bims-moremu 2025-01-26 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–01–26
33 papers selected by
Anna Vainshtein, Craft Science Inc.

Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis.
Role of cardiolipin in skeletal muscle function and its therapeutic implications.
mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.
Brain-derived neurotrophic factor drives muscle adaptation similar to aerobic training in mice.
Hypotonic Swelling Method for the Isolation of Pure Mitochondria From Primary Human Skeletal Myoblasts for Proteomic Studies.
Differential transcriptomic profiling of lipid metabolism and collagen remodeling in fast- and slow-twitch skeletal muscles in aging.
Loss or inhibition of lysosomal acid lipase in vitro leads to cholesteryl ester accumulation without affecting muscle formation or mitochondrial function.
Muscular TOR knockdown and endurance exercise ameliorate high salt and age-related skeletal muscle degradation by activating the MTOR-mediated pathway.
The role of MEGF10 in myoblast fusion and hypertrophic response to overload of skeletal muscle.
Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels.
The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.
Intracellular Membrane Contact Sites in Skeletal Muscle Cells.
Nitric oxide in exercise physiology: past and present perspectives.
Extrusion-Based Printing of Myoblast-Loaded Fibrin Microthreads to Induce Myogenesis.
Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in female rats: which one to blame?
Muscle-derived extracellular vesicles mediate crosstalk between skeletal muscle and other organs.
Skeletal muscle disorders as risk factors for type 2 diabetes.
Calponin 3 Regulates Myoblast Proliferation and Differentiation Through Actin Cytoskeleton Remodeling and YAP1-Mediated Signaling in Myoblasts.
Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin-/-/Utrophin-/- Double-Knockout Mice.
The complexity of Nrf2 in experimental autoimmune myositis-induced mice.
Structural changes in troponin during activation of skeletal and heart muscle determined in situ by polarised fluorescence.
Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner.
The Hormetic Potential of GDF15 in Skeletal Muscle Health and Regeneration: A Comprehensive Systematic Review.
Combined effects of natural products and exercise on apoptosis pathways in obesity-related skeletal muscle dysfunction.
Sustained efficacy of CRISPR-Cas13b gene therapy for FSHD is challenged by immune response to Cas13b.
High-intensity interval training alleviates exhaustive exercise-induced HSP70-assisted selective autophagy in skeletal muscle.
BCL6 coordinates muscle mass homeostasis with nutritional states.
Effect of human myoblasts on tenogenic progression in 2D and 3D culture models.
The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1.
Exosomes and microRNAs as mediators of the exercise.
Muscle fiber types switched during the development of experimental autoimmune myasthenia gravis via the PI3K/Akt signaling pathway.
The surprising link between muscle and the reproductive system.
From Clinical to Benchside: Lacticaseibacillus and Faecalibacterium Are Positively Associated With Muscle Health and Alleviate Age-Related Muscle Disorder.

Metabolites. 2025 Jan 16. pii: 59. [Epub ahead of print]15(1):

Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis.

Jiayin Wang, Dandan Jia, Zhiwang Zhang, Dan Wang.

  Background/Objectives: Sarcopenia, characterized by the progressive loss of muscle mass and strength, is linked to physical disability, metabolic dysfunction, and an increased risk of mortality. Exercise therapy is currently acknowledged as a viable approach for addressing sarcopenia. Nevertheless, the molecular mechanisms behind exercise training or physical activity remain poorly understood. The disruption of mitochondrial homeostasis is implicated in the pathogenesis of sarcopenia. Exercise training effectively delays the onset of sarcopenia by significantly maintaining mitochondrial homeostasis, including promoting mitophagy, improving mitochondrial biogenesis, balancing mitochondrial dynamics, and maintaining mitochondrial redox. Exerkines (e.g., adipokines, myokines, hepatokines, and osteokines), signaling molecules released in response to exercise training, may potentially contribute to skeletal muscle metabolism through ameliorating mitochondrial homeostasis, reducing inflammation, and regulating protein synthesis as a defense against sarcopenia. Methods: In this review, we provide a detailed summary of exercise-induced exerkines and confer their benefit, with particular focus on their impact on mitochondrial homeostasis in the context of sarcopenia. Results: Exercise induces substantial adaptations in skeletal muscle, including increased muscle mass, improved muscle regeneration and hypertrophy, elevated hormone release, and enhanced mitochondrial function. An expanding body of research highlights that exerkines have the potential to regulate processes such as mitophagy, mitochondrial biogenesis, dynamics, autophagy, and redox balance. These mechanisms contribute to the maintenance of mitochondrial homeostasis, thereby supporting skeletal muscle metabolism and mitochondrial health. Conclusions: Through a comprehensive investigation of the molecular mechanisms within mitochondria, the context reveals new insights into the potential of exerkines as key exercise-protective sensors for combating sarcopenia.

Keywords:  exercise; exerkines; mitochondrial homeostasis; sarcopenia

DOI:  https://doi.org/10.3390/metabo15010059
Cell Commun Signal. 2025 Jan 21. 23(1): 36

Role of cardiolipin in skeletal muscle function and its therapeutic implications.

Youngbum Yoo, MyeongHoon Yeon, Mee-Sup Yoon, Young-Kyo Seo.

  Cardiolipin, a unique phospholipid predominantly present in the inner mitochondrial membrane, is critical for maintaining mitochondrial integrity and function. Its dimeric structure and role in supporting mitochondrial dynamics, energy production, and mitophagy make it indispensable for skeletal muscle health. This review provides a comprehensive overview of cardiolipin biosynthesis, remodeling processes, and essential functions within mitochondria. We explore the influences of cardiolipin on the stability of the mitochondrial complexes, cristae formation, and calcium handling, all of which are vital for efficient oxidative phosphorylation and muscle contraction. Skeletal muscle, with its high energy demands, is particularly dependent on cardiolipin for optimal performance. We discuss the impact of aging on cardiolipin levels, which correlates with a decline in mitochondrial function and muscle mass, contributing to conditions such as sarcopenia. Furthermore, we examined the relationship between cardiolipin and endurance exercise, highlighting the effects of exercise-induced increase in cardiolipin levels on the improvement of mitochondrial function and muscle health. The role of Crls1 in cardiolipin synthesis has been emphasized as a potential therapeutic target for the treatment of sarcopenia. Increasing cardiolipin levels through gene therapy, pharmacological interventions, or specific exercise and nutritional strategies holds promise for mitigating muscle atrophy and promoting muscle regeneration. By focusing on the multifaceted role of cardiolipin in mitochondria and muscle health, we aimed to provide new insights into therapeutic approaches for enhancing muscle function and combating age-related muscle decline.

Keywords:   Crls1 ; Cardiolipin; Exercise; Mitochondrial function; Muscle atrophy; Oxidative phosphorylation; Sarcopenia; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-025-02032-2
FASEB J. 2025 Jan 31. 39(2): e70277

mTOR Ser1261 is an AMPK-dependent phosphosite in mouse and human skeletal muscle not required for mTORC2 activity.

Jingwen Li, Agnete B Madsen, Jonas R Knudsen, Carlos Henriquez-Olguin, Kaspar W Persson, Zhencheng Li, Steffen H Raun, Tianjiao Li, Bente Kiens, Jørgen F P Wojtaszewski, Erik A Richter, Leonardo Nogara, Bert Blaauw, Riki Ogasawara, Thomas E Jensen.

