on wild-type mice, expressed as a decrease in the efficiency of mitochondrial oxidative phosphorylation, SR stress development, ultrastructural disturbances in the quadriceps, and a reduction in animal endurance in the wire-hanging test. This paper discusses the impact of MKT077 modulation of mitochondrial dysfunction on the development of skeletal muscle pathology in mdx mice.

Keywords:  Duchenne muscular dystrophy; GRP75; MKT077; UPR; calcium; mdx mice; skeletal muscle mitochondria

DOI:  https://doi.org/10.3390/ijms25189892
Free Radic Biol Med. 2024 Sep 27. pii: S0891-5849(24)00694-4. [Epub ahead of print]

The repeated bout effect evokes the training-induced skeletal muscle cellular memory.

Miguel Calvo-Rubio, Esther Garcia-Domiguez, Eva Tamayo-Torres, Silvana Soto-Rodríguez, Gloria Olaso-Gonzalez, Luigi Ferrucci, Rafael de Cabo, Maria Carmen Gómez-Cabrera.

  Physical exercise is well-established as beneficial for health. With the 20th-century epidemiological transition, promoting healthy habits like exercise has become crucial for preventing chronic diseases. Stress can yield adaptive long-term benefits, potentially transmitted trans-generationally. Physical training exposes individuals to metabolic, thermal, mechanical, and oxidative stressors, activating cell signaling pathways that regulate gene expression and adaptive responses, thereby enhancing stress tolerance-a phenomenon known as hormesis. Muscle memory is the capacity of skeletal muscle to respond differently to environmental stimuli in an adaptive (positive) or maladaptive (negative) manner if the stimuli have been encountered previously. The Repeated Bout Effect encompasses our skeletal muscle capacity to activate an intrinsic protective mechanism that reacts to eccentric exercise-induced damage by activating an adaptive response that resists subsequent damage stimuli. Deciphering the molecular mechanism of this phenomenon would allow the incorporation of muscle memory in training programs for professional athletes, active individuals looking for the health benefits of exercise training, and patients with "exercise intolerance." Moreover, enhancing the adaptive response of muscle memory could promote healing in individuals who traditionally do not recover after immobilization. The improvement could be part of an exercise program but could also be targeted pharmacologically. This review explores Repeated Bout Effect mechanisms: neural adaptations, tendon and muscle fiber property changes, extracellular matrix remodeling, and improved inflammatory responses.

Keywords:  Eccentric exercise; Hormesis; Muscle cellular memory; Repeated bout effect; Skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.09.047
bioRxiv. 2024 Sep 21. pii: 2024.09.17.613547. [Epub ahead of print]

Myofiber-specific FoxP1 knockout protects against pancreatic cancer-induced muscle wasting in male but not female mice.

Martin M Schonk, Jeremy B Ducharme, Daria Neyroud, Rachel L Nosacka, Haley O Tucker, Sarah M Judge, Andrew R Judge.

Cancer cachexia affects up to 80% of cancer patients and results in reduced quality of life and survival. We previously demonstrated that the transcriptional repressor Forkhead box P1 (FoxP1) is upregulated in skeletal muscle of cachectic mice and people with cancer, and when overexpressed in skeletal muscle is sufficient to induce pathological features characteristic of cachexia. However, the role of myofiber-derived FoxP1 in both normal muscle physiology and cancer-induced muscle wasting remains largely unexplored. To address this gap, we generated a conditional mouse line with myofiber-specific ablation of FoxP1 (FoxP1 SkmKO ) and found that in cancer-free mice, deletion of FoxP1 in skeletal myofibers resulted in increased myofiber size in both males and females, with a significant increase in muscle mass in males. In response to murine KPC pancreatic tumor burden, we found that myofiber-derived FoxP1 is required for cancer-induced muscle wasting and diaphragm muscle weakness in male mice. In summary, our findings identify myofiber-specific FoxP1 as a negative regulator of skeletal muscle with sex-specific differences in the context of cancer.
NEW & NOTEWORTHY: Here we identify myofiber-derived FoxP1 as a negative regulator of skeletal muscle with sex-specific effects in cancer. Under cancer-free conditions, FoxP1 knockout increased myofiber size in male and female mice. However, in response to pancreatic cancer, FoxP1 was required for muscle wasting and weakness in males but not females. This highlights the need to consider sexual dimorphism in cancer-induced muscle pathologies and provides evidence suggesting that targeting FoxP1 could help mitigate these effects in males.

DOI: https://doi.org/10.1101/2024.09.17.613547
Antioxidants (Basel). 2024 Sep 03. pii: 1073. [Epub ahead of print]13(9):

Challenging Sarcopenia: Exploring AdipoRon in Aging Skeletal Muscle as a Healthspan-Extending Shield.

Camille M Selvais, Maria A Davis-López de Carrizosa, Romain Versele, Nicolas Dubuisson, Laurence Noel, Sonia M Brichard, Michel Abou-Samra.

  Sarcopenia, characterized by loss of muscle mass, quality, and function, poses significant risks in aging. We previously demonstrated that long-term treatment with AdipoRon (AR), an adiponectin receptor agonist, alleviated myosteatosis and muscle degeneration in middle-aged obese mice. This study aimed to determine if a shorter AR treatment could effectively offset sarcopenia in older mice. Two groups of old mice (20-23 months) were studied, one untreated (O) and one orally-treated with AR (O-AR) at 50 mg/kg/day for three months, compared with control 3-month-old young mice (Y) or 10-month-old young-adult mice (C-10). Results showed that AR remarkably inversed the loss of muscle mass by restoring the sarcopenia index and fiber count, which were greatly diminished with age. Additionally, AR successfully saved muscle quality of O mice by halving the accumulation of tubular aggregates and aberrant mitochondria, through AMPK pathway activation and enhanced autophagy. AR also bolstered muscle function by rescuing mitochondrial activity and improving exercise endurance. Finally, AR markedly curbed muscle fibrosis and mitigated local/systemic inflammation. Thus, a late three-month AR treatment successfully opposed sarcopenia and counteracted various hallmarks of aging, suggesting AR as a promising anti-aging therapy for skeletal muscles, potentially extending healthspan.

