bims-moremu 2025-01-12 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2025–01–12
37 papers selected by
Anna Vainshtein, Craft Science Inc.

Integrating Physical and Biochemical Cues for Muscle Engineering: Scaffolds and Graft Durability.
PEAR1 Promotes Myoblast Proliferation Through Notch Signaling Pathway.
PIEZO1 activation enhances myogenesis and mitigates muscle degeneration in rotator cuff tear.
Exercise-driven cellular autophagy: A bridge to systematic wellness.
Exercise promotes peripheral glycolysis in skeletal muscle through miR-204 induction via the HIF-1α pathway.
Skeletal muscle ribosome analysis: A comparison of common assay methods and utilization of a novel RiboAb antibody cocktail.
Immature Skeletal Myotubes Are an Effective Source for Improving the Terminal Differentiation of Skeletal Muscle.
Macrophage Immunometabolism - Emerging Targets for Regrowth in Aging Muscle.
BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.
Muscle-specific miRNAs in plasma and skeletal muscle of patients with idiopathic inflammatory myopathy are modulated by disease and training.
Pharmacological reduction of lipid hydroperoxides as a potential modulator of sarcopenia.
Periodic paralysis across the life course: age-related phenotype transition and sarcopenia overlap.
Sarcolemma resilience and skeletal muscle health require O-mannosylation of dystroglycan.
Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions.
Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.
The effect of exercise and physical activity on skeletal muscle epigenetics and metabolic adaptations.
Cannabis (THC) Aggravates the Deleterious Effects of Alcohol (EtOH) on Skeletal Muscles' Mitochondrial Respiration: Modulation by Age and Metabolic Phenotypes.
Accelerated Sarcopenia Phenotype in the DJ-1/Park7-Knockout Zebrafish.
Exploring the potential regulation of DUOX in thyroid hormone‑autophagy signaling via IGF‑1 in the skeletal muscle (Review).
Enhancing muscle and brain resilience: The role of prehabilitative exercise in mitigating disuse effects.
Previous short-term disuse dictates muscle gene expression and physiological adaptations to subsequent resistance exercise.
Role of the PPARGC1A Gene and Its rs8192678 Polymorphism on Sport Performance, Aerobic Capacity, Muscle Adaptation and Metabolic Diseases: A Narrative Review.
miRNA-1 regulation is necessary for mechanical overload-induced muscle hypertrophy in male mice.
Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.
The role of skeletal muscle respiratory capacity in exercise performance.
Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.
In situ spatial transcriptomic analysis of human skeletal muscle using the Xenium platform.
Skeletal muscle oxidative capacity related to intramyocellular lipid in young but not in older individuals.
Utilizing zebrafish models to elucidate mechanisms and develop therapies for skeletal muscle atrophy.
m6A modified pre-miR-503-5p contributes to myogenic differentiation through the activation of mTOR pathway.
Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro.
Analyzing Muscle Stem Cell Function Ex Vivo.
Mechanisms and Countermeasures for Muscle Atrophy in Microgravity.
Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.
Ribitol and ribose treatments differentially affect metabolism of muscle tissue in FKRP mutant mice.
Diacylglycerol kinase δ is required for skeletal muscle development and regeneration.
Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.

Bioengineering (Basel). 2024 Dec 09. pii: 1245. [Epub ahead of print]11(12):

Integrating Physical and Biochemical Cues for Muscle Engineering: Scaffolds and Graft Durability.

Farbod Yousefi, Lauren Ann Foster, Omar A Selim, Chunfeng Zhao.

  Muscle stem cells (MuSCs) are essential for skeletal muscle regeneration, influenced by a complex interplay of mechanical, biochemical, and molecular cues. Properties of the extracellular matrix (ECM) such as stiffness and alignment guide stem cell fate through mechanosensitive pathways, where forces like shear stress translate into biochemical signals, affecting cell behavior. Aging introduces senescence which disrupts the MuSC niche, leading to reduced regenerative capacity via epigenetic alterations and metabolic shifts. Transplantation further challenges MuSC viability, often resulting in fibrosis driven by dysregulated fibro-adipogenic progenitors (FAPs). Addressing these issues, scaffold designs integrated with pharmacotherapy emulate ECM environments, providing cues that enhance graft functionality and endurance. These scaffolds facilitate the synergy between mechanotransduction and intracellular signaling, optimizing MuSC proliferation and differentiation. Innovations utilizing human pluripotent stem cell-derived myogenic progenitors and exosome-mediated delivery exploit bioactive properties for targeted repair. Additionally, 3D-printed and electrospun scaffolds with adjustable biomechanical traits tackle scalability in treating volumetric muscle loss. Advanced techniques like single-cell RNA sequencing and high-resolution imaging unravel muscle repair mechanisms, offering precise mapping of cellular interactions. Collectively, this interdisciplinary approach fortifies tissue graft durability and MuSC maintenance, propelling therapeutic strategies for muscle injuries and degenerative diseases.

Keywords:  cellular senescence; exosomes; external cues; extracellular matrix; fibrosis; mechanotransduction; pharmacotherapy; skeletal muscle regeneration; tissue scaffolds

DOI:  https://doi.org/10.3390/bioengineering11121245
Biology (Basel). 2024 Dec 19. pii: 1063. [Epub ahead of print]13(12):

PEAR1 Promotes Myoblast Proliferation Through Notch Signaling Pathway.

Yahao Zhao, Lu Zhang, Ruotong Hao, Shuang Li, Shufeng Li, Shuai Shi, Huili Tong, Bingchen Liu.

  PEAR1, also known as platelet endothelial aggregation receptor 1, is known to play a crucial role in the migration and differentiation of muscle satellite cells (MuSCs). However, its specific effects on skeletal muscle development and regeneration require further exploration. In this study, the expression of PEAR1; the proliferation marker proteins of Pax7, CCNB1, and PCNA; and the key molecules of N1-ICD, N2-ICD, and Hes1 were all increased gradually during the process of C2C12 cell proliferation. Furthermore, Western blotting and EdU results showed that when PEAR1 was over-expressed or inhibited, the proliferation status of C2C12 cell was increased or reduced respectively. This implied that PEAR1 could regulate myoblast proliferation and might be relate to Notch cell signaling pathway. A subsequent immunoprecipitation experiment result showed that the interaction between PEAR1 and Notch1 or Notch2, respectively. Then Western blotting and EdU results showed that the proliferation of C2C12 cell was inhibited under the treatment of Notch signaling pathway inhibitor RIN1. Meanwhile, the proliferation capacity of C2C12 cell could not be improved by treatment with RIN1 even though PEAR1 was over-expressed. These results showed that PEAR1 may regulated C2C12 cell proliferation though Notch signaling pathway. Additionally, a mouse model of muscle injury repair injected with bupivacaine hydrochloride was established in this study. Immunohistochemistry results exhibited that PEAR1 may regulate skeletal muscle post-injury regeneration relevant to Notch1 and Notch2 in different patterns. These findings provide valuable insights into the potential involvement of PEAR1 in skeletal muscle development and post-injury regeneration.

Keywords:  Notch signaling pathway; PEAR1; myoblast proliferation; skeletal muscle regeneration

DOI:  https://doi.org/10.3390/biology13121063
Regen Ther. 2025 Mar;28 143-152

PIEZO1 activation enhances myogenesis and mitigates muscle degeneration in rotator cuff tear.

Tihui Wang, Shujing Feng, Hao Zhou, Wenhua Mao, Ruijun Bai, Yuan Xia, Jianghu Huang, Rui Zhang, Feiyue Lin.

  Muscle degeneration is a common issue caused by rotator cuff tear (RCT) which significantly affects prognosis. Muscle stem cells (MuSCs) play a crucial role to prevent muscle degeneration after RCT. However, the pathological changes and detailed molecular mechanism underlying the myogenesis of MuSCs after RCT remain incomplete. The current study established single-cell landscape of supraspinatus muscles and found decreased expression of PIEZO1 and impaired myogenic potential of MuSCs from RCT patients. Reduced expression of PIEZO1 impaired the myogenesis of MuSCs by inhibiting the ERK/MAPK pathways. Furthermore, selective PIEZO1 agonist Yoda1 had the potential to alleviate muscle degeneration and improve shoulder function following RCT. This study emphasized the role of PIEZO1 in the myogenesis of MuSCs and suggested that activating PIEZO1 could be a potential non-surgical treatment option to reduce muscle degeneration after RCT.

Keywords:  Muscle degeneration; Muscle stem cells; Rotator cuff tear

DOI:  https://doi.org/10.1016/j.reth.2024.12.002
J Adv Res. 2025 Jan 03. pii: S2090-1232(24)00613-1. [Epub ahead of print]

Exercise-driven cellular autophagy: A bridge to systematic wellness.

Xiao-Han Zhou, Ya-Xi Luo, Xiu-Qing Yao.