  The kinases AMPK, and mTOR as part of either mTORC1 or mTORC2, are major orchestrators of cellular growth and metabolism. Phosphorylation of mTOR Ser1261 is reportedly stimulated by both insulin and AMPK activation and a regulator of both mTORC1 and mTORC2 activity. Intrigued by the possibilities that Ser1261 might be a convergence point between insulin and AMPK signaling in skeletal muscle, we investigated the regulation and function of this site using a combination of human exercise, transgenic mouse, and cell culture models. Ser1261 phosphorylation on mTOR did not respond to insulin in any of our tested models, but instead responded acutely to contractile activity in human and mouse muscle in an AMPK activity-dependent manner. Contraction-stimulated mTOR Ser1261 phosphorylation in mice was decreased by Raptor muscle knockout (mKO) and increased by Raptor muscle overexpression, yet was not affected by Rictor mKO, suggesting most of Ser1261 phosphorylation occurs within mTORC1 in skeletal muscle. In accordance, HEK293 cells mTOR Ser1261Ala mutation strongly impaired phosphorylation of mTORC1 substrates but not mTORC2 substrates. However, neither mTORC1 nor mTORC2-dependent phosphorylations were affected in muscle-specific kinase-dead AMPK mice with no detectable mTOR Ser1261 phosphorylation in skeletal muscle. Thus, mTOR Ser1261 is an exercise but not insulin-responsive AMPK-dependent phosphosite in human and murine skeletal muscle, playing an unclear role in mTORC1 regulation but clearly not required for mTORC2 activity.

Keywords:  AMPK; exercise; mTORC1; mTORC2; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202402064R
FASEB J. 2025 Jan 31. 39(2): e70321

Brain-derived neurotrophic factor drives muscle adaptation similar to aerobic training in mice.

Alexander D Brown, Alexander D Marko, Daniel M Marko, Bradley J Baranowski, Sebastian Silvera, Michael S Finch, Alex J Yang, Roopan Dhaliwal, Chantal R Ryan, Brian D Roy, Val A Fajardo, Rebecca E K MacPherson.

  This study, in vivo and in vitro, investigated the role of brain-derived neurotrophic factor (BDNF) in skeletal muscle adaptations to aerobic exercise. BDNF is a contraction-induced protein that may play a role in muscle adaptations to aerobic exercise. BDNF is involved in muscle repair, increased fat oxidation, and mitochondrial biogenesis, all of which are adaptations observed with aerobic training. The purpose of this study was two-pronged and investigated the skeletal muscle BDNF response to (1) acute and (2) chronic exercise in male C57BL/6J mice. It also examined if chronic BDNF treatment resulted in similar adaptations to chronic exercise. In aim 1, mice underwent a 2 hr. treadmill exercise bout. In aim 2, mice were assigned to one of four groups: (1) control (CON); (2) endurance training (ET; treadmill running 1 h/day, 5 days/wk); (3) BDNF (BDNF; 0.5 mg/kg·bw, 5 days/wk); (4) endurance training and BDNF (ET + BDNF) for 8 weeks. Results demonstrated that the soleus (SOL) had higher BDNF content compared with the extensor digitorum longus (EDL) and that SOL BDNF increased with acute exercise. After chronic exercise and BDNF treatment, treadmill testing to exhaustion demonstrated a main effect of BDNF and ET on increasing exercise capacity. In vitro contractile assessment of the EDL revealed BDNF treatment resulted in similar increases in the max rate of relaxation as ET. EDL force-frequency analysis showed ET + BDNF produced higher force than CON and BDNF, indicating an additive effect. BDNF increased EDL mitochondrial proteins, COXIV, and CS. These results demonstrate that BDNF contributes to muscle adaptations observed with ET.

Keywords:  aerobic exercise; brain‐derived neurotrophic factor; contraction; mitochondria; skeletal muscle

DOI:  https://doi.org/10.1096/fj.202402421R
J Cell Mol Med. 2025 Jan;29(2): e70370

Hypotonic Swelling Method for the Isolation of Pure Mitochondria From Primary Human Skeletal Myoblasts for Proteomic Studies.

Evrim Aksu-Menges, Eray Taha Kumtepe, Gurler Akpinar, Burcu Balci-Hayta.

  Mitochondria play a fundamental role in energy metabolism, particularly in high-energy-demand tissues such as skeletal muscle. Understanding the proteomic composition of mitochondria in these cells is crucial for elucidating the mechanisms underlying muscle physiology and pathology. However, effective isolation of mitochondria from primary human skeletal muscle cells has been challenging due to the complex cellular architecture and the propensity for contamination with other organelles. Here, we compared four different methods to isolate mitochondria from primary human skeletal myoblasts regarding total protein yield, mitochondrial enrichment capacity and purity of the isolated fraction. We presented a modified method that combines differential centrifugation with a hypotonic swelling step and a subsequent purification process to minimise cellular contamination. We validated our method by demonstrating its ability to obtain highly pure mitochondrial fractions, as confirmed by Western Blot with mitochondrial, cytosolic and nuclear markers. We demonstrated that proteomic analysis can be performed with isolated mitochondria. Our approach provides a valuable tool for investigating mitochondrial dynamics, biogenesis and function in the context of skeletal muscle biology in health and disease. This methodological advancement opens new avenues for mitochondrial research and its implications in myopathies, sarcopenia, cachexia and metabolic disorders.

Keywords:  differential centrifugation; hypotonic swelling method; mitochondria isolation; primary human skeletal myoblasts

DOI:  https://doi.org/10.1111/jcmm.70370
FASEB J. 2025 Jan 31. 39(2): e70335

Differential transcriptomic profiling of lipid metabolism and collagen remodeling in fast- and slow-twitch skeletal muscles in aging.

Yujia Liu, Guofang Xia, Simeng Zhu, Yifan Shi, Xueping Huang, Jin Wu, Congfeng Xu, Ailian Du.

  Skeletal muscle function gradually declines with aging, presenting substantial health and societal challenges. Comparative analysis of how aging affects fast- and slow-twitch muscles remains lacking. We utilized 20-month-old mice to reveal the aging effects on muscle structure and fiber composition, followed by bulk RNA sequencing for fast- and slow-twitch muscles and integration with human single-cell RNA sequencing dataset providing a comparative analysis across species. In mouse slow-twitch muscles, aging induced a switch from fast to slow fibers and distinctively altered lipid metabolism in ceramide and triglyceride, with the upregulation of regulatory genes Gk and Ppargc1a also observed in human slow fibers. Additionally, both types of muscles exhibited common collagen deposition and fibrosis, possibly due to the imbalance between collagen synthesis and degradation. The extracellular matrix gene changes substantially overlapped between mice and humans in aging, yet also highlighted clear differences. This integrative analysis provides further understanding of aged fast- and slow-twitch muscles and offers new insights into the molecular changes in aging.

Keywords:  RNA‐seq; aging; fast‐twitch fiber; skeletal muscles; slow‐twitch fiber

DOI:  https://doi.org/10.1096/fj.202402294R
BBA Adv. 2025 ;7 100135

Loss or inhibition of lysosomal acid lipase in vitro leads to cholesteryl ester accumulation without affecting muscle formation or mitochondrial function.

Alena Akhmetshina, Laszlo Schooltink, Melina Amor, Katharina B Kuentzel, Silvia Rainer, Ananya Nandy, Hansjoerg Habisch, Tobias Madl, Elizabeth Rendina-Ruedy, Katharina Leithner, Nemanja Vujić, Dagmar Kratky.

  Skeletal muscle (SM) is essential for movement, stability, and overall body function, and it readily adapts to changes in energy demand. Myogenesis is energy-intensive and involves complex molecular and cellular events. We recently demonstrated that the absence of lysosomal acid lipase (LAL) in vivo significantly impacts the SM phenotype, primarily by disrupting energy homeostasis and reducing ATP production. As systemic LAL deficiency affects multiple organs, we hypothesized that the altered SM phenotype resulted from systemic rather than SM-specific loss of LAL activity. To distinguish between systemic and cell-intrinsic effects, we used primary myoblasts isolated from Lal-deficient (-/-) mice as well as C2C12 cells treated with the pharmacological inhibitor of LAL, Lalistat-2. We found a significant accumulation of cholesteryl esters in both models studied, highlighting the central role of LAL in lipid catabolism in the SM. However, lipid accumulation was absent under lipoprotein-deficient culture conditions. Neither genetic loss nor pharmacological inhibition of LAL affected myofiber formation or mitochondrial function in vitro, in contrast to what we observed in SM isolated from Lal-/- mice. Tracing [13C6]-labeled glucose in both cell culture models revealed only minor changes in tricarboxylic acid cycle metabolites. These results suggest that although LAL plays an essential role in lipid metabolism, its impact on the processes involved in muscle differentiation and cellular energy production is minor. We conclude that the cell-intrinsic effects of Lal-/- SM are unlikely to drive the SM phenotype observed in vivo.