Keywords:  AMPK; abnormal mitochondria; adiponectin; adiponectin agonist; autophagy; sarcopenia; tubular aggregates

DOI:  https://doi.org/10.3390/antiox13091073
Acta Physiol (Oxf). 2024 Oct 03. e14234

p38α kinase governs muscle strength through PGC1α in mice.

Leticia Herrera-Melle, Beatriz Cicuéndez, Juan Antonio López, Phillip A Dumesic, Sarah E Wilensky, Elena Rodríguez, Luis Leiva-Vega, Ainoa Caballero, Marta León, Jesús Vázquez, Bruce M Spiegelman, Cintia Folgueira, Alfonso Mora, Guadalupe Sabio.

   AIMS: Skeletal muscle, with its remarkable plasticity and dynamic adaptation, serves as a cornerstone of locomotion and metabolic homeostasis in the human body. Muscle tissue, with its extraordinary capacity for force generation and energy expenditure, plays a fundamental role in the movement, metabolism, and overall health. In this context, we sought to determine the role of p38α in mitochondrial metabolism since mitochondrial dynamics play a crucial role in the development of muscle-related diseases that result in muscle weakness.
METHODS: We conducted our study using male mice (MCK-cre, p38αMCK-KO and PGC1α MCK-KO) and mouse primary myoblasts. We analyzed mitochondrial metabolic, physiological parameters as well as proteomics, western blot, RNA-seq analysis from muscle samples.
RESULTS: Our findings highlight the critical involvement of muscle p38α in the regulation of mitochondrial function, a key determinant of muscle strength. The absence of p38α triggers changes in mitochondrial dynamics through the activation of PGC1α, a central regulator of mitochondrial biogenesis. These results have substantial implications for understanding the complex interplay between p38α kinase, PGC1α activation, and mitochondrial content, thereby enhancing our knowledge in the control of muscle biology.
CONCLUSIONS: This knowledge holds relevance for conditions associated with muscle weakness, where disruptions in these molecular pathways are frequently implicated in diminishing physical strength. Our research underscores the potential importance of targeting the p38α and PGC1α pathways within muscle, offering promising avenues for the advancement of innovative treatments. Such interventions hold the potential to improve the quality of life for individuals affected by muscle-related diseases.

Keywords:  mitochondrial biogenesis; mitochondrial dynamics; muscle strength; p38α; skeletal muscle

DOI:  https://doi.org/10.1111/apha.14234
NPJ Microgravity. 2024 Oct 03. 10(1): 92

The MyoGravity project to study real microgravity effects on human muscle precursor cells and tissue.

Ester Sara Di Filippo, Sara Chiappalupi, Stefano Falone, Vincenza Dolo, Fernanda Amicarelli, Silvia Marchianò, Adriana Carino, Gabriele Mascetti, Giovanni Valentini, Sara Piccirillo, Michele Balsamo, Marco Vukich, Stefano Fiorucci, Guglielmo Sorci, Stefania Fulle.

Microgravity (µG) experienced during space flights promotes adaptation in several astronauts' organs and tissues, with skeletal muscles being the most affected. In response to reduced gravitational loading, muscles (especially, lower limb and antigravity muscles) undergo progressive mass loss and alteration in metabolism, myofiber size, and composition. Skeletal muscle precursor cells (MPCs), also known as satellite cells, are responsible for the growth and maintenance of muscle mass in adult life as well as for muscle regeneration following damage and may have a major role in µG-induced muscle wasting. Despite the great relevance for astronaut health, very few data are available about the effects of real µG on human muscles. Based on the MyoGravity project, this study aimed to analyze: (i) the cellular and transcriptional alterations induced by real µG in human MPCs (huMPCs) and (ii) the response of human skeletal muscle to normal gravitational loading after prolonged exposure to µG. We evaluated the transcriptomic changes induced by µG on board the International Space Station (ISS) in differentiating huMPCs isolated from Vastus lateralis muscle biopsies of a pre-flight astronaut and an age- and sex-matched volunteer, in comparison with the same cells cultured on the ground in standard gravity (1×g) conditions. We found that huMPCs differentiated under real µG conditions showed: (i) upregulation of genes related to cell adhesion, plasma membrane components, and ion transport; (ii) strong downregulation of genes related to the muscle contraction machinery and sarcomere organization; and (iii) downregulation of muscle-specific microRNAs (myomiRs). Moreover, we had the unique opportunity to analyze huMPCs and skeletal muscle tissue of the same astronaut before and 30 h after a long-duration space flight on board the ISS. Prolonged exposure to real µG strongly affected the biology and functionality of the astronaut's satellite cells, which showed a dramatic reduction of responsiveness to activating stimuli and proliferation rate, morphological changes, and almost inability to fuse into myotubes. RNA-Seq analysis of post- vs. pre-flight muscle tissue showed that genes involved in muscle structure and remodeling are promptly activated after landing following a long-duration space mission. Conversely, genes involved in the myelination process or synapse and neuromuscular junction organization appeared downregulated. Although we have investigated only one astronaut, these results point to a prompt readaptation of the skeletal muscle mechanical components to the normal gravitational loading, but the inability to rapidly recover the physiological muscle myelination/innervation pattern after landing from a long-duration space flight. Together with the persistent functional deficit observed in the astronaut's satellite cells after prolonged exposure to real µG, these results lead us to hypothesize that a condition of inefficient regeneration is likely to occur in the muscles of post-flight astronauts following damage.

DOI: https://doi.org/10.1038/s41526-024-00432-1
J Physiol. 2024 Oct 02.

Contribution of vascular endothelium to the regeneration of neuromuscular junctions after degenerative injury to adult skeletal muscle.