   BACKGROUND: Exercise enhances health by supporting homeostasis, bolstering defenses, and aiding disease recovery. It activates autophagy, a conserved cellular process essential for maintaining balance, while dysregulated autophagy contributes to disease progression. Despite extensive research on exercise and autophagy independently, their interplay remains insufficiently understood.
AIM OF REVIEW: This review explores the molecular mechanisms of exercise-induced autophagy in various tissues, focusing on key transduction pathways. It examines how different types of exercise trigger specific autophagic responses, supporting cellular balance and addressing systemic dysfunctions. The review also highlights the signaling pathways involved, their roles in protecting organ function, reducing disease risk, and promoting longevity, offering a clear understanding of the link between exercise and autophagy.
KEY SCIENTIFIC CONCEPTS OF REVIEW: Exercise-induced autophagy is governed by highly coordinated and dynamic pathways integrating direct and indirect mechanical forces and biochemical signals, linking physical activity to cellular and systemic health across multiple organ systems. Its activation is influenced by exercise modality, intensity, duration, and individual biological characteristics, including age, sex, and muscle fiber composition. Aerobic exercises primarily engage AMPK and mTOR pathways, supporting mitochondrial quality and cellular homeostasis. Anaerobic training activates PI3K/Akt signaling, modulating molecules like FOXO3a and Beclin1 to drive muscle autophagy and repair. In pathological contexts, exercise-induced autophagy enhances mitochondrial function, proteostasis, and tissue regeneration, benefiting conditions like sarcopenia, neurodegeneration, myocardial ischemia, metabolic disorders, and cancer. However, excessive exercise may lead to autophagic overactivation, leading to muscle atrophy or pathological cardiac remodeling. This underscores the critical need for balanced exercise regimens to maximize therapeutic efficacy while minimizing risks. Future research should prioritize identifying reliable biomarkers, optimizing exercise protocols, and integrating exercise with pharmacological strategies to enhance therapeutic outcomes.

Keywords:  Autophagy; Exercise; Health; Macroautophagy; Physical activity; Well-being

DOI:  https://doi.org/10.1016/j.jare.2024.12.036
Sci Rep. 2025 Jan 09. 15(1): 1487

Exercise promotes peripheral glycolysis in skeletal muscle through miR-204 induction via the HIF-1α pathway.

Sang R Lee, Kang Joo Jeong, Moeka Mukae, Jinhee Lee, Eui-Ju Hong.

  The mechanisms underlying exercise-induced insulin sensitization are of great interest, as exercise is a clinically critical intervention for diabetic patients. Some microRNAs (miRs) are secreted from skeletal muscle after exercise where they regulate insulin sensitivity, and have potential as diagnostic markers in diabetic patients. miR-204 is well-known for its involvement in development, cancer, and metabolism; however, its role in exercise-induced glycemic control remains unclear. In the present study, endurance exercise in mice increased miR-204 expression levels in skeletal muscle. In a chronic exercise model, miR-204 expression levels were elevated along with glycolytic enzymes in skeletal muscle. When muscular hypoxia was induced after exercise, miR-204 expression also increased with the upregulation of hypoxia-inducible factor 1-alpha (HIF-1α). Furthermore, HIF-1α overexpression led to increased miR-204 expression. Treatment with a miR-204 mimic in C2C12 cells significantly enhanced the glycolysis rate and the mRNA expression of glycolytic enzymes. Notably, intravenous administration of miR-204 in mice increased the glucose clearance rate following refeeding. miR-204 initially elevated blood glucose levels at an early stage of refeeding but later promoted blood glucose reduction as refeeding continued. Additionally, glycolytic enzymes were upregulated in the skeletal muscles of miR-204-injected mice. These findings suggest a novel physiological role for miR-204 in promoting skeletal muscle glycolysis, particularly in situations where insulin action is limited.

Keywords:  Diabetes; Exercise; Glycolysis; miR-204; miRNA

DOI:  https://doi.org/10.1038/s41598-025-85174-0
Physiol Rep. 2025 Jan;13(1): e70173

Skeletal muscle ribosome analysis: A comparison of common assay methods and utilization of a novel RiboAb antibody cocktail.

Joshua S Godwin, J Max Michel, C Brooks Mobley, Gustavo A Nader, Michael D Roberts.

  While total RNA concentrations putatively represent ribosome content, there is a need to homologize various quantification approaches. Thus, total RNA concentrations ([RNA]) provided through UV-Vis spectroscopy (UV), fluorometry-only (Fluor), and fluorometry-based microfluidic chip electrophoresis (MFGE) were examined in C2C12 myotubes and mouse skeletal muscle to determine if values aligned with [18S + 28S rRNA] (i.e., criterion ribosome metric). A novel antibody cocktail (termed RiboAb) was also tested and compared to [18S + 28S rRNA] in these models. In myotubes, 24-h IGF-1 treatments increased [18S + 28S rRNA] (~2.0-fold) and [RNA] based on UV (~1.9-fold), Fluor (~2.3 fold), and MFGE (~2.1-fold). In C57BL/6 mice, 10 days of mechanical overload (MOV) elevated plantaris [18S + 28S rRNA] (~1.7-fold) and [RNA] according to UV (~1.5-fold), Fluor (~1.6-fold), and MFGE (~1.8-fold). Myotube and mouse plantaris RiboAb levels were significantly higher with IGF-1 treatments and MOV, respectively, versus controls (1.3-fold and 1.7-fold, respectively), and values correlated with [18S + 28S rRNA] (r = 0.637 and r = 0.853, respectively, p ≤ 0.005). UV, Fluor, and MFGE [RNA] are seemingly valid surrogates of cell/tissue ribosome content, although each method has advantages (e.g., ease of use) and disadvantages (e.g., magnitudes of bias) discussed herein. Finally, the RiboAb cocktail may also represent ribosome content, although this should be further explored in other models.

Keywords:  RiboAb; UV–Vis; electrophoresis; fluorometry; ribosome pelleting; total RNA

DOI:  https://doi.org/10.14814/phy2.70173
Cells. 2024 Dec 23. pii: 2136. [Epub ahead of print]13(24):

Immature Skeletal Myotubes Are an Effective Source for Improving the Terminal Differentiation of Skeletal Muscle.

Seung Yeon Jeong, Jun Hee Choi, Paul D Allen, Eun Hui Lee.

  Injured or atrophied adult skeletal muscles are regenerated through terminal differentiation of satellite cells to form multinucleated muscle fibers. Transplantation of satellite cells or cultured myoblasts has been used to improve skeletal muscle regeneration. Some of the limitations observed result from the limited number of available satellite cells that can be harvested and the efficiency of fusion of cultured myoblasts with mature muscle fibers (i.e., terminal differentiation) upon transplantation. However, the possible use of immature myotubes in the middle of the terminal differentiation process instead of satellite cells or cultured myoblasts has not been thoroughly investigated. Herein, myoblasts (Mb) or immature myotubes on differentiation day 2 (D2 immature myotubes) or 3 (D3 immature myotubes) were transferred to plates containing D2 or D3 immature myotubes as host cells. The transferred Mb/immature myotubes on the plates were further co-differentiated with host immature myotubes into mature myotubes in six conditions: Mb-to-D2, D2-to-D2, D3-to-D2, Mb-to-D3, D2-to-D3, and D3-to-D3. Among these six co-differentiation conditions, the D2-to-D3 co-differentiation condition exhibited the most characteristic myotube appearance and the greatest availability of Ca2+ for skeletal muscle contraction. Compared with non-co-differentiated control myotubes, D2-to-D3 co-differentiated myotubes presented increased MyoD and myosin heavy chain II (MyHC II) expression and increased myotube width, accompanied by parallel and swirling alignment. These increases correlated with functional increases in both electrically induced intracellular Ca2+ release and extracellular Ca2+ entry due to the increased expression of ryanodine receptor 1 (RyR1), sarcoplasmic/endoplasmic reticulum Ca2+-ATPase 1a (SERCA1a), and stromal interaction molecule 1 (STIM1). These increases were not detected in any of the other co-differentiation conditions. These results suggest that in vitro-cultured D2-to-D3 co-differentiated mature myotubes could be a good alternative source of satellite cells or cultured myoblasts for skeletal muscle regeneration.

Keywords:  co-differentiation; immature myotube; terminal differentiation

DOI:  https://doi.org/10.3390/cells13242136
Am J Physiol Endocrinol Metab. 2025 Jan 06.

Macrophage Immunometabolism - Emerging Targets for Regrowth in Aging Muscle.

Zachary J Fennel, Ryan M O'Connell, Micah J Drummond.

  The recovery from muscle atrophy is impaired with aging as characterized by improper muscle remodeling and sustained functional deficits. Age-related deficits in muscle regrowth are tightly linked with the loss of early pro-inflammatory macrophage responses and subsequent cellular dysregulation within the skeletal muscle niche. Macrophage inflammatory phenotype is regulated at the metabolic level, highlighting immunometabolism as an emerging strategy to enhance macrophage responses and restore functional muscle regrowth. Accordingly, metabolic targets with an emphasis on glycolytic, hypoxia, and redox-related pathways stand out for their role in promoting macrophage inflammation and enhancing muscle regrowth in aging. Here we highlight promising immuno-metabolic targets which could be leveraged to restore optimal pro-inflammatory macrophage function in aging and enhance muscle regrowth following muscular atrophy.