Keywords:  C2C12 cells; Energy metabolism; LAL; LAL deficiency; Myogenesis; Primary myoblast; Skeletal muscle

DOI:  https://doi.org/10.1016/j.bbadva.2024.100135
PLoS One. 2025 ;20(1): e0311159

Muscular TOR knockdown and endurance exercise ameliorate high salt and age-related skeletal muscle degradation by activating the MTOR-mediated pathway.

Shi-Jie Wang, Deng-Tai Wen, Ying-Hui Gao, Jing-Feng Wang, Xing-Feng Ma.

The target of rapamycin(TOR)gene is closely related to metabolism and cellular aging, but it is unclear whether the TOR pathways mediate endurance exercise against the accelerated aging of skeletal muscle induced by high salt intake. In this study, muscular TOR gene overexpression and RNAi were constructed by constructing MhcGAL4/TOR-overexpression and MhcGAL4/TORUAS-RNAi systems in Drosophila. The results showed that muscle TOR knockdown and endurance exercise significantly increased the climbing speed, climbing endurance, the expression of autophagy related gene 2(ATG2), silent information regulator 2(SIR2), and pparγ coactivator 1(PGC-1α) genes, and superoxide dismutases(SOD) activity, but it decreased the expression of the TOR gene and reactive oxygen species(ROS) level, and it protected the myofibrillar fibers and mitochondria of skeletal muscle in Drosophila on a high-salt diet. TOR overexpression yielded similar results to the high salt diet(HSD) alone, with the opposite effect of TOR knockout found in regard to endurance exercise and HSD-induced age-related skeletal muscle degradation. Therefore, the current findings confirm that the muscle TOR gene plays an important role in endurance exercise against HSD-induced age-related skeletal muscle degeneration, as it determines the activity of the mammalian target of rapamycin(MTOR)/SIR2/PGC-1α and MTOR/ATG2/PGC-1α pathways in skeletal muscle.

DOI: https://doi.org/10.1371/journal.pone.0311159
J Muscle Res Cell Motil. 2025 Jan 18.

The role of MEGF10 in myoblast fusion and hypertrophic response to overload of skeletal muscle.

Louise Richardson, Ruth Hughes, Colin A Johnson, Stuart Egginton, Michelle Peckham.

  Biallelic mutations in multiple EGF domain protein 10 (MEGF10) gene cause EMARDD (early myopathy, areflexia, respiratory distress and dysphagia) in humans, a severe recessive myopathy, associated with reduced numbers of PAX7 positive satellite cells. To better understand the role of MEGF10 in satellite cells, we overexpressed human MEGF10 in mouse H-2kb-tsA58 myoblasts and found that it inhibited fusion. Addition of purified extracellular domains of human MEGF10, with (ECD) or without (EGF) the N-terminal EMI domain to H-2kb-tsA58 myoblasts, showed that the ECD was more effective at reducing myoblast adhesion and fusion by day 7 of differentiation, yet promoted adhesion of myoblasts to non-adhesive surfaces, highlighting the importance of the EMI domain in these behaviours. We additionally tested the role of Megf10 in vivo using transgenic mice with reduced (Megf10+/-) or no (Megf10-/-) Megf10. We found that the extensor digitorum longus muscle had fewer anti-Pax7 stained cell nuclei and was less able to undergo hypertrophy in response to muscle overload concomitant with a lower level of satellite cell activation. Taken together, our data suggest that MEGF10 may promote satellite cell adhesion and survival and prevent premature fusion helping to explain its role in EMARDD.

Keywords:  MEGF10; Myogenesis; Overload model; Satellite cells; Skeletal muscle

DOI:  https://doi.org/10.1007/s10974-024-09686-4
Cell Mol Life Sci. 2025 Jan 18. 82(1): 43

Palmitate potentiates the SMAD3-PAI-1 pathway by reducing nuclear GDF15 levels.

Marta Montori-Grau, Emma Barroso, Javier Jurado-Aguilar, Mona Peyman, Walter Wahli, Xavier Palomer, Manuel Vázquez-Carrera.

  Nuclear growth differentiation factor 15 (GDF15) reduces the binding of the mothers' against decapentaplegic homolog (SMAD) complex to its DNA-binding elements. However, the stimuli that control this process are unknown. Here, we examined whether saturated fatty acids (FA), particularly palmitate, regulate nuclear GDF15 levels and the activation of the SMAD3 pathway in human skeletal myotubes and mouse skeletal muscle, where most insulin-stimulated glucose use occurs in the whole organism. Human LHCN-M2 myotubes and skeletal muscle from wild-type and Gdf15-/- mice fed a standard (STD) or a high-fat (HFD) diet were subjected to a series of studies to investigate the involvement of lipids in nuclear GDF15 levels and the activation of the SMAD3 pathway. The saturated FA palmitate, but not the monounsaturated FA oleate, increased the expression of GDF15 in human myotubes and, unexpectedly, decreased its nuclear levels. This reduction was prevented by the nuclear export inhibitor leptomycin B. The decrease in nuclear GDF15 levels caused by palmitate was accompanied by increases in SMAD3 protein levels and in the expression of its target gene SERPINE1, which encodes plasminogen activator inhibitor 1 (PAI-1). HFD-fed Gdf15-/- mice displayed aggravated glucose intolerance compared to HFD-fed WT mice, with increased levels of SMAD3 and PAI-1 in the skeletal muscle. The increased PAI-1 levels in the skeletal muscle of HFD-fed Gdf15-/- mice were accompanied by a reduction in one of its targets, hepatocyte growth factor (HGF)α, a cytokine involved in glucose metabolism. Interestingly, PAI-1 acts as a ligand of signal transducer and activator of transcription 3 (STAT3) and the phosphorylation of this transcription factor was exacerbated in HFD-fed Gdf15-/- mice compared to HFD-fed WT mice. At the same time, the protein levels of insulin receptor substrate 1 (IRS-1) were reduced. These findings uncover a potential novel mechanism through which palmitate induces the SMAD3-PAI-1 pathway to promote insulin resistance in skeletal muscle by reducing nuclear GDF15 levels.

Keywords:  GDF15; Insulin resistance; Muscle; Oleate; PAI-1; Palmitate; SMAD3

DOI:  https://doi.org/10.1007/s00018-024-05571-y
J Physiol Sci. 2024 ;pii: S1880-6546(24)00096-9. [Epub ahead of print]74(1): 8

The role of GPR81-cAMP-PKA pathway in endurance training-induced intramuscular triglyceride accumulation and mitochondrial content changes in rats.

Lin Li, Xiangdeng Lai, Yihan Ni, Siyu Chen, Yaqian Qu, Zhiqiang Hu, Jingquan Sun.

  The athlete's paradox phenomenon involves the accumulation of intramuscular triglycerides (IMTG) in both insulin-resistant and insulin-sensitive endurance athletes. Nevertheless, a complete understanding of this phenomenon is yet to be achieved. Recent research indicates that lactate, a common byproduct of physical activity, may increase the accumulation of IMTG in skeletal muscle. This is achieved through the activation of G protein-coupled receptor 81 (GPR81) leads to the suppression of the cyclic adenosine monophosphate-protein kinase A (cAMP-PKA) pathway. The mechanism accountable for the increase in mitochondrial content in skeletal muscle triggered by lactate remains incomprehensible. Based on current research, our objective is to explore the role of the GPR81-inhibited cAMP-PKA pathway in the aggregation of IMTG and the increase in mitochondrial content as a result of prolonged exercise. The GPR81-cAMP-PKA-signaling pathway regulates the buildup of IMTG caused by extended periods of endurance training (ET). This is likely due to a decrease in proteins related to fat breakdown and an increase in proteins responsible for fat production. It is possible that the GPR81-cAMP-PKA pathway does not contribute to the long-term increase in mitochondrial biogenesis and content, which is induced by chronic ET. Additional investigation is required to explore the possible hindrance of the mitochondrial biogenesis and content process during physical activity by the GPR81-cAMP-PKA signal.