Joe V Chakkalakal.



Keywords:  development; endothelial cells; muscle physiology; stem cell; transgenic mouse

DOI:  https://doi.org/10.1113/JP287384
Sci Rep. 2024 10 03. 14(1): 22965

Molecular composition of skeletal muscle in infants and adults: a comparative proteomic and transcriptomic study.

Alexander Schaiter, Andreas Hentschel, Felix Kleefeld, Julia Schuld, Vincent Umathum, Tara Procida-Kowalski, Christopher Nelke, Angela Roth, Andreas Hahn, Heidrun H Krämer, Tobias Ruck, Rita Horvath, Peter F M van der Ven, Marek Bartkuhn, Andreas Roos, Anne Schänzer.

  To gain a deeper understanding of skeletal muscle function in younger age and aging in elderly, identification of molecular signatures regulating these functions under physiological conditions is needed. Although molecular studies of healthy muscle have been conducted on adults and older subjects, there is a lack of research on infant muscle in terms of combined morphological, transcriptomic and proteomic profiles. To address this gap of knowledge, we performed RNA sequencing (RNA-seq), tandem mass spectrometry (LC-MS/MS), morphometric analysis and assays for mitochondrial maintenance in skeletal muscle biopsies from both, infants aged 4-28 months and adults aged 19-65 years. We identified differently expressed genes (DEGs) and differentially expressed proteins (DEPs) in adults compared to infants. The down-regulated genes in adults were associated with functional terms primarily related to sarcomeres, cellular maintenance, and metabolic, immunological and developmental processes. Thus, our study indicates age-related differences in the molecular signatures and associated functions of healthy skeletal muscle. Moreover, the findings assert that processes previously associated solely with aging are indeed part of development and healthy aging. Hence, combined findings of this study also indicate that age-dependent controls are crucial in muscle disease studies, as otherwise the comparative results may not be reliable.

Keywords:  Bioinformatics in omics; Mitochondria in aging; Muscle proteomics; Muscle transcriptomics

DOI:  https://doi.org/10.1038/s41598-024-74913-4
J Cell Biochem. 2024 Sep 30. e30662

A Novel Assay Reveals the Early Setting-Up of Membrane Repair Machinery in Human Skeletal Muscle Cells.

Léna d'Agata, Phoebe Rassinoux, Céline Gounou, Flora Bouvet, Dounia Bouragba, Kamel Mamchaoui, Anthony Bouter.

  Defect in membrane repair contributes to the development of muscular dystrophies such as limb girdle muscular dystrophy (LGMD) type R2 or R12. Nevertheless, many other muscular dystrophies may also result from a defect in this process. Identifying these pathologies requires the development of specific methods to inflict sarcolemma damage on a large number of cells and rapidly analyze their response. We adapted a protocol hitherto used to study the behavior of cancer cells to mechanical constraint. This method is based on forcing the passage of cells through a thin needle, which induces shear stress. Due to size considerations, this method requires working with mononuclear muscle cells instead of myotubes or muscle fibers. Although functional sarcolemma repair was thought to be restricted to myotubes and muscle fibers, we show here that 24h-differentiated myoblasts express a complete machinery capable of addressing membrane damage. At this stage, muscle cells do not yet form myotubes, revealing that the membrane repair machinery is set up early throughout the differentiation process. When submitted to the shear-stress assay, these cells were observed to repair membrane damage in a Ca2+-dependent manner, as previously reported. We show that this technique is able to identify the absence of membrane resealing in muscle cells from patient suffering from LGMDR2. The proposed technique provides therefore a suitable method for identifying cellular dysregulations in membrane repair of dystrophic human muscle cells.

Keywords:  fluorescence microscopy; limb girdle muscular dystrophy; membrane repair; muscular dystrophy; shear‐stress assay; skeletal muscle

DOI:  https://doi.org/10.1002/jcb.30662
Sci Rep. 2024 09 27. 14(1): 22147

Heme deficiency in skeletal muscle exacerbates sarcopenia and impairs autophagy by reducing AMPK signaling.

Takeru Akabane, Hiromori Sagae, Koen van Wijk, Shinichi Saitoh, Tomohiro Kimura, Satoshi Okano, Ken Kodama, Kiwamu Takahashi, Motowo Nakajima, Tohru Tanaka, Michiaki Takagi, Osamu Nakajima.

  Heme serves as a prosthetic group in hemoproteins, including subunits of the mammalian mitochondrial electron transfer chain. The first enzyme in vertebrate heme biosynthesis, 5-aminolevulinic acid synthase 1 (ALAS1), is ubiquitously expressed and essential for producing 5-aminolevulinic acid (ALA). We previously showed that Alas1 heterozygous mice at 20-35 weeks (aged-A1+/-s) manifested impaired glucose metabolism, mitochondrial malformation in skeletal muscle, and reduced exercise tolerance, potentially linked to autophagy dysfunction. In this study, we investigated autophagy in A1+/-s and a sarcopenic phenotype in A1+/-s at 75-95 weeks (senile-A1+/-s). Senile-A1+/-s exhibited significantly reduced body and gastrocnemius muscle weight, and muscle strength, indicating an accelerated sarcopenic phenotype. Decreases in total LC3 and LC3-II protein and Map1lc3a mRNA levels were observed in aged-A1+/-s under fasting conditions and in Alas1 knockdown myocyte-differentiated C2C12 cells (A1KD-C2C12s) cultured in high- or low-glucose medium. ALA treatment largely reversed these declines. Reduced AMP-activated protein kinase (AMPK) signaling was associated with decreased autophagy in aged-A1+/-s and A1KD-C2C12s. AMPK modulation using AICAR (activator) and dorsomorphin (inhibitor) affected LC3 protein levels in an AMPK-dependent manner. Our findings suggest that heme deficiency contributes to accelerated sarcopenia-like defects and reduced autophagy in skeletal muscle, primarily due to decreased AMPK signaling.