Keywords:  aging; immune cells; inflammation; metabolism; muscle remodeling

DOI:  https://doi.org/10.1152/ajpendo.00403.2024
Cancers (Basel). 2024 Dec 11. pii: 4133. [Epub ahead of print]16(24):

BNIP3 Downregulation Ameliorates Muscle Atrophy in Cancer Cachexia.

Claudia Fornelli, Marc Beltrà, Antonio Zorzano, Paola Costelli, David Sebastian, Fabio Penna.

   BACKGROUND AND AIMS: Cancer cachexia is a complex syndrome affecting most cancer patients and is directly responsible for about 20% of cancer-related deaths. Previous studies showed muscle proteolysis hyper-activation and mitophagy induction in tumor-bearing animals. While basal mitophagy is required for maintaining muscle mass and quality, excessive mitophagy promotes uncontrolled protein degradation, muscle loss and impaired function. BNIP3, a key mitophagy-related protein, is significantly increased in the muscles of both mice and human cancer hosts. This study aimed to define the potential of mitigating mitophagy via BNIP3 downregulation in preserving mitochondrial integrity, counteracting skeletal muscle loss in experimental cancer cachexia.
METHODS: Two in vivo gene delivery methods were performed to knock down muscle BNIP3: electroporation of a BNIP3-specific shRNA expression vector or adenovirus injection.
RESULTS: The electroporation effectively reduced muscle BNIP3 in healthy mice but was ineffective in C26 tumor-bearing mice. In contrast, adenovirus-mediated BNIP3 knockdown successfully decreased BNIP3 levels also in tumor hosts. Although BNIP3 knockdown did not impact overall on body or muscle mass, it improved muscle fiber size in C26-bearing miceh2, suggesting partial prevention of muscle atrophy. Mitochondrial respiratory chain complexes (OxPhos) and TOM20 protein levels were consistently rescued, indicating improvements in mitochondrial mass, while H2O2 levels were unchanged among the groups, suggesting that BNIP3 downregulation does not impair the endogenous control of oxidative balance.
CONCLUSIONS: These findings suggest that a fine balance between mitochondrial disposal and biogenesis is fundamental for preserving muscle homeostasis and highlight a potential role for BNIP3 modulation against cancer-induced muscle wasting.

Keywords:  BNIP3; cancer cachexia; mitochondria; mitophagy; muscle wasting

DOI:  https://doi.org/10.3390/cancers16244133
Rheumatology (Oxford). 2025 Jan 07. pii: keae704. [Epub ahead of print]

Muscle-specific miRNAs in plasma and skeletal muscle of patients with idiopathic inflammatory myopathy are modulated by disease and training.

Nikoleta Alchus Laiferová, Lucia Vernerová, Michal Nemec, Daria Barkova, Katarína Rerková, Karin Marček Malenovská, Martina Vokurková, Sabína Oreská, Martin Klein, Maja Špiritović, Michal Tomčík, Jozef Ukropec, Jiří Vencovský, Barbara Ukropcová.

   OBJECTIVES: Objective of this work was to examine myomiR levels in plasma, skeletal muscle, and skeletal muscle cells of patients with idiopathic inflammatory myopathy (IIM), their interrelations with the disease-related clinical phenotypes and with the effects of the disease-modifying 6-month training-intervention.
METHODS: Samples of vastus lateralis muscle (n = 12/13) and plasma (n = 20/21) were obtained from IIM patients and healthy controls, respectively. Muscle and plasma were obtained before and after a 6-month training-intervention in 7 patients. MyomiRs miR-1,-206,-133a,-133b were quantified by qPCR. Effects of pro-inflammatory (TNF), metabolic (glucose, insulin) systemic factors and the immunosuppressive therapy (dexamethasone) on the myomiRs were examined in muscle cells in vitro.
RESULTS: MiR-133b was lower in skeletal muscle of IIM patients compared with healthy controls (p= 0.03). Levels of miR-133a, miR-1, and miR-206 were not regulated. Moreover, plasma levels of miR-133b and miR-1 were reduced in IIM compared with healthy controls (p< 0.05). Exercise induced reciprocal regulation of specific myomiRs in muscle and plasma of IIM patients, it lowered miR-133b in muscle while increasing miR-133b and miR-206 in plasma. Treatment of myotubes with TNF, insulin, and glucose and dexamethasone induced distinct myomiRs down-regulation.
CONCLUSION: Lower myomiR levels in skeletal muscle of IIM patients might indicate reduced muscle regenerative potential in IIM, which could be linked to inflammation, metabolic dysfunction, and immunosuppressive therapy. Training-induced changes of muscle and plasma myomiRs indicate an increase in myomiRs release, which could contribute to the adaptive response underlying the positive systemic effects of exercise in IIM.

Keywords:  exercise; idiopathic inflammatory myopathy; microRNA; muscle cells; myomiR; plasma; skeletal muscle; training intervention

DOI:  https://doi.org/10.1093/rheumatology/keae704
J Physiol. 2025 Jan 08.

Pharmacological reduction of lipid hydroperoxides as a potential modulator of sarcopenia.

Jacob L Brown, Hongyang Xu, Elizabeth Duggan, Craig S Rosenfeld, Holly Van Remmen.

  We previously reported that elevated expression of phospholipid hydroperoxide glutathione peroxidase 4, an enzyme that regulates membrane lipid hydroperoxides, can mitigate sarcopenia in mice. However, it is still unknown whether a pharmacological intervention designed to modulate lipid hydroperoxides might be an effective strategy to reduce sarcopenia in aged mice. Here we asked whether a newly developed compound, CMD-35647 (CMD), can reduce muscle atrophy induced by sciatic nerve transection. We treated mice daily with vehicle or CMD (15 mg/kg, i.p. injection) starting 1 day prior to denervation. CMD treatment reduced hydroperoxide generation and blunted muscle atrophy by over 17% in denervated muscle. To test whether CMD can reduce ageing-induced muscle atrophy and weakness, we treated mice with either vehicle or CMD (15 mg/kg, i.p. injection) 3 days per week for 8 months, starting at 18 months of age until 26 months of age. We measured muscle mass, functional status of neuromuscular junctions, muscle contractile function and mitochondrial function in control and CMD-treated 26-month-old female mice. Treatment with CMD conferred protection against muscle atrophy in both tibialis anterior and extensor digitorum longus that was associated with maintenance of fibre size of MHC 2b and 2x fibres. Mitochondrial respiration was also protected in CMD-treated mice. We also found that muscle force generation was protected with CMD treatment despite denervation in ∼25% of the muscle fibres. Overall, this study shows that pharmacological interventions designed to reduce lipid hydroperoxides might be effective for preventing sarcopenia. KEY POINTS: Sarcopenia in aged mice is associated with muscle loss, contractile dysfunction, denervation, and reduced mitochondrial respiration. CMD-35647 is a pharmocological compound that can neutralize lipid hydroperoxides. 8 month treatment of CMD-35647 mitigated muscle atrophy in tibialis anterior and extensor digitorum longus. 8 month treatment of CMD-35647 improved muscle function in aged mice independent of the neuromuscular junction. Aged mice treated with CMD-35647 had greater respiration in red gastrocnemius muscle when compared to vehicle treated mice.

Keywords:  Aging; Mitochondria; Neuromuscular junction; lipid hydroperoxide; muscle atrophy; muscle weakness; oxylipin; sarcopenia

DOI:  https://doi.org/10.1113/JP287090
Front Neurol. 2024 ;15 1507485

Periodic paralysis across the life course: age-related phenotype transition and sarcopenia overlap.

Karen Suetterlin, Sinead Law, William David Arnold.

  In Periodic Paralysis (PP), a rare inherited condition caused by mutation in skeletal muscle ion channels, the phenotype changes with age, transitioning from the episodic attacks of weakness that give the condition its name, to a more degenerative phenotype of permanent progressive weakness and myopathy. This leads to disability and reduced quality of life. Neither the cause of this phenotype transition, nor why it occurs around the age of 40 is known. However, 40 is also the age of onset of 'normal' age-related physiological decline when we consider (a) muscle mass and strength (b) physical function at the world class level and (c) age-related mitochondrial dysfunction. Elevated Na+, mitochondrial dysfunction and sarcoplasmic Ca2+ leak via the skeletal muscle ryanodine receptor (RyR1) have been implicated in both periodic paralysis myopathy and skeletal muscle ageing. We suggest this combination may trigger a negative spiral ultimately leading to progressive muscle failure. Understanding the interaction between ageing physiology and disease phenotype will provide a window into the healthy ageing process but also help understand how, and why PP phenotype changes with age. Understanding the mechanism underlying PP phenotype-transition and its link with ageing physiology, not only has the potential to identify the first disease modifying therapies for PP, but also to identify novel and potentially tractable mechanisms that contribute to sarcopenia, the pathological loss of muscle mass and function with age.

Keywords:  ageing; channelopathy; life course; mitochondria; myopathy; periodic paralysis; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3389/fneur.2024.1507485
Skelet Muscle. 2025 Jan 09. 15(1): 1

Sarcolemma resilience and skeletal muscle health require O-mannosylation of dystroglycan.

Jeffrey M Hord, Sarah Burns, Tobias Willer, Matthew M Goddeeris, David Venzke, Kevin P Campbell.