Keywords:  Endurance training; Intramuscular triglyceride; Lactate; Mitochondrial content; Skeletal muscle; cAMP

DOI:  https://doi.org/10.1186/s12576-024-00902-x
Membranes (Basel). 2025 Jan 14. pii: 29. [Epub ahead of print]15(1):

Intracellular Membrane Contact Sites in Skeletal Muscle Cells.

Matteo Serano, Stefano Perni, Enrico Pierantozzi, Annunziatina Laurino, Vincenzo Sorrentino, Daniela Rossi.

  Intracellular organelles are common to eukaryotic cells and provide physical support for the assembly of specialized compartments. In skeletal muscle fibers, the largest intracellular organelle is the sarcoplasmic reticulum, a specialized form of the endoplasmic reticulum primarily devoted to Ca2+ storage and release for muscle contraction. Occupying about 10% of the total cell volume, the sarcoplasmic reticulum forms multiple membrane contact sites, some of which are unique to skeletal muscle. These contact sites primarily involve the plasma membrane; among these, specialized membrane contact sites between the transverse tubules and the terminal cisternae of the sarcoplasmic reticulum form triads. Triads are skeletal muscle-specific contact sites where Ca2+ channels and regulatory proteins assemble to form the so-called calcium release complex. Additionally, the sarcoplasmic reticulum contacts mitochondria to enable a more precise regulation of Ca2+ homeostasis and energy metabolism. The sarcoplasmic reticulum and the plasma membrane also undergo dynamic remodeling to allow Ca2+ entry from the extracellular space and replenish the stores. This process involves the formation of dynamic membrane contact sites called Ca2+ Entry Units. This review explores the key processes in biogenesis and assembly of intracellular membrane contact sites as well as the membrane remodeling that occurs in response to muscle fatigue.

Keywords:  calcium signaling; endoplasmic reticulum; muscle contraction; sarcoplasmic reticulum

DOI:  https://doi.org/10.3390/membranes15010029
Front Physiol. 2024 ;15 1504978

Nitric oxide in exercise physiology: past and present perspectives.

Breanna J Mueller, Michael D Roberts, Christopher B Mobley, Robert L Judd, Andreas N Kavazis.

  Nitric oxide (NO) is a ubiquitous signaling molecule known to modulate various physiological processes, with specific implications in skeletal muscle and broader applications in exercise performance. This review focuses on the modulation of skeletal muscle function, mitochondrial adaptation and function, redox state by NO, and the effect of nitrate supplementation on exercise performance. In skeletal muscle function, NO is believed to increase the maximal shortening velocity and peak power output of muscle fibers. However, its effect on submaximal contraction is still undetermined. In mitochondria, NO may stimulate biogenesis and affect respiratory efficiency. NO also plays a role in the redox state within the skeletal muscle, partially through its interaction with respiratory chain enzymes and transcriptional regulators of antioxidant production. Nitrate supplementation leads to an increased bioavailability of NO in skeletal muscle. Thus, nitrate supplementation has been investigated for its ability to impact performance outcomes in endurance and resistance exercise. The effect of nitrate supplementation on endurance exercise is currently indecisive, although evidence indicates that it may extend the time to exhaustion in endurance exercise. Alternatively, the effect of nitrate supplementation on resistance exercise performance has been less studied. Limited research indicates that nitrate supplementation may improve repetitions to failure. Further research is needed to investigate the influence of training status, age, sex, and duration of supplementation to further elucidate the impact of nitrate supplementation on exercise performance.

Keywords:  exercise performance; mitochondria; nitrate supplementation; nitric oxide; redox state; skeletal muscle; vasodilation

DOI:  https://doi.org/10.3389/fphys.2024.1504978
J Funct Biomater. 2025 Jan 10. pii: 21. [Epub ahead of print]16(1):

Extrusion-Based Printing of Myoblast-Loaded Fibrin Microthreads to Induce Myogenesis.

Hanson S Lee, Bryanna L Samolyk, George D Pins.

  Large skeletal muscle injuries such as volumetric muscle loss (VML) disrupt native tissue structures, including biophysical and biochemical signaling cues that promote the regeneration of functional skeletal muscle. Various biofabrication strategies have been developed to create engineered skeletal muscle constructs that mimic native matrix and cellular microenvironments to enhance muscle regeneration; however, there remains a need to create scalable engineered tissues that provide mechanical stability as well as structural and spatiotemporal signaling cues to promote cell-mediated regeneration of contractile skeletal muscle. We describe a novel strategy for bioprinting multifunctional myoblast-loaded fibrin microthreads (myothreads) that recapitulate the cellular microniches to drive myogenesis and aligned myotube formation. We characterized myoblast alignment, myotube formation, and tensile properties of myothreads as a function of cell-loading density and culture time. We showed that increasing myoblast loading densities enhances myotube formation. Additionally, alignment analyses indicate that the bioprinting process confers myoblast alignment in the constructs. Finally, tensile characterizations suggest that myothreads possess the structural stability to serve as a potential platform for developing scalable muscle scaffolds. We anticipate that our myothread biofabrication approach will enable us to strategically investigate biophysical and biochemical signaling cues and cellular mechanisms that enhance functional skeletal muscle regeneration for the treatment of VML.

Keywords:  biomaterials; bioprinting; cell alignment; fibrin microthreads; myotube formation; skeletal muscle; tensile properties; tissue engineering; volumetric muscle loss

DOI:  https://doi.org/10.3390/jfb16010021
Biogerontology. 2025 Jan 24. 26(1): 47

Age, cancer, and the dual burden of cancer and doxorubicin in skeletal muscle wasting in female rats: which one to blame?

Alexandra Moreira-Pais, Rita Ferreira, Inês Aires, Cláudia Sousa-Mendes, Rita Nogueira-Ferreira, Fernanda Seixas, Adelino Leite-Moreira, Paula A Oliveira, José A Duarte.

  Sarcopenia and cancer cachexia are two life-threatening conditions often misdiagnosed. The skeletal muscle is one of the organs most adversely affected by these conditions, culminating in poor quality of life and premature mortality. In addition, it has been suggested that chemotherapeutic agents exacerbate cancer cachexia, as is the case of doxorubicin. Herein, we sought to investigate markers of inflammation and neuromuscular junction (NMJ) remodeling during aging and in response to cancer or cancer with chemotherapy. To address this, we utilized female rats across three age groups - young, adult, and old - to examine age-related changes, with old rats serving as a sarcopenia model. Additionally, a chemically-induced breast cancer (BCa) model was implemented in female adult rats, both without (adult BCa) or with doxorubicin administration (adult BCaDOX), to study cancer cachexia. The atrophy of the gastrocnemius muscle was observed in old, adult BCa and adult BCaDOX rats compared to adult ones. No signs of inflammation or NMJ impairment were observed in adult BCa or adult BCaDOX rats, except for the low levels of the subunit α1 of the acetylcholine receptor in adult BCaDOX rats compared to adult ones. In contrast, old rats presented high serum levels of interleukin 6, brain-derived neurotrophic factor (BDNF) and calcitonin gene-related peptide compared to young rats. In the gastrocnemius muscle, BDNF levels were decreased in old rats compared to adult rats, suggesting impaired skeletal muscle regeneration upon age-induced damage. The BDNF muscle levels were inversely correlated with its levels in circulation in adult and old rats. Hence, this work highlights BDNF as a specific biomarker of age-induced skeletal muscle atrophy, at least, in the differential diagnosis against cancer- or cancer with chemotherapy-induced muscle wasting.