Keywords:  5-aminolevulinic acid; 5-aminolevulinic acid synthase 1 (ALAS1); Autophagy; Heme; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-024-73049-9
J Cachexia Sarcopenia Muscle. 2024 Oct 02.

Prenatal and progressive coenzyme Q10 administration to mitigate muscle dysfunction in mitochondrial disease.

Juan Diego Hernández-Camacho, Cristina Vicente-García, Lorena Ardila-García, Ana Padilla-Campos, Guillermo López-Lluch, Carlos Santos-Ocaña, Peter S Zammit, Jaime J Carvajal, Plácido Navas, Daniel J M Fernández-Ayala.

   BACKGROUND: ADCK genes encode aarF domain-containing mitochondrial kinases involved in coenzyme Q (CoQ) biosynthesis and regulation. Haploinsufficiency of ADCK2 in humans leads to adult-onset physical incapacity with reduced mitochondrial CoQ levels in skeletal muscle, resulting in mitochondrial myopathy and alterations in fatty acid β-oxidation. The sole current treatment for CoQ deficiencies is oral administration of CoQ10, which causes only partial recovery with postnatal treatment, underscoring the importance of early diagnosis for successful intervention.
METHODS: We used Adck2 heterozygous mice to examine the influence of this gene on muscle structure, function and regeneration throughout development, growth and ageing. This investigation involved techniques including immunohistochemistry, analysis of CoQ levels, mitochondrial respiratory content, muscle transcriptome analysis and functional tests.
RESULTS: We demonstrated that Adck2 heterozygous mice exhibit defects from embryonic development, particularly in skeletal muscle (1102 genes deregulated). Adck2 heterozygous embryos were 7% smaller in size and displayed signs of delayed development. Prenatal administration of CoQ10 could mitigate these embryonic defects. Heterozygous Adck2 mice also showed a decrease in myogenic cell differentiation, with more severe consequences in 'aged' mice (41.63% smaller) (P < 0.01). Consequently, heterozygous Adck2 mice displayed accelerated muscle wasting associated with ageing in muscle structure (P < 0.05), muscle function (less grip strength capacity) (P < 0.001) and muscle mitochondrial respiration (P < 0.001). Furthermore, progressive CoQ10 administration conferred protective effects on mitochondrial function (P < 0.0001) and skeletal muscle (P < 0.05).
CONCLUSIONS: Our work uncovered novel aspects of CoQ deficiencies, revealing defects during embryonic development in mammals for the first time. Additionally, we identified the gradual establishment and progression of the deleterious Adck2 mouse phenotype. Importantly, CoQ10 supplementation demonstrated a protective effect when initiated during development.

Keywords:  ageing; coenzyme Q; development; mitochondria; satellite cell; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.13574
Geroscience. 2024 Oct 02.

Aging enhances pro-atrogenic gene expression and skeletal muscle loss following respiratory syncytial virus infection.

J Sophie Sagawe, Verity I P Loake, Peter J M Openshaw, Paul Kemp, Fiona J Culley.

  Aging and many age-related health conditions are associated with skeletal muscle loss. Furthermore, older adults are more susceptible to severe respiratory infections, which can in turn lead to muscle wasting. The mechanisms by which respiratory viral infection can impact skeletal muscle in older adults are not well understood. We determined the effects of acute infection with respiratory syncytial virus (RSV) on the lung and skeletal muscle of aged mice. RSV infection caused more severe disease in aged mice with enhanced weight loss, reduced feeding, higher viral load, and greater airway inflammation. Aged but not young mice showed decreased leg muscle weight at the peak of illness and decreased size of leg muscle fibers. Aged mice increased muscle-specific expression of atrophy-promoting enzymes (Atrogin-1 and MuRF-1) and failed to increase the rate of muscle protein synthesis during RSV infection. In aged mice, the changes in Atrogin-1 and MuRF-1 gene expression in skeletal muscle correlated with IL-6 levels in the lungs. These findings indicate that RSV infection of aged mice provides a model for studying the diverse adverse systemic consequences of respiratory viral infections on health and wellbeing in older adults.

Keywords:  Aging; Infection; Muscle; Respiratory

DOI:  https://doi.org/10.1007/s11357-024-01370-2
Int J Mol Sci. 2024 Sep 15. pii: 9962. [Epub ahead of print]25(18):

Does Vitamin B6 Act as an Exercise Mimetic in Skeletal Muscle?

Norihisa Kato, Yongshou Yang, Chanikan Bumrungkit, Thanutchaporn Kumrungsee.

  Marginal vitamin B6 (B6) deficiency is common in various segments worldwide. In a super-aged society, sarcopenia is a major concern and has gained significant research attention focused on healthy aging. To date, the primary interventions for sarcopenia have been physical exercise therapy. Recent evidence suggests that inadequate B6 status is associated with an increased risk of sarcopenia and mortality among older adults. Our previous study showed that B6 supplementation to a marginal B6-deficient diet up-regulated the expression of various exercise-induced genes in the skeletal muscle of rodents. Notably, a supplemental B6-to-B6-deficient diet stimulates satellite cell-mediated myogenesis in rodents, mirroring the effects of physical exercise. These findings suggest the potential role of B6 as an exercise-mimetic nutrient in skeletal muscle. To test this hypothesis, we reviewed relevant literature and compared the roles of B6 and exercise in muscles. Here, we provide several pieces of evidence supporting this hypothesis and discuss the potential mechanisms behind the similarities between the effects of B6 and exercise on muscle. This research, for the first time, provides insight into the exercise-mimetic roles of B6 in skeletal muscle.

Keywords:  AMPK; H2S; NLRP3 inflammasome; PLP enzyme; exercise; inflammation; myogenesis; pyridoxal 5′-phosphate; skeletal muscle; vitamin B6

DOI:  https://doi.org/10.3390/ijms25189962
J Biol Chem. 2024 Sep 30. pii: S0021-9258(24)02344-5. [Epub ahead of print] 107842

Calpain-5 regulates muscle-specific protein expression and nuclear positioning during myoblast differentiation.