   BACKGROUND: Maintaining the connection between skeletal muscle fibers and the surrounding basement membrane is essential for muscle function. Dystroglycan (DG) serves as a basement membrane extracellular matrix (ECM) receptor in many cells, and is also expressed in the outward-facing membrane, or sarcolemma, of skeletal muscle fibers. DG is a transmembrane protein comprised of two subunits: alpha-DG (α-DG), which resides in the peripheral membrane, and beta-DG (β-DG), which spans the membrane to intracellular regions. Extensive post-translational processing and O-mannosylation are required for α-DG to bind ECM proteins, which is mediated by a glycan structure known as matriglycan. O-mannose glycan biosynthesis is initiated by the protein O-mannosyltransferase 1 (POMT1) and POMT2 enzyme complex and leads to three subtypes of glycans called core M1, M2, and M3. The lengthy core M3 is capped with matriglycan. Genetic defects in post-translational O-mannosylation of DG interfere with its receptor function and result in muscular dystrophy with central nervous system and skeletal muscle pathophysiology.
METHODS: To evaluate how the loss of O-mannosylated DG in skeletal muscle affects the development and progression of myopathology, we generated and characterized mice in which the Pomt1 gene was specifically deleted in skeletal muscle (Pomt1skm) to interfere with POMT1/2 enzyme activity. To investigate whether matriglycan is the primary core M glycan structure that provides the stabilizing link between the sarcolemma and ECM, we generated mice that retained cores M1, M2, and M3, but lacked matriglycan (conditional deletion of like-acetylglucosaminyltransferase 1; Large1skm). Next, we restored Pomt1 using gene transfer via AAV2/9-MCK-mPOMT1 and determined the effect on Pomt1skm pathophysiology.
RESULTS: Our data showed that in Pomt1skm mice O-mannosylated DG is required for sarcolemma resilience, remodeling of muscle fibers and muscle tissue, and neuromuscular function. Notably, we observed similar body size limitations, sarcolemma weakness, and neuromuscular weakness in Large1skm mice that only lacked matriglycan. Furthermore, our data indicate that genetic rescue of Pomt1 in Pomt1skm mice limits contraction-induced sarcolemma damage and skeletal muscle pathology.
CONCLUSIONS: Collectively, our data indicate that DG modification by Pomt1/2 results in core M3 capped with matriglycan, and that this is required to reinforce the sarcolemma and enable skeletal muscle health and neuromuscular strength.

Keywords:   O-mannosylation; Dystroglycan; Like-acetylglucosaminyltransferase 1 (LARGE1); Matriglycan; Protein O-mannosyltransferase 1 (POMT1); Skeletal muscle

DOI:  https://doi.org/10.1186/s13395-024-00370-2
MedComm (2020). 2025 Jan;6(1): e70030

Sarcopenia and cachexia: molecular mechanisms and therapeutic interventions.

Tiantian Wang, Dong Zhou, Zhen Hong.

  Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

Keywords:  cachexia; molecules; pathogenesis; sarcopenia; targeted therapy

DOI:  https://doi.org/10.1002/mco2.70030
Ann Neurol. 2025 Jan 06.

Loss of TDP-43 Splicing Repression Occurs in Myonuclei of Inclusion Body Myositis Patients.

Chiseko Ikenaga, Andrew B Wilson, Katherine E Irwin, Aswathy Peethambaran Mallika, Collin Kilgore, Irika R Sinha, Elizabeth H Michelle, Jonathan P Ling, Philip C Wong, Thomas E Lloyd.

OBJECTIVE: Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by endomysial inflammation, rimmed vacuoles, and cytoplasmic mislocalization of transactive response DNA-binding protein 43 (TDP-43). We aimed to determine whether loss of TDP-43 splicing repression led to the production of "cryptic peptides" that could be detected in muscle biopsies as a useful biomarker for IBM.
METHODS: We used an antisera against a neoepitope encoded by a TDP-43-dependent cryptic exon within hepatoma-derived growth factor-like protein 2 (HDGFL2) for immunohistochemical analysis on muscle biopsy samples of 122 patients with IBM, 181 disease controls, and 16 healthy controls without abnormal muscle pathology. In situ hybridization was also utilized to detect the localization of cryptic HDGFL2 transcripts.
RESULTS: We found cryptic HDGFL2 peptides localized within myonuclei from muscle biopsies in 79 of 122 patients with IBM (65%), and this staining correlated with TDP-43 depletion. In contrast, cryptic HDGFL2 immunoreactivity was absent in 197 muscle biopsies from a variety of disease controls, except for 2 patients with vacuolar myopathies. Notably, we show that cryptic HDGFL2 transcripts are accompanied by the detection of cryptic HDGFL2 in muscle fibers of IBM without rimmed vacuoles and TDP-43 aggregates.
INTERPRETATION: Together, our findings establish that loss of TDP-43 splicing repression occurs in myonuclei of IBM skeletal muscle and suggest that detection of cryptic peptides in muscle biopsies may be a useful biomarker. We suggest that a therapeutic strategy designed to restore TDP-43 function should be considered to attenuate the degeneration of skeletal muscle in this devastating disease. ANN NEUROL 2025.

DOI: https://doi.org/10.1002/ana.27167
Eur J Appl Physiol. 2025 Jan 08.

The effect of exercise and physical activity on skeletal muscle epigenetics and metabolic adaptations.

Gregg Mallett.

  Physical activity (PA) and exercise elicit adaptations and physiological responses in skeletal muscle, which are advantageous for preserving health and minimizing chronic illnesses. The complicated atmosphere of the exercise response can be attributed to hereditary and environmental variables. The primary cause of these adaptations and physiological responses is the transcriptional reactions that follow exercise, whether endurance- (ET) or resistance- training (RT). As a result, the essential metabolic and regulatory pathways and myogenic genes associated with skeletal muscle alter in response to acute and chronic exercise. Epigenetics is the study of the relationship between genetics and the environment. Exercise evokes signaling pathways that strongly alter myofiber metabolism and skeletal muscle physiological and contractile properties. Epigenetic modifications have recently come to light as essential regulators of exercise adaptations. Research has shown various epigenetic markers linked to PA and exercise. The most critical epigenetic alterations in gene transcription identified are DNA methylation and histone modifications, which are associated with the transcriptional response of skeletal muscle to exercise and facilitate the modification to exercise. Other changes in the epigenetic markers are starting to emerge as essential processes for gene transcription, including acetylation as a new epigenetic modification, mediated changes by methylation, phosphorylation, and micro-RNA (miRNA). This review briefly introduces PA and exercise and associated benefits, provides a summary of epigenetic modifications, and a fundamental review of skeletal muscle physiology. The objectives of this review are 1) to discuss exercise-induced adaptations related to epigenetics and 2) to examine the interaction between exercise metabolism and epigenetics.

Keywords:  Chronic disease; Endurance training; Metabolism; Resistance training; Skeletal muscle epigenetics

DOI:  https://doi.org/10.1007/s00421-025-05704-6
Biology (Basel). 2024 Dec 21. pii: 1080. [Epub ahead of print]13(12):

Cannabis (THC) Aggravates the Deleterious Effects of Alcohol (EtOH) on Skeletal Muscles' Mitochondrial Respiration: Modulation by Age and Metabolic Phenotypes.

Anne-Laure Charles, Margherita Giannini, Alain Meyer, Anne Charloux, Samy Talha, Thomas Vogel, Jean-Sébastien Raul, Valérie Wolff, Bernard Geny.

  The anti-inflammatory and analgesic properties of cannabis might be useful to treat muscle diseases, including those linked or not to alcohol. Nevertheless, delta 9 tetrahydrocannabinol (THC) and ethanol (EtOH), often used concomitantly, can have deleterious effects on cardiac mitochondria. We therefore determined whether EtOH, alone and associated with THC, impairs skeletal muscle mitochondrial respiration. Further, we investigated potential modulation by metabolic phenotype and age by analyzing predominantly glycolytic gastrocnemius and oxidative soleus muscles in young and middle-aged rats (12 and 49 weeks). Considering the gastrocnemius, EtOH impaired mitochondrial respiration in a similar manner in young- and middle-aged muscles (-34.97 ± 2.97% vs. -37.50 ± 6.03% at 2.1 × 10-5 M; p < 0.05). Interestingly, concomitant THC aggravated EtOH-related mitochondrial impairment in young gastrocnemius (-49.92 ± 1.69%, vs. -34.97 ± 2.97 p < 0.05). Concerning the soleus, EtOH alone mainly decreased young muscle mitochondrial respiration (-42.39 ± 2.42% vs. -17.09 ± 7.61% at 2.1 × 10-5 M, p < 0.001, at 12 and 49 weeks). The soleus was less impaired at 12 weeks by THC and EtOH association than the gastrocnemius (-49.92 ±1.69 vs. -27.22 ± 8.96% in gastrocnemius and soleus, respectively, p < 0.05). In conclusion, EtOH, alone and associated with THC, significantly impairs skeletal muscle mitochondrial respiration and THC aggravates EtOH-induced effects on young glycolytic muscle. Age and metabolic phenotypes modulate these deleterious effects, with the glycolytic muscles of young rats being more prone to impairments than oxidative muscles.