Keywords:  Cachexia; Chemotherapy; Inflammation; Muscle atrophy; Neuromuscular junction; Sarcopenia

DOI:  https://doi.org/10.1007/s10522-024-10182-y
Front Physiol. 2024 ;15 1501957

Muscle-derived extracellular vesicles mediate crosstalk between skeletal muscle and other organs.

Jiajie Jia, Lu Wang, Yue Zhou, Peng Zhang, Xiaoping Chen.

  Skeletal muscle (SKM) has crucial roles in locomotor activity and posture within the body and also functions have been recognized as an actively secretory organ. Numerous bioactive molecules are secreted by SKM and transported by extracellular vesicles (EVs), a novel class of mediators of communication between cells and organs that contain various types of cargo molecules including lipids, proteins and nucleic acids. SKM-derived EVs (SKM-EVs) are intercellular communicators with significant roles in the crosstalk between SKM and other organs. In this review, we briefly describe the biological characteristics, composition, and uptake mechanisms of EVs, particularly exosomes, comprehensively summarize the regulatory effects of SKM-EVs on the function of, which include myogenesis, muscle repair and regeneration, as well as metabolic regulation. Furthermore, we explore the impact of SKM- EVs on various organs including bone, the cardiovascular system, adipose tissue, and nervous system. As emerging evidence suggests that SKM-EVs are involved in the development and regulation of type 2 diabetes (T2D), systemic inflammation, and other chronic diseases, we also highlight the potential of SKM-EVs as therapeutic targets and diagnostic biomarkers, emphasizing the need for further research to elucidate the complex mechanisms underlying intercellular communication in physiological and pathological contexts.

Keywords:  cargo; crosstalk; extracellular vesicles; microRNAs; skeletal muscle

DOI:  https://doi.org/10.3389/fphys.2024.1501957
Mol Cell Endocrinol. 2025 Jan 21. pii: S0303-7207(25)00017-6. [Epub ahead of print] 112466

Skeletal muscle disorders as risk factors for type 2 diabetes.

Eshwar R Tammineni, Carlo Manno, Goldie Oza, Lourdes Figueroa.

  The incidence and prevalence of muscular disorders and of type 2 diabetes (T2D) is increasing and both represent highly significant healthcare problems, both economically and compromising quality of life. Interestingly, skeletal muscle dysfunction and T2D share some commonalities including dysregulated glucose homeostasis, increased oxidative stress, dyslipidemia, and cytokine alterations. Several lines of evidence have hinted to a relationship between skeletal muscle dysfunction and T2D. For instance, T2D affects skeletal muscle morphology, functionality, and overall health through altered protein metabolism, impaired mitochondrial function, and ultimately cell viability. Conversely, humans suffering from myopathies and their experimental models demonstrated increased incidence of T2D through altered muscle glucose disposal function due to abnormal calcium homeostasis, compromised mitochondrial function, dyslipidemia, increased inflammatory cytokines and fiber size alterations and disproportions. Lifestyle modifications are essential for improving and maintaining mobility and metabolic health in individuals suffering from myopathies along with T2D. In this review, we updated current literature evidence on clinical incidence of T2D in inflammatory, mitochondrial, metabolic myopathies, and muscular dystrophies and further discussed the molecular basis of these skeletal muscle disorders leading to T2D.

Keywords:  Calcium dysregulation; Insulin Resistance; Myopathies; Oxidative stress; Skeletal muscle; Type 2 Diabetes

DOI:  https://doi.org/10.1016/j.mce.2025.112466
Cells. 2025 Jan 18. pii: 142. [Epub ahead of print]14(2):

Calponin 3 Regulates Myoblast Proliferation and Differentiation Through Actin Cytoskeleton Remodeling and YAP1-Mediated Signaling in Myoblasts.

Mai Thi Nguyen, Quoc Kiet Ly, Thanh Huu Phan Ngo, Wan Lee.

  An actin-binding protein, known as Calponin 3 (CNN3), modulates the remodeling of the actin cytoskeleton, a fundamental process for the maintenance of skeletal muscle homeostasis. Although the roles of CNN3 in actin remodeling have been established, its biological significance in myoblast differentiation remains largely unknown. This study investigated the functional significance of CNN3 in myogenic differentiation, along with its effects on actin remodeling and mechanosensitive signaling in C2C12 myoblasts. CNN3 knockdown led to a marked increase in filamentous actin, which promoted the nuclear localization of Yes-associated protein 1 (YAP1), a mechanosensitive transcriptional coactivator required for response to the mechanical cues that drive cell proliferation. Subsequently, CNN3 depletion enhanced myoblast proliferation by upregulating the expression of the YAP1 target genes related to cell cycle progression, such as cyclin B1, cyclin D1, and PCNA. According to a flow cytometry analysis, CNN3-deficient cells displayed higher S and G2/M phase fractions, which concurred with elevated proliferation rates. Furthermore, CNN3 knockdown impaired myogenic differentiation, as evidenced by reduced levels of MyoD, MyoG, and MyHC, key markers of myogenic commitment and maturation, and immunocytochemistry showed that myotube formation was diminished in CNN3-suppressed cells, which was supported by lower differentiation and fusion indices. These findings reveal that CNN3 is essential for myogenic differentiation, playing a key role in regulating actin remodeling and cellular localization of YAP1 to orchestrate the proliferation and differentiation in myogenic progenitor cells. This study highlights CNN3 as a critical regulator of skeletal myogenesis and suggests its therapeutic potential as a target for muscle atrophy and related disorders.

Keywords:  YAP1; actin cytoskeleton remodeling; calponin; mechanotransduction; myogenic differentiation; proliferation

DOI:  https://doi.org/10.3390/cells14020142
Cells. 2025 Jan 14. pii: 116. [Epub ahead of print]14(2):

Targeting EP2 Receptor Improves Muscle and Bone Health in Dystrophin-/-/Utrophin-/- Double-Knockout Mice.

Xueqin Gao, Yan Cui, Greg Zhang, Joseph J Ruzbarsky, Bing Wang, Jonathan E Layne, Xiang Xiao, Johnny Huard.

  Duchenne muscular dystrophy (DMD) is a severe genetic muscle disease occurring due to mutations of the dystrophin gene. There is no cure for DMD. Using a dystrophin-/-utrophin-/- (DKO-Hom) mouse model, we investigated the PGE2/EP2 pathway in the pathogenesis of dystrophic muscle and its potential as a therapeutic target. We found that Ep2, Ep4, Cox-2, 15-Pgdh mRNA, and PGE2 were significantly increased in DKO-Hom mice compared to wild-type (WT) mice. The EP2 and EP4 receptors were mainly expressed in CD68+ macrophages and were significantly increased in the muscle tissues of both dystrophin-/- (mdx) and DKO-Hom mice compared to WT mice. Osteogenic and osteoclastogenic gene expression in skeletal muscle also increased in DKO-Hom mice, which correlates with severe muscle heterotopic ossification (HO). Treatment of DKO-Hom mice with the EP2 antagonist PF04418948 for 2 weeks increased body weight and reduced HO and muscle pathology by decreasing both total macrophages (CD68+) and senescent macrophages (CD68+P21+), while increasing endothelial cells (CD31+). PF04418948 also increased bone volume/total volume (BV/TV), the trabecular thickness (Tb.Th) of the tibia trabecular bone, and the cortical bone thickness of both the femur and tibia without affecting spine trabecular bone microarchitecture. In summary, our results indicate that targeting EP2 improves muscle pathology and improves bone mass in DKO mice.

Keywords:  EP2; EP4; PF04418948; PGE2; bone microarchitecture; heterotopic ossification; muscular dystrophy

DOI:  https://doi.org/10.3390/cells14020116
J Physiol. 2025 Jan 24.