Nobuhiro Morishima, Yoshihiro Ito.

  Intracellular calcium dynamics is key to regulating various physiological events. Myotube formation by myoblast fusion is controlled by the release of Ca2+ from the endoplasmic reticulum (ER), and the calpain (CAPN) family is postulated to be an executioner of the process. However, the activation of a specific member of the family or its physiological substrates is unclear. In this study, we explore the involvement of a CAPN in myoblast differentiation. Time-course experiments showed that the reduction in potential substrates of calpains, c-Myc and STAT3 (signal transducer and activator of transcription 3) and generation of STAT3 fragments occurred multiple times at an early stage of myoblast differentiation. Inhibition of the ER Ca2+ release suppressed these phenomena, suggesting that the reduction was dependent on the cleavage by a CAPN. CAPN5 knockdown suppressed the reduction. In vitro reconstitution assay showed Ca2+- and CAPN5-dependent degradation of c-Myc and STAT3. These results suggest the activation of CAPN5 in differentiating myoblasts. Fusion of the Capn5 knockdown myoblast efficiently occurred; however, the upregulation of muscle-specific proteins (myosin and actinin) was suppressed. Myofibrils were poorly formed in the fused cells with a bulge where nuclei formed a cluster, suggesting that the myonuclear positioning was abnormal. STAT3 was hyperactivated in those fused cells, possibly inhibiting the upregulation of muscle-specific proteins necessary for the maturation of myotubes. These results suggest that the CAPN5 activity is essential in myoblast differentiation.

Keywords:  Myc (c-Myc); STAT3; calcium; calpain; myogenesis; myonuclei; proteolysis; skeletal muscle

DOI:  https://doi.org/10.1016/j.jbc.2024.107842
Biomedicines. 2024 Sep 01. pii: 1975. [Epub ahead of print]12(9):

'Exerkines': A Comprehensive Term for the Factors Produced in Response to Exercise.

Giuseppe Novelli, Giuseppe Calcaterra, Federico Casciani, Sergio Pecorelli, Jawahar L Mehta.

  Regular exercise and physical activity are now considered lifestyle factors with positive effects on human health. Physical activity reduces disease burden, protects against the onset of pathologies, and improves the clinical course of disease. Unlike pharmacological therapies, the effects mediated by exercise are not limited to a specific target organ but act in multiple biological systems simultaneously. Despite the substantial health benefits of physical training, the precise molecular signaling processes that lead to structural and functional tissue adaptation remain largely unknown. Only recently, several bioactive molecules have been discovered that are produced following physical exercise. These molecules are collectively called "exerkines". Exerkines are released from various tissues in response to exercise, and play a crucial role in mediating the beneficial effects of exercise on the body. Major discoveries involving exerkines highlight their diverse functions and health implications, particularly in metabolic regulation, neuroprotection, and muscle adaptation. These molecules, including peptides, nucleic acids, lipids, and microRNAs, act through paracrine, endocrine, and autocrine pathways to exert their effects on various organs and tissues. Exerkines represent a complex network of signaling molecules that mediate the multiple benefits of exercise. Their roles in metabolic regulation, neuroprotection, and muscle adaptation highlight the importance of physical activity in maintaining health and preventing disease.

Keywords:  biomolecules; exerkines; inflammation; omics; physical exercise

DOI:  https://doi.org/10.3390/biomedicines12091975
Front Physiol. 2024 ;15 1429317

Muscle-fiber specific genetic manipulation of Drosophila sallimus severely impacts neuromuscular development, morphology, and physiology.

Andrew H Michael, Tadros A Hana, Veronika G Mousa, Kiel G Ormerod.

  The ability of skeletal muscles to contract is derived from the unique genes and proteins expressed within muscles, most notably myofilaments and elastic proteins. Here we investigated the role of the sallimus (sls) gene, which encodes a structural homologue of titin, in regulating development, structure, and function of Drosophila melanogaster. Knockdown of sls using RNA interference (RNAi) in all body-wall muscle fibers resulted in embryonic lethality. A screen for muscle-specific drivers revealed a Gal4 line that expresses in a single larval body wall muscle in each abdominal hemisegment. Disrupting sls expression in single muscle fibers did not impact egg or larval viability nor gross larval morphology but did significantly alter the morphology of individual muscle fibers. Ultrastructural analysis of individual muscles revealed significant changes in organization. Surprisingly, muscle-cell specific disruption of sls also severely impacted neuromuscular junction (NMJ) formation. The extent of motor-neuron (MN) innervation along disrupted muscles was significantly reduced along with the number of glutamatergic boutons, in MN-Is and MN-Ib. Electrophysiological recordings revealed a 40% reduction in excitatory junctional potentials correlating with the extent of motor neuron loss. Analysis of active zone (AZ) composition revealed changes in presynaptic scaffolding protein (brp) abundance, but no changes in postsynaptic glutamate receptors. Ultrastructural changes in muscle and NMJ development at these single muscle fibers were sufficient to lead to observable changes in neuromuscular transduction and ultimately, locomotory behavior. Collectively, the data demonstrate that sls mediates critical aspects of muscle and NMJ development and function, illuminating greater roles for sls/titin.

Keywords:  Drosophila; elastic protein; muscle; neuromuscular junction; sallimus; sarcomere; titin

DOI:  https://doi.org/10.3389/fphys.2024.1429317
Am J Physiol Cell Physiol. 2024 Sep 30.

Mitochondrial antioxidant SkQ1 attenuates C26 cancer-induced muscle wasting in males and improves muscle contractility in female tumor-bearing mice.

Stavroula Tsitkanou, Francielly Morena da Silva, Ana Regina Cabrera, Eleanor R Schrems, Ruqaiza Muhyudin, Pieter J Koopmans, Sabin Khadgi, Seongkyun Lim, Luca J Delfinis, Tyrone A Washington, Kevin A Murach, Christopher G R Perry, Nicholas P Greene.

  Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1x106 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (~250 nmol/kg body weight/day) and administered to mice beginning seven days following tumor induction, while control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post-hoc test when interactions were significant (p≤0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1, Serca1 and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC.

Keywords:  cancer cachexia; protein turnover; reactive oxygen species; sexual dimorphism; skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00497.2024
Int J Mol Sci. 2024 Sep 13. pii: 9915. [Epub ahead of print]25(18):

Skeletal Muscle Involvement in Friedreich Ataxia.

Elisabetta Indelicato, Julia Wanschitz, Wolfgang Löscher, Sylvia Boesch.

  Friedreich Ataxia (FRDA) is an inherited neuromuscular disorder triggered by a deficit of the mitochondrial protein frataxin. At a cellular level, frataxin deficiency results in insufficient iron-sulfur cluster biosynthesis and impaired mitochondrial function and adenosine triphosphate production. The main clinical manifestation is a progressive balance and coordination disorder which depends on the involvement of peripheral and central sensory pathways as well as of the cerebellum. Besides the neurological involvement, FRDA affects also the striated muscles. The most prominent manifestation is a hypertrophic cardiomyopathy, which also represents the major determinant of premature mortality. Moreover, FRDA displays skeletal muscle involvement, which contributes to the weakness and marked fatigue evident throughout the course of the disease. Herein, we review skeletal muscle findings in FRDA generated by functional imaging, histology, as well as multiomics techniques in both disease models and in patients. Altogether, these findings corroborate a disease phenotype in skeletal muscle and support the notion of progressive mitochondrial damage as a driver of disease progression in FRDA. Furthermore, we highlight the relevance of skeletal muscle investigations in the development of biomarkers for early-phase trials and future therapeutic strategies in FRDA.

Keywords:  Friedreich Ataxia; biomarker; frataxin; mitochondria; proteomics; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.3390/ijms25189915
Mol Cell Biochem. 2024 Sep 28.

Therapeutic applications and challenges in myostatin inhibition for enhanced skeletal muscle mass and functions.

Brock Wetzlich, Benard B Nyakundi, Jinzeng Yang.

  Myostatin, a potent negative regulator of skeletal muscle mass, has garnered significant attention as a therapeutic target for muscle dystrophies. Despite extensive research and promising preclinical results, clinical trials targeting myostatin inhibition in muscle dystrophies have failed to yield substantial improvements in muscle function or fitness in patients. This review details the mechanisms behind myostatin's function and the various inhibitors that have been tested preclinically and clinically. It also examines the challenges encountered in clinical translation, including issues with drug specificity, differences in serum myostatin concentrations between animal models and humans, and the necessity of neural input for functional improvements. Additionally, we explore promising avenues of research beyond muscle dystrophies, particularly in the treatment of metabolic syndromes and orthopedic disorders. Insights from these alternative applications suggest that myostatin inhibition may hold the potential for addressing a broader range of pathologies, providing new directions for therapeutic development.

Keywords:  Clinical trials; Diabetes; Muscular dystrophy; Myostatin; Myostatin inhibitors; Obesity; Orthopedic disease; Skeletal muscle

DOI:  https://doi.org/10.1007/s11010-024-05120-y
NPJ Microgravity. 2024 Oct 04. 10(1): 94

Profiling muscle transcriptome in mice exposed to microgravity using gene set enrichment analysis.

Anup Mammen Oommen, Phillip Stafford, Lokesh Joshi.

Space exploration's advancement toward long-duration missions prompts intensified research on physiological effects. Despite adaptive physiological stability in some variables, persistent changes affect genome integrity, immune response, and cognitive function. Our study, utilizing multi-omics data from GeneLab, provides crucial insights investigating muscle atrophy during space mission. Leveraging NASA GeneLab's data resources, we apply systems biology-based analyses, facilitating comprehensive understanding and enabling meta-analysis. Through transcriptomics, we establish a reference profile of biological processes underlying muscle atrophy, crucial for intervention development. We emphasize the often-overlooked role of glycosylation in muscle atrophy. Our research sheds light on fundamental molecular mechanisms, bridging gaps between space research and terrestrial conditions. This study underscores the importance of interdisciplinary collaboration and data-sharing initiatives like GeneLab in advancing space medicine research.

DOI: https://doi.org/10.1038/s41526-024-00434-z
Int J Mol Sci. 2024 Sep 20. pii: 10116. [Epub ahead of print]25(18):

Irisin Protects Musculoskeletal Homeostasis via a Mitochondrial Quality Control Mechanism.

Chong Zhao, Yonghao Wu, Shuaiqi Zhu, Haiying Liu, Shuai Xu.

  Irisin, a myokine derived from fibronectin type III domain-containing 5 (FNDC5), is increasingly recognized for its protective role in musculoskeletal health through the modulation of mitochondrial quality control. This review synthesizes the current understanding of irisin's impact on mitochondrial biogenesis, dynamics, and autophagy in skeletal muscle, elucidating its capacity to bolster muscle strength, endurance, and resilience against oxidative-stress-induced muscle atrophy. The multifunctional nature of irisin extends to bone metabolism, where it promotes osteoblast proliferation and differentiation, offering a potential intervention for osteoporosis and other musculoskeletal disorders. Mitochondrial quality control is vital for cellular metabolism, particularly in energy-demanding tissues. Irisin's influence on this process is highlighted, suggesting its integral role in maintaining cellular homeostasis. The review also touches upon the regulatory mechanisms of irisin secretion, predominantly induced by exercise, and its systemic effects as an endocrine factor. While the therapeutic potential of irisin is promising, the need for standardized measurement techniques and further elucidation of its mechanisms in humans is acknowledged. The collective findings underscore the burgeoning interest in irisin as a keystone in musculoskeletal health and a candidate for future therapeutic strategies.