Keywords:  EtOH; THC; aging; alcohol; cannabis; ethanol; glycolytic; marijuana; metabolic phenotype; mitochondria; oxidative; skeletal muscle; tetrahydrocannabinoid

DOI:  https://doi.org/10.3390/biology13121080
Antioxidants (Basel). 2024 Dec 11. pii: 1509. [Epub ahead of print]13(12):

Accelerated Sarcopenia Phenotype in the DJ-1/Park7-Knockout Zebrafish.

Kristine O Rostad, Tobias Trognitz, Ann Kristin Frøyset, Ersilia Bifulco, Kari E Fladmark.

  Age-dependent loss of muscle mass and function is associated with oxidative stress. DJ-1/Park7 acts as an antioxidant through multiple signalling pathways. DJ-1-knockout zebrafish show a decline in swimming performance and loss of weight gain between 6 and 9 months of age. Here, we address the degree to which this is associated with muscle degeneration and identify molecular changes preceding dysregulation of muscle performance. Loss of DJ-1 reduced the skeletal muscle fibre cross-section area. The highly mitochondrial-dependent red slow muscle was more affected than the white muscle, and degeneration of sub-sarcolemma red muscle mitochondria was observed. Using TandemMassTag-based quantitative proteomics, we identified a total of 3721 proteins in the multiplex sample of 4 and 12-month-old muscles. A total of 68 proteins, mainly associated with inflammation and mitochondrial function, were dysregulated in the young DJ-1-null adults, with Annexin A3, Sphingomyelin phosphodiesterase acid-like 3B, Complement C3a, and 2,4-dienoyl CoA reductase 1 being the most affected. The loss of DJ-1 also accelerated molecular features associated with sarcopenia, such as a decrease in the NAD+/NADH ratio and a reduction in Prostaglandin reductase 2 and Cytosolic glycerol-3-phosphate dehydrogenase levels. In view of the experimental power of zebrafish, the DJ-1-null zebrafish makes a valuable model for understanding the connection between oxidative stress and age-dependent muscle loss and function.

Keywords:  DJ-1; Parkinson’s disease; mitochondria; park7; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.3390/antiox13121509
Biomed Rep. 2025 Mar;22(3): 39

Exploring the potential regulation of DUOX in thyroid hormone‑autophagy signaling via IGF‑1 in the skeletal muscle (Review).

Andreas Adiwinata Then, Hanna Goenawan, Ronny Lesmana, Andreas Christoper, Nova Sylviana, Julia Windi Gunadi.

  Dual oxidases (DUOX) are enzymes that have the main function in producing reactive oxygen species (ROS) in various tissues. DUOX also play an important role in the synthesis of H2O2, which is essential for the production of thyroid hormone. Thyroid hormones can influence the process of muscle development through direct stimulation of ROS, 5' AMP-activated protein kinase (AMPK) and mTOR and indirect effect autophagy and the insulin-like growth factor 1 (IGF-1) pathway. IGF-1 signaling controls autophagy in two ways: Inhibiting autophagy through activation of the PI3K/AKT/mTOR/MAPK pathway and promoting mitophagy through the nuclear factor erythroid 2-related factor 2-binding receptor Bcl2/adenovirus E1B 19 kDa protein-interacting protein 3. Thyroid hormone deficiency caused by the absence of DUOX should be considered because it might have a significant effect on the growth of skeletal muscle. The effect of DUOX regulation on thyroid hormone autophagy via IGF-1 in skeletal muscle has not been well investigated. The present review discussed the regulatory interactions between DUOX, thyroid hormone, IGF-1 and autophagy, which can influence skeletal muscle development.

Keywords:  autophagy; dual oxidases; insulin-like growth factor 1; skeletal muscle; thyroid hormone

DOI:  https://doi.org/10.3892/br.2024.1917
J Physiol. 2025 Jan 06.

Enhancing muscle and brain resilience: The role of prehabilitative exercise in mitigating disuse effects.

Casper Soendenbroe, Carl-Johan Boraxbekk, Abigail L Mackey.

  Short-term disuse leads to rapid declines in muscle mass and strength. These declines are driven by changes at all levels of the neuromuscular system; the brain, spinal cord and skeletal muscle. In addition to neural input from the central and peripheral nervous systems to the muscle, molecular factors originating in the muscle can be transported to the central nervous system. These interactions highlight the interconnected nature of the neuromuscular system during exercise and disuse, and form the basis for this review. Although it is well known that physical activity confers a myriad of health benefits, a recent interest in targeted exercise before periods of disuse or immobility, termed prehabilitation, has emerged. Clinical studies within multiple medical specialities suggest positive effects of prehabilitative exercise on preserving muscle function, reducing adverse outcomes and shortening the length of hospital stay. Yet, the studies available are few and heterogeneous, and the underlying protective mechanisms of prehabilitative exercise remain elusive. In this review, we examine the ramifications of disuse across all levels of the neuromuscular system and explore how prehabilitation may counteract these effects. We summarize these mechanisms into three primary categories: (1) enhancing pre-disuse capacity; (2) establishing neural and muscle memory; and (3) fostering structural adaptations in both muscle and brain.

Keywords:  muscle memory; muscle–brain cross‐talk; neuromuscular system; physical activity; prehabilitation

DOI:  https://doi.org/10.1113/JP284499
J Physiol. 2025 Jan 10.

Previous short-term disuse dictates muscle gene expression and physiological adaptations to subsequent resistance exercise.

Martino V Franchi, Julián Candia, Fabio Sarto, Giuseppe Sirago, Giacomo Valli, Matteo Paganini, Lisa Hartnell, Emiliana Giacomello, Luana Toniolo, Elena Monti, Leonardo Nogara, Tatiana Moro, Antonio Paoli, Marta Murgia, Lorenza Brocca, Maria Antonietta Pellegrino, Bruno Grassi, Roberto Bottinelli, Giuseppe De Vito, Luigi Ferrucci, Marco V Narici.

  Short-term unloading experienced following injury or hospitalisation induces muscle atrophy and weakness. The effects of exercise following unloading have been scarcely investigated. We investigated the functional and molecular adaptations to a resistance training (RT) programme following short-term unloading. Eleven males (22.09 ± 2.91 years) underwent 10 days of unilateral lower limb suspension (ULLS) followed by 21 days of knee extensor RT (three times/week). Data collection occurred at Baseline (LS0), after ULLS (LS10) and at active recovery (AR21). Knee extensor maximum voluntary contraction (MVC) was evaluated. Quadriceps volume was estimated by ultrasonography. Muscle fibre cross-sectional area, fibre type distribution, glycogen content and succinate dehydrogenase (SDH) activity were measured from vastus lateralis biopsies. Mitochondrial-related proteins were quantified by western blot and transcriptional responses were assessed by RNA sequencing. Following ULLS, quadriceps volume and MVC decreased significantly (3.7%, P < 0.05; 29.3%, P < 0.001). At AR21 (vs. LS10), MVC was fully restored (42%) and quadriceps volume increased markedly (18.6%, P < 0.001). Glycogen content and whole-body water increased at AR21 (14%, P < 0.001; 3.1%, P < 0.05). We observed a marked increase in fibre type I at AR21 (38%, P < 0.05). SDH immunoreactivity increased significantly after exercise (20%, P < 0.001). Mitochondrial fusion (MFN1, MFN2 and OPA1) and fission (DRP1) proteins were markedly increased by RT, and the most differentially expressed genes belonged to oxidative phosphorylation pathways. In contrast with what is usually observed after RT, oxidative metabolism, slow fibre type and mitochondrial dynamics were enhanced beyond expected. We propose that prior exposure to short-term muscle unloading may drive the nature of molecular adaptations to subsequent RT. KEY POINTS: Short-term unloading is often experienced during recovery from injuries and hospitalisation, leading to loss of muscle mass and strength. Although exercise can be beneficial in mitigating/reversing such alterations during disuse, only a few studies have focused on the effects of exercise following muscle unloading. With an integrative physiological approach, we aimed to elucidate the basic mechanisms of muscle function recovery in response to 21 days of resistance exercise that followed 10 days of unilateral lower limb suspension (ULLS), assessing whether the mechanisms underlying recovery are defined by a specific reversal of those that occurred during disuse. Resistance training was successful in recovering functional and structural muscle properties after 10 days of ULLS, but in contrast with what is usually observed in response to this training modality, oxidative metabolism and slow fibre type were mostly enhanced. We propose that prior exposure to short-term muscle unloading may drive the adaptations to subsequent exercise.

Keywords:  exercise physiology; gene expression; muscle adaptation; muscle atrophy; muscle physiology; muscle plasticity; resistance training; unloading responses

DOI:  https://doi.org/10.1113/JP287003
Genes (Basel). 2024 Dec 20. pii: 1631. [Epub ahead of print]15(12):

Role of the PPARGC1A Gene and Its rs8192678 Polymorphism on Sport Performance, Aerobic Capacity, Muscle Adaptation and Metabolic Diseases: A Narrative Review.

David Varillas-Delgado.