The complexity of Nrf2 in experimental autoimmune myositis-induced mice.

Kayani Shanmuganathan.



Keywords:  CD8+ T‐lymphocytes; Nrf2; experimental autoimmune myositis; idiopathic inflammatory myopathies; inflammation; skeletal muscle; weakness

DOI:  https://doi.org/10.1113/JP287977
Biophys Rev. 2024 Dec;16(6): 753-772

Structural changes in troponin during activation of skeletal and heart muscle determined in situ by polarised fluorescence.

Ivanka R Sevrieva, Thomas Kampourakis, Malcolm Irving.

  Calcium binding to troponin triggers the contraction of skeletal and heart muscle through structural changes in the thin filaments that allow myosin motors from the thick filaments to bind to actin and drive filament sliding. Here, we review studies in which those changes were determined in demembranated fibres of skeletal and heart muscle using fluorescence for in situ structure (FISS), which determines domain orientations using polarised fluorescence from bifunctional rhodamine attached to cysteine pairs in the target domain. We describe the changes in the orientations of the N-terminal lobe of troponin C (TnCN) and the troponin IT arm in skeletal and cardiac muscle cells associated with contraction and compare the orientations with those determined in isolated cardiac thin filaments by cryo-electron microscopy. We show that the orientations of the IT arm determined by the two approaches are essentially the same and that this region acts as an almost rigid scaffold for regulatory changes in the more mobile regions of troponin. However, the TnCN orientations determined by the two methods are clearly distinct in both low- and high-calcium conditions. We discuss the implications of these results for the role of TnCN in mediating the multiple signalling pathways acting through troponin in heart muscle cells and the general advantages and limitations of FISS and cryo-EM for determining protein domain orientations in cells and multiprotein complexes.

Keywords:  Calcium; Heart; Muscle regulation; Skeletal muscle; Troponin

DOI:  https://doi.org/10.1007/s12551-024-01245-y
Cell Death Dis. 2025 Jan 22. 16(1): 37

Sarcoglycans are enriched at the neuromuscular junction in a nerve-dependent manner.

Michela Gloriani, Bianca Cheli, Chiara D'Ercole, Veronica Ruggieri, Marianna Cosentino, Mireia Serrat Pineda, Biliana Lozanoska-Ochser, Francesca Grassi, Marina Bouché, Luca Madaro, Carles Sánchez Riera.

Sarcoglycanopathies are heterogeneous proximo-distal diseases presenting severe muscle alterations. Although there are 6 different sarcoglycan isoforms, sarcoglycanopathies are caused exclusively by mutations in genes coding for one of the four sarcoglycan transmembrane proteins (alpha, beta, gamma and delta) forming the sarcoglycan complex (SGC) in skeletal and cardiac muscle. Little is known about the different roles of the SGC beyond the dystrophin glycoprotein complex (DGC) structural role. Here, we show that SGC proteins are enriched at the post-synaptic membrane of neuromuscular junctions (NMJs). Using a mouse model lacking the beta-sarcoglycan subunit, we describe for the first time that the loss of the SGC in the NMJ area results in alterations of pre- and postsynaptic membrane, as well as a significant reduction of membrane potential. Moreover, using different denervated wild-type mouse models, we demonstrate that nerve presence precedes the sarcoglycan enrichment at NMJ, suggesting a nerve-dependent sarcoglycan expression. Altogether, our findings suggest that pathological decline should no longer be understood only in terms of sarcolemma damage but also in terms of sarcoglycans' participation in the NMJ. Henceforth, our work paves the way for the identification of new mechanisms involving sarcoglycans and new approaches for the treatment of sarcoglycanopathies.

DOI: https://doi.org/10.1038/s41419-025-07353-1
Curr Mol Med. 2025 Jan 20.

The Hormetic Potential of GDF15 in Skeletal Muscle Health and Regeneration: A Comprehensive Systematic Review.

Livio Tarchi, Gaia Maiolini, Gianluca Villa, Paolo Rovero, Francesco De Logu, Romina Nassini, Rachele Garella, Chiara Sassoli, Valdo Ricca, Giovanni Castellini, Roberta Squecco.

   BACKGROUND: Growth Differentiation Factor 15 (GDF15) has been described as influencing skeletal physiology. Nevertheless, no systematic appraisal of the effect of GDF15 on skeletal muscle tissues has been developed to the present day.
OBJECTIVE: The aim of the present work was to review the evidence on the topic.
METHODS: In this preregistered systematic review (https://osf.io/wa8xr), articles were retrieved from MEDLINE/PubMed, EMBASE, and WebOfScience. Inclusion criteria comprised studies on humans or animal models, assessment of peripheral or local tissue GDF15 concentrations, as well as the direct expression of GDF15 in skeletal muscle, and direct or indirect correlates of GDF15 with physical activity/ sarcopenia/trophism/ function.
RESULTS: A total of 646 studies were retrieved, and 144 finally included. Molecular inducers or inhibitors of GDF15 in skeletal muscle tissues were described. GDF15 was reported to promote skeletal muscle health, metabolic homeostasis, and overall physical conditioning. In pathology, GDF15 seems to be correlated to the degree of muscle impairment and mitochondrial stress. GDF15 has also been described as having the potential to stratify patients based on clinical prognosis and functional outcome.
CONCLUSION: A hormetic hypothesis for GDF15 on skeletal muscle was proposed. In fact, GDF15 exhibited beneficial effects when expressed at high levels facing acute stressors (i.e., "myoprotection"). Conversely, GDF15 exhibited maladaptive effects, such as chronic low-grade inflammation, when chronically expressed in pathological processes (e.g., obesity, aging). GDF15 may be a potential molecular target for disease-modifying interventions. The current review underscores the need for further research on GDF15 to elucidate its therapeutic potential across different pathological states. The study protocol, registered before data collection and analysis, can be retrieved at https://osf.io/wa8xr. It should be noted that the study deviated from the protocol after peer review, including other electronic databases beyond MEDLINE/PubMed alone.

Keywords:  Cytokines; Growth Factors; Mitokines; Muscle Fatigue; Muscle Strength; Myokines; Psychomotor Performance; TGF-β Superfamily.

DOI:  https://doi.org/10.2174/0115665240327723241018073535
Apoptosis. 2025 Jan 20.

Combined effects of natural products and exercise on apoptosis pathways in obesity-related skeletal muscle dysfunction.

Chun Pan, Yiying Yang, Zailin Zhao, Jingye Hu.

  Obesity and related metabolic disorders are closely linked to increased apoptosis in skeletal muscle, leading to muscle degeneration, insulin resistance, and the progression of diseases such as type 2 diabetes and sarcopenia. This review explores the combined effects of natural products, including resveratrol, curcumin, and quercetin, and physical exercise on modulating apoptosis pathways in skeletal muscle. Both natural products and regular physical activity independently reduce oxidative stress and improve mitochondrial function, thereby regulating the balance between pro-apoptotic and anti-apoptotic signals. When combined, these interventions amplify their protective effects on muscle health, promoting mitochondrial biogenesis, reducing apoptosis, and enhancing muscle regeneration. This review also discusses the molecular mechanisms by which these strategies influence apoptosis, with a focus on the Bcl-2 pathway, and explores the clinical implications for the prevention and treatment of obesity-related diseases. The synergistic benefits of combining exercise with natural product supplementation offer a promising therapeutic approach for managing metabolic disorders, preserving muscle function, and improving overall metabolic health.

Keywords:  Apoptosis; Exercise; Natural products; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1007/s10495-024-02069-7
bioRxiv. 2024 Dec 19. pii: 2024.12.18.629250. [Epub ahead of print]

Sustained efficacy of CRISPR-Cas13b gene therapy for FSHD is challenged by immune response to Cas13b.

Afrooz Rashnonejad, Manal Farea, Gholamhossein Amini-Chermahini, Gerald Coulis, Noah Taylor, Allison Fowler, Armando Villalta, Oliver D King, Scott Q Harper.