Keywords:  irisin; mitochondrial quality control; musculoskeletal health; myokine; osteoporosis; skeletal muscle

DOI:  https://doi.org/10.3390/ijms251810116
Physiol Rep. 2024 Oct;12(19): e70036

Submaximal eccentric resistance training increases serial sarcomere number and improves dynamic muscle performance in old rats.

Avery Hinks, Ethan Vlemmix, Geoffrey A Power.

  The age-related loss of muscle mass is partly accounted for by the loss of sarcomeres in series, contributing to declines in muscle mechanical performance. Resistance training biased to eccentric contractions increases serial sarcomere number (SSN) in young muscle, however, maximal eccentric training in old rats previously did not alter SSN and worsened performance. A submaximal eccentric training stimulus may be more conducive to adaptation for aged muscle. The purpose of this study was to assess whether submaximal eccentric training can increase SSN and improve mechanical function in old rats. Twelve 32-month-old male F344/BN rats completed 4 weeks of submaximal (60% maximum) eccentric plantar-flexion training 3 days/week. Pre- and post-training, we assessed in-vivo maximum isometric torque at a stretched and neutral ankle angle, the passive torque-angle relationship, and the isotonic torque-velocity-power relationship. The soleus and medial gastrocnemius (MG) were harvested for SSN measurements via laser diffraction, with the untrained leg as a control. SSN increased 11% and 8% in the soleus and MG, respectively. Training also shifted optimal torque production towards longer muscle lengths, reduced passive torque 42%, and increased peak isotonic power 23%. Submaximal eccentric training was beneficial for aged muscle adaptations, increasing SSN, reducing muscle passive tension, and improving dynamic contractile performance.

Keywords:  fisher 344/Brown Norway rats; muscle architecture; power; sarcomerogenesis; velocity

DOI:  https://doi.org/10.14814/phy2.70036
Int J Mol Sci. 2024 Sep 23. pii: 10189. [Epub ahead of print]25(18):

Distinct Genomic Expression Signatures after Low-Force Electrically Induced Exercises in Persons with Spinal Cord Injury.

Michael A Petrie, Manish Suneja, Richard K Shields.

  People with a spinal cord injury are at an increased risk of metabolic dysfunction due to skeletal muscle atrophy and the transition of paralyzed muscle to a glycolytic, insulin-resistant phenotype. Providing doses of exercise through electrical muscle stimulation may provide a therapeutic intervention to help restore metabolic function for people with a spinal cord injury, but high-frequency and high-force electrically induced muscle contractions increase fracture risk for the underlying osteoporotic skeletal system. Therefore, we investigated the acute molecular responses after a session of either a 3 Hz or 1 Hz electrically induced exercise program. Ten people with a complete spinal cord injury completed a 1 h (3 Hz) or 3 h (1 Hz) unilateral electrically induced exercise session prior to a skeletal muscle biopsy of the vastus lateralis. The number of pulses was held constant. Tissue samples were analyzed for genomic and epigenomic expression profiles. There was a strong acute response after the 3 Hz exercise leading to the upregulation of early response genes (NR4A3, PGC-1α, ABRA, IRS2, EGR1, ANKRD1, and MYC), which have prominent roles in regulating molecular pathways that control mitochondrial biogenesis, contractile protein synthesis, and metabolism. Additionally, these genes, and others, contributed to the enrichment of pathways associated with signal transduction, cellular response to stimuli, gene expression, and metabolism. While there were similar trends observed after the 1 Hz exercise, the magnitude of gene expression changes did not reach our significance thresholds, despite a constant number of stimuli delivered. There were also no robust acute changes in muscle methylation after either form of exercise. Taken together, this study supports that a dose of low-force electrically induced exercise for 1 h using a 3 Hz stimulation frequency is suitable to trigger an acute genomic response in people with chronic paralysis, consistent with an expression signature thought to improve the metabolic and contractile phenotype of paralyzed muscle, if performed on a regular basis.

Keywords:  gene expression; low force exercise; methylation expression; rehabilitation

DOI:  https://doi.org/10.3390/ijms251810189
Biology (Basel). 2024 Sep 12. pii: 719. [Epub ahead of print]13(9):

From Brain to Muscle: The Role of Muscle Tissue in Neurodegenerative Disorders.

Elisa Duranti, Chiara Villa.

  Neurodegenerative diseases (NDs), like amyotrophic lateral sclerosis (ALS), Alzheimer's disease (AD), and Parkinson's disease (PD), primarily affect the central nervous system, leading to progressive neuronal loss and motor and cognitive dysfunction. However, recent studies have revealed that muscle tissue also plays a significant role in these diseases. ALS is characterized by severe muscle wasting as a result of motor neuron degeneration, as well as alterations in gene expression, protein aggregation, and oxidative stress. Muscle atrophy and mitochondrial dysfunction are also observed in AD, which may exacerbate cognitive decline due to systemic metabolic dysregulation. PD patients exhibit muscle fiber atrophy, altered muscle composition, and α-synuclein aggregation within muscle cells, contributing to motor symptoms and disease progression. Systemic inflammation and impaired protein degradation pathways are common among these disorders, highlighting muscle tissue as a key player in disease progression. Understanding these muscle-related changes offers potential therapeutic avenues, such as targeting mitochondrial function, reducing inflammation, and promoting muscle regeneration with exercise and pharmacological interventions. This review emphasizes the importance of considering an integrative approach to neurodegenerative disease research, considering both central and peripheral pathological mechanisms, in order to develop more effective treatments and improve patient outcomes.

Keywords:  muscle; neurodegenerative diseases; therapy

DOI:  https://doi.org/10.3390/biology13090719
Biology (Basel). 2024 Sep 06. pii: 701. [Epub ahead of print]13(9):

Exploring the Impact of Exercise-Derived Extracellular Vesicles in Cancer Biology.