   BACKGROUND/OBJECTIVES: The PPARGC1A gene, encoding the PGC-1α protein, is a critical regulator of energy metabolism, influencing mitochondrial biogenesis, fatty acid oxidation, and carbohydrate metabolism. This narrative review aims to evaluate the role of the PPARGC1A gene, with a specific focus on the c.1444G<A polymorphism (rs8192678), in sports performance, including its impact on aerobic capacity, muscle adaptation, and its potential implications for metabolic health.
METHODS: A comprehensive literature search was conducted using databases such as PubMed, Scopus, Science Direct, and Web of Science, following PRISMA guidelines. Studies investigating the rs8192678 polymorphism in athletes, its relationship with physical performance, and its broader metabolic effects were included. Data were synthesized qualitatively, and heterogeneity among findings was assessed. The rs8192678 polymorphism influences sports performance differently.
RESULTS: the G allele is associated with enhanced mitochondrial efficiency, higher aerobic capacity, and a greater proportion of fatigue-resistant type I muscle fibers, benefiting endurance sports like cycling and triathlon. Conversely, the A allele correlates with reduced mitochondrial biogenesis and oxidative capacity, potentially impairing endurance but showing possible utility in strength-based sports. Furthermore, the A allele is linked to increased risks of metabolic conditions, including type 2 diabetes and obesity. Discrepancies in results highlight the influence of genetic, environmental, and training interactions.
CONCLUSIONS: the PPARGC1A rs8192678 polymorphism plays a significant role in athletic performance and metabolic regulation. While the G allele confers advantages in endurance sports, the A allele presents mixed implications for strength and metabolic health. These findings support the potential for genetic profiling in personalized training and health interventions but emphasize the need for further research to clarify genotype-environment interactions.

Keywords:  PGC-1α protein; PPARGC1A gene; metabolic diseases; muscle adaptation; sport performance

DOI:  https://doi.org/10.3390/genes15121631
Physiol Rep. 2025 Jan;13(1): e70166

miRNA-1 regulation is necessary for mechanical overload-induced muscle hypertrophy in male mice.

Shengyi Fei, Blake D Rule, Joshua S Godwin, C Brooks Mobley, Michael D Roberts, Ferdinand von Walden, Ivan J Vechetti.

  MicroRNAs (miRNAs) are small, noncoding RNAs that play a critical role in regulating gene expression post-transcriptionally. They are involved in various developmental and physiological processes, and their dysregulation is linked to various diseases. Skeletal muscle-specific miRNAs, including miR-1, play a crucial role in the development and maintenance of skeletal muscle. It has been demonstrated that the expression of miR-1 decreases by approximately 50% in response to hypertrophic stimuli, suggesting its potential involvement in muscle hypertrophy. In our study, we hypothesize that reduction of miR-1 levels is necessary for skeletal muscle growth due to its interaction to essential pro-growth genes. Promoting a smaller reduction of miR-1 levels, we observed a blunted hypertrophic response in mice undergoing a murine model of muscle hypertrophy. In addition, our results suggest that miR-1 inhibits the expression of Itm2a, a membrane-related protein, as potential miR-1-related candidate for skeletal muscle hypertrophy. While the exact mechanism in muscle hypertrophy has not been identified, our results suggest that miR-1-regulated membrane proteins are important for skeletal muscle hypertrophy.

Keywords:  hypertrophy; miR‐1; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70166
Cell Commun Signal. 2025 Jan 09. 23(1): 17

Regulation of calcium homeostasis in endoplasmic reticulum-mitochondria crosstalk: implications for skeletal muscle atrophy.

Xuexin Li, Xin Zhao, Zhengshan Qin, Jie Li, Bowen Sun, Li Liu.

  This review comprehensively explores the critical role of calcium as an essential small-molecule biomessenger in skeletal muscle function. Calcium is vital for both regulating muscle excitation-contraction coupling and for the development, maintenance, and regeneration of muscle cells. The orchestrated release of calcium from the endoplasmic reticulum (ER) is mediated by receptors such as the ryanodine receptor (RYR) and inositol 1,4,5-trisphosphate receptor (IP3R), which is crucial for skeletal muscle contraction. The sarcoendoplasmic reticulum calcium ATPase (SERCA) pump plays a key role in recapturing calcium, enabling the muscle to return to a relaxed state. A pivotal aspect of calcium homeostasis involves the dynamic interaction between mitochondria and the ER. This interaction includes local calcium signaling facilitated by RYRs and a "quasi-synaptic" mechanism formed by the IP3R-Grp75-VDAC/MCU axis, allowing rapid calcium uptake by mitochondria with minimal interference at the cytoplasmic level. Disruption of calcium transport can lead to mitochondrial calcium overload, triggering the opening of the mitochondrial permeability transition pore and subsequent release of reactive oxygen species and cytochrome C, ultimately resulting in muscle damage and atrophy. This review explores the complex relationship between the ER and mitochondria and how these organelles regulate calcium levels in skeletal muscle, aiming to provide valuable perspectives for future research on the pathogenesis of muscle diseases and the development of prevention strategies.

Keywords:  Atrophy; Calcium; Endoplasmic reticulum; Mitochondria; Skeletal muscle

DOI:  https://doi.org/10.1186/s12964-024-02014-w
Free Radic Biol Med. 2025 Jan 02. pii: S0891-5849(24)01169-9. [Epub ahead of print]

The role of skeletal muscle respiratory capacity in exercise performance.

Pablo M Garcia-Roves, Jorge Alvarez-Luis, Sandra Cutanda-Tesouro.

  The connection between the respiratory capacity of skeletal muscle mitochondria and athletic performance is widely acknowledged in contemporary research. Building on a solid foundation of prior studies, current research has fostered an environment where scientists can effectively demonstrate how a tailored regimen of exercise intensity, duration, and frequency significantly boosts mitochondrial function within skeletal muscles. The range of exercise modalities is broad, spanning from endurance and high-intensity interval training to resistance-based exercises, allowing for an in-depth exploration of effective strategies to enhance mitochondrial respiratory capacity-a key factor in improving exercise performance, in other words offering a better skeletal muscle capacity to cope with exercise demands. By identifying optimal training strategies, individuals can significantly improve their performance, leading to better outcomes in their fitness and athletic endeavours. This review provides the prevailing insights on skeletal muscle mitochondrial respiratory capacity and its role in exercise performance, covering essential instrumental and methodological aspects, findings from animal studies, potential sex differences, a review of existing human studies, and considerations for future research directions.

Keywords:  Exercise; athletic performance; mitochondrial respiratory capacity; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2024.12.060
bioRxiv. 2024 Dec 26. pii: 2024.12.26.628172. [Epub ahead of print]

Inhibition of Mitochondrial Fission Protein Drp1 Ameliorates Myopathy in the D2-mdx Model of Duchenne Muscular Dystrophy.

H Grace Rosen, Nicolas J Berger, Shantel N Hodge, Atsutaro Fujishiro, Jared Lourie, Vrusti Kapadia, Melissa A Linden, Eunbin Jee, Jonghan Kim, Yuho Kim, Kai Zou.

Although current treatments for Duchenne Muscular Dystrophy (DMD) have proven to be effective in delaying myopathy, there remains a strong need to identify novel targets to develop additional therapies. Mitochondrial dysfunction is an early pathological feature of DMD. A fine balance of mitochondrial dynamics (fission and fusion) is crucial to maintain mitochondrial function and skeletal muscle health. Excessive activation of Dynamin-Related Protein 1 (Drp1)-mediated mitochondrial fission was reported in animal models of DMD. However, whether Drp1-mediated mitochondrial fission is a viable target for treating myopathy in DMD remains unknown. Here, we treated a D2-mdx model of DMD (9-10 weeks old) with Mdivi-1, a selective Drp1 inhibitor, every other day (i.p. injection) for 5 weeks. We demonstrated that Mdivi-1 effectively improved skeletal muscle strength and reduced serum creatine kinase concentration. Mdivi-1 treatment also effectively inhibited mitochondrial fission regulatory protein markers, Drp1(Ser616) phosphorylation and Fis1 in skeletal muscles from D2-mdx mice, which resulted in reduced content of damaged and fragmented mitochondria. Furthermore, Mdivi-1 treatment attenuated lipid peroxidation product, 4-HNE, in skeletal muscle from D2-mdx mice, which was inversely correlated with muscle grip strength. Finally, we revealed that Mdivi-1 treatment downregulated Alpha 1 Type I Collagen (Col1a1) protein expression, a marker of fibrosis, and Interleukin-6 (IL-6) mRNA expression, a marker of inflammation. In summary, these results demonstrate that inhibition of Drp1-mediated mitochondrial fission by Mdivi-1 is effective in improving muscle strength and alleviating muscle damage in D2-mdx mice. These improvements are associated with improved skeletal muscle mitochondrial integrity, leading to attenuated lipid peroxidation.

DOI: https://doi.org/10.1101/2024.12.26.628172
Cell Tissue Res. 2025 Jan 09.

In situ spatial transcriptomic analysis of human skeletal muscle using the Xenium platform.

Nejc Umek, Marija Meznarič, Žiga Šink, Kaja Blagotinšek Cokan, Uršula Prosenc Zmrzljak, Simon Horvat.