Facioscapulohumeral muscular dystrophy (FSHD) is a potentially devastating muscle disease caused by de-repression of the toxic DUX4 gene in skeletal muscle. FSHD patients may benefit from DUX4 inhibition therapies, and although several experimental strategies to reduce DUX4 levels in skeletal muscle are being developed, no approved disease modifying therapies currently exist. We developed a CRISPR-Cas13b system that cleaves DUX4 mRNA and reduces DUX4 protein level, protects cells from DUX4-mediated death, and reduces FSHD-associated biomarkers in vitro . In vivo delivery of the CRISPR-Cas13b system with adeno-associated viral vectors reduced acute damage caused by high DUX4 levels in a mouse model of severe FSHD. However, protection was not sustained over time, with decreases in Cas13b and guide RNA levels between 8 weeks and 6 months after injection. In addition, wild-type mice injected with AAV6.Cas13b showed muscle inflammation with infiltrates containing Cas13b-responsive CD8+ cytotoxic T cells. Our RNA-seq data confirmed that several immune response pathways were significantly increased in human FSHD myoblasts transfected with Cas13b. Overall, our findings suggest that CRISPR-Cas13b is highly effective for DUX4 silencing but successful implementation of CRISPR/Cas13-based gene therapies may require strategies to mitigate immune responses.

DOI: https://doi.org/10.1101/2024.12.18.629250
J Physiol Sci. 2023 ;pii: S1880-6546(24)00026-X. [Epub ahead of print]73(1): 32

High-intensity interval training alleviates exhaustive exercise-induced HSP70-assisted selective autophagy in skeletal muscle.

Jiao Lu, Liu-Mei Zhang, Jing-Jing Liu, Yu-Ting Liu, Xiao-Ye Lin, Xue-Qi Wang, Yuan Zhang, Qiang Tang, Lin Liu.

  This study was designed to probe the effect of chaperone-assisted selective autophagy (CASA) on the maintenance of proteostasis during exhaustive exercise and uncover the alteration of CASA in muscle fibers with pre-high-intensity interval training (HIIT) intervention-induced muscle adaptation in response to exhaustive exercise. Rats were randomly divided into a control group; an exhaustive exercise group; and an HIIT + exhaustive exercise group. Results show myofibril damage and BiP levels were increased after exhaustive exercise, and the levels of the HSP70, BAG3, ubiquitin, autophagy-related proteins, and their interactions were increased. HIIT intervention before exhaustive exercise could decrease myofibril injury and BiP levels, accompanied by down-regulation of HSP70/BAG3 complex and selective autophagy. In conclusion, exhaustive exercise promotes CASA to clear protein aggregation for keeping proteostasis in muscle fibers; pre-HIIT intervention improves myofibril injury and unfold protein response caused by exhaustive exercise, which might contribute to inhibit the augmentation of CASA.

Keywords:  Autophagy; Chaperone; Exhaustive exercise; High-intensity interval exercise; Skeletal muscle

DOI:  https://doi.org/10.1186/s12576-023-00884-2
Proc Natl Acad Sci U S A. 2025 Jan 28. 122(4): e2408896122

BCL6 coordinates muscle mass homeostasis with nutritional states.

Hui J Wang, Weiwei Fan, Sihao Liu, Kyeongkyu Kim, Ayami Matsushima, Satoshi Ogawa, Hyun Gyu Kang, Jonathan Zhu, Gabriela Estepa, Mingxiao He, Lillian Crossley, Christopher Liddle, Minseok S Kim, Morgan L Truitt, Ruth T Yu, Annette R Atkins, Michael Downes, Ronald M Evans.

  Nutritional status is a determining factor for growth during development and homeostatic maintenance in adulthood. In the context of muscle, growth hormone (GH) coordinates growth with nutritional status; however, the detailed mechanisms remain to be fully elucidated. Here, we show that the transcriptional repressor B cell lymphoma 6 (BCL6) maintains muscle mass by sustaining GH action. Muscle-specific genetic deletion of BCL6 at either perinatal or adult stages profoundly reduces muscle mass and compromises muscle strength. Conversely, muscle-directed viral overexpression of BCL6 significantly reverses the loss of muscle mass and strength. Mechanistically, we show that BCL6 transcriptionally represses the suppressor of cytokine signaling 2 to sustain the anabolic actions of GH in muscle. Additionally, we find that GH itself transcriptionally inhibits BCL6 through the Janus kinase and signal transducer and activator of transcription 5 (JAK/STAT5) pathway. Supporting the physiologic relevance of this feedback regulation, we show the coordinated suppression of muscle Bcl6 expression with the induction of GH in the fasted state. These findings reveal the complexity of the feedback controls modulating GH signaling and identify BCL6 as a key homeostatic regulator coordinating muscle mass with nutrient availability. Moreover, these studies open avenues for targeted therapeutic strategies to combat muscle-wasting conditions.

Keywords:  BCL6; SOCS2; growth hormone; muscle mass; transcriptional repression

DOI:  https://doi.org/10.1073/pnas.2408896122
J Anat. 2025 Jan 23.

Effect of human myoblasts on tenogenic progression in 2D and 3D culture models.

Yoshifumi Tsuchiya, Ching-Yan Chloé Yeung, Rene B Svensson, Michael Kjaer.

  Tendon injuries and disorders associated with mechanical tendon overuse are common musculoskeletal problems. Even though tendons play a central role in human movement, the intrinsic healing process of tendon is very slow. So far, it is known that tendon cell activity is supported by several interstitial cells within the tendon. However, the interplay between the tendon and the adjacent muscle for tendon regeneration and development processes has not been fully investigated. Here, we tested whether factors released from muscle derived myogenic cells (myoblasts) enhance tenogenic progressions of human tendon derived cells (tendon fibroblasts) using two-dimensional (2D) culture model and a three-dimensional (3D)-engineered tendon construct culture model, which mimics tendon regeneration and development. The conditioned media from myoblasts and unconditioned media as control were applied to tendon fibroblasts. In 2D, immunofluorescence analysis revealed increased collagen type I expressing area and increased migration potential when conditioned media from myoblasts were applied. In the 3D-engineered human tendon construct model, wet weight, diameter, and cross-sectional area of the tendon constructs were increased in response to the application of conditioned media from myoblasts, whereas the collagen density was lower and mechanical function was reduced both at the functional level (maximum stiffness) and the material level (maximum stress and modulus). These results indicate that myoblast-derived factors extend collagen expressing area and enhance migration of tendon fibroblasts, while factors involved in the robustness of extra-cellular matrix deposition of tissue-engineered tendon constructs are lacking. Our findings suggest that adjacent muscle affects the signaling interplay in tendons.

Keywords:  cell communication; myoblasts; satellite cells; skeletal muscle; tendon; tendon fibroblasts; tendon regeneration; tenocytes

DOI:  https://doi.org/10.1111/joa.14224
J Clin Invest. 2025 Jan 07. pii: e185426. [Epub ahead of print]

The Splice Index as a prognostic biomarker of strength and function in myotonic dystrophy type 1.

Marina Provenzano, Kobe Ikegami, Kameron Bates, Alison Gaynor, Julia M Hartman, Aileen S Jones, Amanda Butler, Kiera N Berggren, Jeanne Dekdebrun, Man Hung, Dana M Lapato, Michael Kiefer, Charles A Thornton, Nicholas E Johnson, Melissa A Hale.