Monica Silvestri, Elisa Grazioli, Guglielmo Duranti, Paolo Sgrò, Ivan Dimauro.

  Cancer remains a major challenge in medicine, prompting exploration of innovative therapies. Recent studies suggest that exercise-derived extracellular vesicles (EVs) may offer potential anti-cancer benefits. These small, membrane-bound particles, including exosomes, carry bioactive molecules such as proteins and RNA that mediate intercellular communication. Exercise has been shown to increase EV secretion, influencing physiological processes like tissue repair, inflammation, and metabolism. Notably, preclinical studies have demonstrated that exercise-derived EVs can inhibit tumor growth, reduce metastasis, and enhance treatment response. For instance, in a study using animal models, exercise-derived EVs were shown to suppress tumor proliferation in breast and colon cancers. Another study reported that these EVs reduced metastatic potential by decreasing the migration and invasion of cancer cells. Additionally, exercise-induced EVs have been found to enhance the effectiveness of chemotherapy by sensitizing tumor cells to treatment. This review highlights the emerging role of exercise-derived circulating biomolecules, particularly EVs, in cancer biology. It discusses the mechanisms through which EVs impact cancer progression, the challenges in translating preclinical findings to clinical practice, and future research directions. Although research in this area is still limited, current findings suggest that EVs could play a crucial role in spreading molecules that promote better health in cancer patients. Understanding these EV profiles could lead to future therapies, such as exercise mimetics or targeted drugs, to treat cancer.

Keywords:  biological mechanisms; cancer; extracellular vesicles; physical activity; tumor growth

DOI:  https://doi.org/10.3390/biology13090701
Curr Opin Clin Nutr Metab Care. 2024 Nov 01. 27(6): 523-526

Muscle loss: does one size fit all? A comment on Bozzetti's paper.

Maria Cristina Gonzalez, Alfonso J Cruz-Jentoft, Stuart M Phillips, Carla M Prado.

DOI: https://doi.org/10.1097/MCO.0000000000001072
Exp Gerontol. 2024 Oct 03. pii: S0531-5565(24)00246-8. [Epub ahead of print]197 112600

MicroRNAs as commonly expressed biomarkers for sarcopenia and frailty: A systematic review.

Hyung Eun Shin, Jae Young Jang, Heeeun Jung, Chang Won Won, Miji Kim.

   BACKGROUND: Coexistent sarcopenia and frailty is more strongly associated with adverse health outcomes than each condition alone. As the importance of coexistent sarcopenia and frailty increases, exploring their underlying mechanisms is warranted. Recently, noncoding ribonucleic acids (RNAs) have been suggested as potential biomarkers of sarcopenia and frailty. This systematic review aimed to summarize noncoding RNAs commonly expressed in sarcopenia and frailty, and to search the predicted target genes and biological pathways of them.
METHODS: We systematically searched the literatures on PubMed, Embase, Cochrane Library, Web of Science, and Scopus for literature published till November 15, 2023. A total of 7,202 literatures were initially retrieved. After de-duplication, 34 studies (26 sarcopenia-related and 8 frailty-related) were full-text reviewed, and 15 studies (11 sarcopenia-related and 4 frailty-related) were finally included.
RESULTS: miR-29a-3p, miR-29b-3p, and miR-328 were identified as commonly expressed in same direction in sarcopenia and frailty. These microRNAs (miRNAs), identified in the literature search using PubMed, modulate transforming growth factor-β signaling via extracellular matrix components and calcineurin/nuclear factor of activated T cells 3 signaling via sarcoplasmic/endoplasmic reticulum Ca2+ ATPase 2a, which are involved in regulating skeletal muscle fibrosis and the growth of slow-twitch muscle fibers, respectively. miR-155-5p, miR-486, and miR-23a-3p were also commonly expressed in two conditions, although in different or conflicting directions.
CONCLUSION: In this systematic review, we highlight the potential of shared miRNAs that exhibit consistent expression patterns as biomarkers for the early diagnosis and progression assessment of both sarcopenia and frailty.

Keywords:  Biomarker; Frailty; Noncoding RNA; Sarcopenia; miRNA

DOI:  https://doi.org/10.1016/j.exger.2024.112600
Int J Environ Res Public Health. 2024 Sep 20. pii: 1246. [Epub ahead of print]21(9):

Association of Gut Microbiome with Muscle Mass, Muscle Strength, and Muscle Performance in Older Adults: A Systematic Review.

Martin Hubert Mayer, Selam Woldemariam, Christoph Gisinger, Thomas Ernst Dorner.

  Sarcopenia, characterized by reduced muscle mass, strength, or performance, is a common condition in older adults. The association between the gut microbiome and sarcopenia remains poorly understood. This systematic review aims to evaluate the relationship between muscle parameters and the intestinal microbiome. A systematic search was conducted in PubMed, EMBASE, Cochrane Library, and Google Scholar for studies published between 2002 and 2022 involving participants aged 50+. Studies were included if they assessed sarcopenia using at least one measure of muscle mass (skeletal muscle mass, bioelectrical impedance analysis, MRI), muscle strength, or muscle performance (SARC-F questionnaire, Timed-Up-and-Go Test, Chair Stand Test, grip strength, gait speed, Short Physical Performance Battery, 400 m Walk Test). The microbiome was measured using at least RNA/DNA sequencing or shotgun metagenomic sequencing. Twelve studies were analyzed. Findings revealed that a higher abundance of bacterial species such as Desulfovibrio piger, and Clostridium symbiosum and reduced diversity of butyrate-producing bacteria was associated with sarcopenia severity, as indicated by decreased grip strength, muscle mass, or physical performance. The gut microbiome plays a significant role in age-related muscle loss. Probiotics, prebiotics, and bacterial products could be potential interventions to improve muscle health in older adults.

Keywords:  microbiota alterations; muscle mass; muscle performance; muscle strength; sarcopenia

DOI:  https://doi.org/10.3390/ijerph21091246