  Traditional transcriptomic studies often overlook the complex heterogeneity of skeletal muscle, as they typically isolate RNA from mixed muscle fibre and cell populations, resulting in an averaged transcriptomic profile that obscures fibre type-specific differences. This study assessed the potential of the recently developed Xenium platform for high-resolution spatial transcriptomic analysis of human skeletal muscle histological sections. Human vastus lateralis muscle samples from two individuals were analysed using the Xenium platform and Human Multi-Tissue and Cancer Panel targeting 377 genes complemented by staining of successive sections for Myosin Heavy Chain isoforms to differentiate between type 1 and type 2 muscle fibres. Manual segmentation of muscle fibres allowed accurate comparisons of transcript densities across fibre types and subcellular regions, overcoming limitations in the platform's automated segmentation. The analysis revealed higher transcript density in type 1 fibres, particularly in nuclear and perinuclear areas, and identified 191 out of 377 genes with differential expression between muscle fibres and perimysium. Genes such as PROX1, S100A1, LGR5, ACTA2, and LPL exhibited higher expression in type 1 fibres, whereas PEBP4, CAVIN1, GATM, and PVALB in type 2 fibres. We demonstrated that the Xenium platform is capable of high-resolution spatial in situ transcriptomic analysis of skeletal muscle histological sections. This study demonstrates that, with manual segmentation, the Xenium platform effectively performs fibre type-specific transcriptomic analysis, providing new insights into skeletal muscle biology.

Keywords:  Muscle fibre; Segmentation; Skeletal muscle; Spatial transcriptomic; Xenium platform

DOI:  https://doi.org/10.1007/s00441-024-03945-z
Appl Physiol Nutr Metab. 2025 Jan 06.

Skeletal muscle oxidative capacity related to intramyocellular lipid in young but not in older individuals.

Akito Yoshiko, Kana Shiozawa, Shiori Niwa, Hideyuki Takahashi, Teruhiko Koike, Kohei Watanabe, Keisho Katayama, Hiroshi Akima.

Skeletal muscles contain lipids inside and outside cells, namely intramyocellular lipids (IMCL) and extramyocellular lipids (EMCL), respectively; lipids have also been found to be interspersed between these muscles as adipose tissue, namely intermuscular adipose tissue (IMAT). Metabolized IMCL has been recognized as an important substrate for energy production and their metabolism is determined by the muscle oxidative capacity. Therefore, it has been speculated that muscle oxidative capacity is related to muscle lipid content. Excessive accumulation of EMCL and IMAT has been confirmed in older individuals, leading to metabolic disorders and a decline in muscle strength. However, whether EMCL and IMAT contribute to muscle lipid metabolism remains unknown. This study aimed to investigate whether muscle oxidative capacity is related to IMCL, EMCL, and IMAT in young and older individuals. A total of 18 young and 14 older individuals were included and their muscle oxidative capacity was assessed based on the recovery rate of muscle oxygen saturation after exercise, using near-infrared spectroscopy of the medial gastrocnemius. IMCL, EMCL, and IMAT were assessed using magnetic resonance spectroscopy and imaging. A relationship between muscle oxidative capacity and IMCL was confirmed in young (r=-0.47, P<0.05) but not older individuals (r=0.22, P=0.45). Muscle oxidative capacity was not related to EMCL or IMAT in either young or older individuals. These results suggest that IMCL in young individuals can contribute to muscle lipid metabolism, but not EMCL and IMAT, and this relationship differs with aging.

DOI: https://doi.org/10.1139/apnm-2024-0272
Life Sci. 2025 Jan 03. pii: S0024-3205(24)00947-0. [Epub ahead of print]362 123357

Utilizing zebrafish models to elucidate mechanisms and develop therapies for skeletal muscle atrophy.

Jing Zhao, Yimeng Fang, Junying Qu, Jiaxuan He, Jia Yi, Rongbing Chen, Qinsi Yang, Kun Zhang, Wei Wu, Da Sun, Bin Fang.

  Skeletal muscle atrophy, resulting from an imbalance in muscle protein synthesis and degradation, compromises muscle quality and function, imposing significant burdens on movement and metabolic stability. Animal models are crucial for understanding the mechanisms of skeletal muscle atrophy and developing clinical prevention and treatment strategies. Zebrafish, as small aquatic vertebrates, exhibit high genetic homology with humans and offer advantages such as rapid reproduction, development, and transparent embryos. Their physiological and anatomical similarities to mammals, including a substantial proportion of skeletal muscle and observable swimming behavior reflecting body dysfunction, make zebrafish an ideal model for studying skeletal muscle-related diseases. This review outlines the development of zebrafish skeletal muscle and highlights key pathways regulating muscle proteins, emphasizing their anatomical and genetic consistency with humans. Various zebrafish models of skeletal muscle atrophy created through physical, chemical, and gene-editing methods are systematically summarized. Current challenges and proposed improvement strategies are also discussed to enhance the reliability and applicability of zebrafish models, providing a comprehensive reference for advancing research on skeletal muscle atrophy.

Keywords:  Muscle disease; Muscle protein; Skeletal muscle atrophy; Zebrafish

DOI:  https://doi.org/10.1016/j.lfs.2024.123357
Int J Biol Macromol. 2025 Jan 04. pii: S0141-8130(25)00066-2. [Epub ahead of print]294 139517

m6A modified pre-miR-503-5p contributes to myogenic differentiation through the activation of mTOR pathway.

Yalong Su, Kaiping Deng, Zhipeng Liu, Zhen Zhang, Zhilin Liu, Zidi Huang, Yuhao Gao, Ke Gao, Yixuan Fan, Yanli Zhang, Feng Wang.

  The post-transcriptional regulation of epigenetic modification is a hot topic in skeletal muscle development research. Both m6A modifications and miRNAs have been well-established as crucial regulators in skeletal muscle development. However, the interacting regulatory mechanisms between m6A modifications and miRNAs in skeletal muscle development remain unclear. In this study, miRNA sequencing analysis of goat primary myoblasts (GPMs) pre- and post-differentiation revealed that miR-503-5p was upregulated during myogenic differentiation, and its precursor was identified to contain m6A modification sites. Combined analysis of RIP, qRT-PCR and mRNA stability assay showed that Ythdf2 could recognize and bind the m6A site on pre-miR-503-5p, thereby facilitating the maturation of pre-miR-503-5p in an m6A-dependent manner. Moreover, the overexpression of miR-503-5p significantly inhibits the proliferation of GPMs, promotes myogenic differentiation, and enhances mitochondrial biogenesis while activating the mTOR pathway. However, the suppression of mTOR activity can effectively counteract the accelerated myogenic differentiation induced by miR-503-5p overexpression. Collectively, our results indicate that Ythdf2-dependent m6A modification facilitates the maturation of pre-miR-503-5p, thereby promoting skeletal muscle differentiation through the activation of the mTOR pathway. These insights lay a valuable foundation for further investigation into the complexities of skeletal muscle development and the potential implications of epigenetic regulation in this process.

Keywords:  MicroRNA maturation; Myogenesis; m6A modification; mTOR pathway; miR-503-5p

DOI:  https://doi.org/10.1016/j.ijbiomac.2025.139517
bioRxiv. 2024 Dec 23. pii: 2024.12.23.629471. [Epub ahead of print]

Ephrin-A5 or EphA7 stimulation is anti-proliferative for human rhabdomyosarcoma in vitro.

A Cecchini, L Ceccon, A Chen, J C Schwesig, Ddw Cornelison.

Rhabdomyosarcoma (RMS) is a tumor which resembles skeletal muscle. Current treatments are limited to surgery and non-targeted chemotherapy, highlighting the need for alternative therapies. Differentiation therapy uses molecules that act to shift the tumor cells' phenotype from proliferating to differentiated, which in the case of skeletal muscle includes exit from the cell cycle and potentially fusion into myofibers. We previously identified EphA7 expressed on terminally differentiated myocytes as a potent driver of skeletal muscle differentiation: stimulation of ephrin-A5-expressing myoblasts with EphA7 causes them to undergo rapid, collective differentiation. We therefore tested EphA7 as a candidate molecule for differentiation therapy on human RMS (hRMS) cell lines. Surprisingly, EphA7 had a lesser effect than ephrin-A5, a difference explained by the divergent suite of Ephs and ephrins expressed by hRMS. We show that in hRMS ephrin-A5 binds and signals to EphA8 and EphA7 binds and signals to ephrin-A2, and that Fc chimeras of both molecules are potent inhibitors of hRMS proliferation. These results identify key differences between hRMS and normal muscle cells and support further research into Eph:ephrin signaling as potential differentiation therapies.
Summary statement: This study identifies EphA7 and ephrin-A5 as external regulators of rhabdomyosarcoma proliferation, highlighting ephrin-A5 as a potential candidate for differentiation therapy in future cancer treatments.

DOI: https://doi.org/10.1101/2024.12.23.629471
Methods Mol Biol. 2025 Jan 09.

Analyzing Muscle Stem Cell Function Ex Vivo.

Julia von Maltzahn.

  Muscle stem cells (MuSCs) lose a large proportion of their characteristics when removed from their niche, hampering the analysis of muscle stem cell functionality. However, the isolation and culture of single floating myofibers with their adjacent muscle stem cells allow the short-term culture and manipulation of muscle stem cells in conditions as close as possible to the endogenous niche. Here, the isolation, culture and transfection with siRNA of muscle stem cells on their adjacent myofibers from young as well as old mice are described.