   BACKGROUND: Myotonic dystrophy type 1 (DM1) is a multisystemic, CTG repeat expansion disorder characterized by a slow, progressive decline in skeletal muscle function. A biomarker correlating RNA mis-splicing, the core pathogenic disease mechanism, and muscle performance is crucial for assessing response to disease-modifying interventions. We evaluated the Myotonic Dystrophy Splice Index (SI), a composite RNA splicing biomarker incorporating 22 disease-specific events, as a potential biomarker of DM1 muscle weakness.
METHODS: Total RNA sequencing of tibialis anterior biopsies from 58 DM1 participants and 33 unaffected/disease controls was used to evaluate RNA splicing events across the disease spectrum. Targeted RNA sequencing was used to derive the SI from biopsies collected at baseline (n = 52) or a 3-month (n = 37) follow-up visit along with clinical measures of muscle performance.
RESULTS: The SI demonstrated significant associations with measures of muscle strength and ambulation, including ankle dorsiflexion strength (ADF) and 10-meter run/fast walk (Pearson r = -0.719 and -0.680, respectively). The SI was relatively stable over 3-months (ICC = 0.863). Latent-class analysis identified three DM1 subgroups stratified by baseline SI (SIMild, SIModerate, SISevere); SIModerate individuals had a significant increase in the SI over 3-months. Multiple linear regression modeling revealed that baseline ADF and SI were predictive of strength at 3-months (adjusted R² = 0.830).
CONCLUSION: The SI is a reliable biomarker that captures associations of RNA mis-splicing with physical strength and mobility and has prognostic utility to predict future function, establishing it as a potential biomarker for assessment of therapeutic target engagement.
TRIAL REGISTRATION: NCT03981575Funding: FDA (7R01FD006071), Myotonic Dystrophy Foundation, Wyck Foundation, Muscular Dystrophy Association, Novartis, Dyne, Avidity, PepGen, Takeda, Sanofi Genzyme, Pfizer, Arthex, and Vertex Pharmaceuticals.

Keywords:  Muscle biology; Neuromuscular disease; RNA processing; Skeletal muscle

DOI:  https://doi.org/10.1172/JCI185426
Eur J Med Res. 2025 Jan 19. 30(1): 38

Exosomes and microRNAs as mediators of the exercise.

Haoyuan Li, Guifang Liu, Bing Wang, Mohammad Reza Momeni.

  MicroRNAs (miRNAs), also known as microribonucleic acids, are small molecules found in specific tissues that are essential for maintaining proper control of genes and cellular processes. Environmental factors, such as physical exercise, can modulate miRNA expression and induce targeted changes in gene transcription. This article presents an overview of the present knowledge on the principal miRNAs influenced by physical activity in different tissues and bodily fluids. Numerous research projects have emphasized the significant impact of miRNAs on controlling biological changes brought about by physical activity. These molecules play main roles in important processes such as the growth of skeletal muscle and heart muscle cells, the creation of mitochondria, the development of the vascular system, and the regulation of metabolism. Studies have shown that physical exertion utilizes the contributions of miR-1, miR-133, miR-206, miR-208, and miR-486 to revitalize and restore skeletal muscle tissue. Moreover, detecting alterations in miRNA levels and connecting them to the specific outcomes of various exercise routines and intensities can act as indicators for physical adaptation and the reaction to physical activity in long-term diseases. Numerous studies have confirmed that extracellular vesicles (EVs) which composed of different members such as exosomes have the ability to reduce inflammation through the activation of the nuclear factor kappa B (NF-κB pathway. Furthermore, physical activity greatly affects the levels of specific miRNAs present in exosomes derived from skeletal muscle. Therefore, exosomal miRNAs target some pathways that are related to growth and development, such asWnt/β-catenin, PI3K/AKT, and insulin-like growth factor 1 (IGF1). Exercise-induced exosomes have also been identified as important mediators in promoting beneficial effects throughout the body. The aim of this review is to summarize the effect of exercise on the function of miRNAs and exosomes.

Keywords:  Biomarker; Epigenetic; Exercise; Exosome; MicroRNA

DOI:  https://doi.org/10.1186/s40001-025-02273-4
Mol Immunol. 2025 Jan 19. pii: S0161-5890(25)00013-6. [Epub ahead of print]178 41-51

Muscle fiber types switched during the development of experimental autoimmune myasthenia gravis via the PI3K/Akt signaling pathway.

Xinrong Li, Xiuhua Yao, Wei Zhao, Bo Wei, Ran Zhang, Geng Yan, Mingyu Ma, Zhenhai Wang, Xijun Liu, Yumei Liu, Guangyou Wang, Hulun Li, Qingfei Kong, Jinghua Wang, Lili Mu.

  As one of the largest organs of our human body, skeletal muscle has good research prospects in myasthenia gravis (MG), the symptoms of which include systemic skeletal muscle weakness. Skeletal muscle is composed of two types of muscle fibers. Different fiber subtypes can be converted into each other; however, the underlying mechanism is not yet clear. In this paper, we firstly established an experimental autoimmune myasthenia gravis (EAMG) rat model and found that the skeletal muscle fibers of the EAMG group were atrophied, with a change in the proportion of fiber subtypes, which switched from type IIa to type I in the EAMG group at the peak stage, as verified by histological and molecular analyses. Second-generation sequencing results predicted that the PI3K-Akt signaling pathway might be involved in the switch, and the mRNA expression levels of the PI3K-Akt pathway-related genesNr4a1, IL2rb, Col1A1 and Ddit4 were significantly different. In conclusion, this study indicates that the switch of muscle fiber subtypes in MG via the PI3K-Akt signaling pathway may be a potential target for the treatment of MG-related skeletal muscle atrophy in the future.

Keywords:  PI3K-Akt signaling pathway; extensor digitorum longus; fiber switch; muscle fiber; myasthenia gravis; soleus muscle

DOI:  https://doi.org/10.1016/j.molimm.2025.01.006
Nature. 2025 Jan 23.

The surprising link between muscle and the reproductive system.



Keywords:  Physiology

DOI:  https://doi.org/10.1038/d41586-025-00129-9
Aging Cell. 2025 Jan 19. e14485

From Clinical to Benchside: Lacticaseibacillus and Faecalibacterium Are Positively Associated With Muscle Health and Alleviate Age-Related Muscle Disorder.

Chaoran Liu, Pui Yan Wong, Nilakshi Barua, Baoqi Li, Hei Yuet Wong, Ning Zhang, Simon Kwoon Ho Chow, Sunny Hei Wong, Jun Yu, Margaret Ip, Wing Hoi Cheung, Gustavo Duque, Christoph Brochhausen, Joseph Jao Yiu Sung, Ronald Man Yeung Wong.

  Sarcopenia is an age-related muscle disorder that increases risks of adverse clinical outcomes, but its treatments are still limited. Gut microbiota is potentially associated with sarcopenia, and its role is still unclear. To investigate the role of gut microbiota in sarcopenia, we first compared gut microbiota and metabolites composition in old participants with or without sarcopenia. Fecal microbiota transplantation (FMT) from human donors to antibiotic-treated recipient mice was then performed. Specific probiotics and their mechanisms to treat aged mice were identified. Old people with sarcopenia had different microbial composition and metabolites, including Paraprevotella, Lachnospira, short-chain fatty acids, and purine. After FMT, mice receiving microbes from people with sarcopenia displayed lower muscle mass and strength compared with those receiving microbes from non-sarcopenic donors. Lacticaseibacillus rhamnosus (LR) and Faecalibacterium prausnitzii (FP) were positively related to muscle health of old people, and enhanced muscle mass and function of aged mice. Transcriptomics showed that genes related to tricarboxylic acid cycle (TCA) were enriched after treatments. Metabolic analysis showed increased substrates of TCA cycle in both LR and FP supernatants. Muscle mitochondria density, ATP content, NAD+/NADH, mitochondrial dynamics and biogenesis proteins, as well as colon tight junction proteins of aged mice were improved by both probiotics. LR and the combination of two probiotics also benefit intestinal immune health by reducing CD8+ IFNγ+ T cells. Gut microbiota dysbiosis is a pathogenesis of sarcopenia, and muscle-related probiotics could alleviate age-related muscle disorders mainly through mitochondria improvement. Further clinical translation is warranted.

Keywords:  aging; fecal microbiota transplantation; gut microbiota; muscle; probiotic; sarcopenia

DOI:  https://doi.org/10.1111/acel.14485