Keywords:  Aging; Differentiation; Muscle stem cell; Myofiber; Satellite cell; Stem cell

DOI:  https://doi.org/10.1007/7651_2024_589
Cells. 2024 Dec 20. pii: 2120. [Epub ahead of print]13(24):

Mechanisms and Countermeasures for Muscle Atrophy in Microgravity.

Yizhou Liu, Xiaojian Cao, Qiuzhi Zhou, Chunchu Deng, Yujie Yang, Danxia Huang, Hongmei Luo, Song Zhang, Yajie Li, Jia Xu, Hong Chen.

  Previous studies have revealed that muscle atrophy emerges as a significant challenge faced by astronauts during prolonged missions in space. A loss in muscle mass results in a weakening of skeletal muscle strength and function, which will not only contribute to a decline in overall physical performance but also elevate the risk of various age-related diseases. Skeletal muscle atrophy in the microgravity environment is thought to be associated with changes in energy metabolism, protein metabolism, calcium ion homeostasis, myostatin levels, and apoptosis. Modulating some pathways could be a promising approach to mitigating muscle atrophy in the microgravity environment. This review serves as a comprehensive summary of research on the impact of microgravity on skeletal muscle, with the aim of providing insights into its pathogenesis and the development of effective treatments.

Keywords:  microgravity; muscle atrophy; muscle regeneration; skeleton muscle; spaceflight

DOI:  https://doi.org/10.3390/cells13242120
Clin Exp Pharmacol Physiol. 2025 Mar;52(3): e70010

Restoring Autophagy by Exercise Ameliorates Insulin Resistance Partly via Calcineurin-Driven TFEB Nuclear Translocation.

Ping Wang, Jiaxin Li, Chun Guang Li, Xian Zhou, Xiaolong Chen, Minghua Zhu, Hongjiang Wang.

  Exercise activates autophagy and lysosome system in skeletal muscle, which are known to play an important role in metabolic adaptation. However, the mechanism of exercise-activated autophagy and lysosome system in obese insulin resistance remains covert. In this study, we investigated the role of exercise-induced activation of autophagy and lysosome system in improving glucose metabolism of skeletal muscle. Male C57BL/6 mice were randomly divided into five groups: the chow diet (CD) group, the high-fat diet (HFD) group, the high-fat diet plus exercise (HFD-E) group and the HFD-E treated with calcineurin inhibitor FK506 (HFD-E-F) or saline (HFD-E-S) groups. The mice in exercise groups (HFD-E, HFD-E-F and HFD-E-S) were subjected to aerobic treadmill exercise (speed at 12 m/min for 1 h per session, 0° slope, 5 days per week for 12 weeks). Mice of HFD-E-F group were intraperitoneally administered FK506 (1 mg/kg), once each day for 2 weeks before the end of exercise. Expressions pTFEB, T-TFEB and autophagy-lysosome markers, including Beclin1, LC3, ULK1, SQSTM1, LAMP1, CTSD and CTSL proteins in gastrocnemius muscle were analysed. We demonstrated that HFD induced insulin resistance and decreased autophagy-lysosomal proteins and the exercise significantly increased transcription factor EB (TFEB) translocation from the cytoplasm to the nucleus, restored the impaired autophagy-lysosomal-related protein expressions, and improved glucose metabolism. The increase in TFEB nuclear translocation was partly blocked by the calcineurin inhibitor FK506. Our results suggest that exercise promotes autophagy and lysosome restoration by regulating calcineurin-mediated TFEB nuclear translocation, ultimately alleviating HFD-induced insulin resistance in mice skeletal muscle.

Keywords:  TFEB; autophagy and lysosome dysfunction; exercise; insulin resistance

DOI:  https://doi.org/10.1111/1440-1681.70010
Sci Rep. 2025 Jan 08. 15(1): 1329

Ribitol and ribose treatments differentially affect metabolism of muscle tissue in FKRP mutant mice.

Marcela P Cataldi, Qi L Lu.

Dystroglycanopathy is characterized by reduced or lack of matriglycan, a cellular receptor for laminin as well as other extracellular matrix proteins. Recent studies have delineated the glycan chain structure of the matriglycan and the pathway with key components identified. FKRP functions as ribitol-5-phosphate transferase with CDP-ribitol as the substrate for the extension of the glycan chain. Supplement of ribitol and ribose have been reported to increase the levels of CDP-ribitol in both cells and in muscles in vivo. Clinical trials with both ribitol and ribose have been reported for treating LGMD2I caused by mutations in the FKRP gene. Here we compared the comprehensive metabolite profiles of the skeletal muscle between ribitol-treated and ribose-treated FKRP mutant mice. The closely related pentose and pentitol show clearly differential impacts on metabolisms despite their similarity in enhancing the levels of CDP-ribitol and matriglycan synthesis. Supplement of ribitol changes lysophospholipid sub-pathway metabolite profiling with a trend towards normalization as reported in the muscle after AAV9-FKRP gene therapy. Ribose treatment significantly increases level of ribonate and elevates levels of advanced glycation end products. Further analysis is required to determine which metabolite is prudent to use for long-term daily treatment of dystroglycanopathies.

DOI: https://doi.org/10.1038/s41598-024-83661-4
FASEB Bioadv. 2025 Jan;7(1): e1481

Diacylglycerol kinase δ is required for skeletal muscle development and regeneration.

Hiromichi Sakai, Chiaki Murakami, Mayumi Takechi, Takeshi Urano, Fumio Sakane.

  Diacylglycerol kinase δ (DGKδ) phosphorylates diacylglycerol to produce phosphatidic acid. Previously, we demonstrated that down-regulation of DGKδ suppresses the myogenic differentiation of C2C12 myoblasts. However, the myogenic roles of DGKδ in vivo remain unclear. In the present study, we generated DGKδ-conditional knockout mice under the control of the myogenic factor 5 (Myf5) gene promoter, which regulates myogenesis and brown adipogenesis. The knockout mice showed a significant body weight reduction and apparent mass decrease in skeletal muscle, including the tibialis anterior (TA) muscle. Moreover, the thickness of a portion of the myofibers was reduced in DGKδ-deficient TA muscles. However, DGKδ deficiency did not substantially affect brown adipogenesis, suggesting that Myf5-driven DGKδ deficiency mainly affects muscle development. Notably, skeletal muscle injury induced by a cardiotoxin highly up-regulated DGKδ protein expression, and the DGKδ deficiency significantly reduced the thickness of myofibers, the expression levels of myogenic differentiation markers such as embryonic myosin heavy chain and myogenin, and the number of newly formed myofibers containing multiple central nuclei during muscle regeneration. DGKδ was strongly expressed in myogenin-positive satellite cells around the injured myofibers and centronucleated myofibers. These results indicate that DGKδ has important roles in muscle regeneration in activated satellite cells. Moreover, the conditional knockout mice fed with a high-fat diet showed increased fat mass and glucose intolerance. Taken together, these results demonstrate that DGKδ plays crucial roles in skeletal muscle development, regeneration, and function.

Keywords:  diacylglycerol kinase; glucose tolerance; muscle development; muscle regeneration; satellite cell; type II diabetes

DOI:  https://doi.org/10.1096/fba.2024-00134
EMBO J. 2025 Jan 06.

Two FAM134B isoforms differentially regulate ER dynamics during myogenesis.

Viviana Buonomo, Kateryna Lohachova, Alessio Reggio, Sara Cano-Franco, Michele Cillo, Lucia Santorelli, Rossella Venditti, Elena Polishchuk, Ivana Peluso, Lorene Brunello, Carmine Cirillo, Sara Petrosino, Malan Silva, Rossella De Cegli, Sabrina Di Bartolomeo, Cesare Gargioli, Paolo Swuec, Mirko Cortese, Alexandra Stolz, Ramachandra M Bhaskara, Paolo Grumati.

  Endoplasmic reticulum (ER) plasticity and ER-phagy are intertwined processes essential for maintaining ER dynamics. We investigated the interplay between two isoforms of the ER-phagy receptor FAM134B in regulating ER remodeling in differentiating myoblasts. During myogenesis, the canonical FAM134B1 is degraded, while its isoform FAM134B2 is transcriptionally upregulated. The switch, favoring FAM134B2, is an important regulator of ER morphology during myogenesis. FAM134B2 partial reticulon homology domain, with its rigid conformational characteristics, enables efficient ER reshaping. FAM134B2 action increases in the active phase of differentiation leading to ER restructuring via ER-phagy, which then reverts to physiological levels when myotubes are mature and the ER is reorganized. Knocking out both FAM134B isoforms in myotubes results in an aberrant proteome landscape and the formation of dilated ER structures, both of which are rescued by FAM134B2 re-expression. Our results underscore how the fine-tuning of FAM134B isoforms and ER-phagy orchestrate the ER dynamics during myogenesis providing insights into the molecular mechanisms governing ER homeostasis in muscle cells.

Keywords:  Autophagy; Endoplasmic Reticulum; FAM134B; Myogenesis; Reticulophagy

DOI:  https://doi.org/10.1038/s44318-024-00356-2