bims-moremu 2026-04-05 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–04–05
thirty papers selected by
Anna Vainshtein, Craft Science Inc.

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.
TRPV2 is essential for calcium signalling in the early stages of myogenesis.
Sex- and skeletal muscle-specific gene expression response of histone 3 lysine 27-modifying enzymes by voluntary running in mice.
Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.
TWEAK-induced alternative NF-κB signaling regulates Cxcl10 and Mymx to promote myoblast-to-myotube fusion and muscle regeneration.
FGF21 targets pathways which enhance insulin sensitivity in brown adipose, but not skeletal muscle in mice.
Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.
The Sirt2-Nur77 axis regulates muscle stem cell quiescence and senescence via epigenetic-metabolic synergy.
ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.
The Crucial Role of Exercise in Promoting Adolescent Muscle Development.
ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.
NAD+ subcellular partitioning mediated by miR-183 and miR-96 regulates muscle stem cell differentiation.
Fibro-Adipogenic Progenitors Regulate Orofacial Neuromuscular Junction Regeneration via Myostatin.
The metalloproteinase inhibitor Marimastat improves skeletal muscle regeneration when administered intravenously after myonecrosis induced by the venom of Bothrops asper.
Exercise increases transglutaminase 2 expression in skeletal muscle.
Neuronal growth regulator 1 modulates actin dynamics to control intracellular GLUT4 trafficking.
Insulin-independent glucose uptake in skeletal muscle by coupled SGLT and Na,K-ATPase transport.
Redox regulation in aging muscles: exercise as a key modulator to combat sarcopenia and frailty.
Exercise-derived exosomes mediate crosstalk between skeletal muscle, adipose tissue, and bone: mechanisms of inter-organ communication and tissue adaptation.
Effects of culture media glucose concentration on LHCN-M2 skeletal muscle cell viability, differentiation and metabolic phenotype: a proof-of-concept study.
Dietary restriction and aerobic exercise alleviate obesity-related skeletal muscle impairment via the miR-130/PPARγ axis and IGF-1/Akt/mTOR signaling activation.
Anabolic resistance in cancer cachexia: a role for sex and chemotherapy.
Exosomes: Molecular messengers shaping muscle physiology and growth.
Transcriptional Remodeling of Human Skeletal Muscle Following Sleep Restriction in Postmenopausal Women.
Distinct postsynaptic morphogenetic strategies across Drosophila embryonic muscles during neuromuscular junction formation.
Mitochondrial Localization Around Central Nuclei in Regenerating Skeletal Muscle Following Eccentric Contraction in Rat Model.
Activation of α7nAChR reduces inflammation and apoptosis, promoting muscle regeneration through the AKT-FOXO1 pathway.
Understanding Bioenergetics of Myogenic Differentiation of Human Mesenchymal Stem Cells Using Label-Free Imaging.
Muscle-to-CNS signaling in physiological homeostasis, aging, and disease.
Transcription Factor Acetylation and Cell Fate Control: A Molecular Switch in Hematopoiesis and Myogenesis.

Proc Natl Acad Sci U S A. 2026 Apr 07. 123(14): e2508286123

Mitochondrial remodeling in skeletal muscle underlies exercise-induced reversal of age-associated functional decline in mice and humans.

Esther García-Domínguez, Cristina García-Domínguez, José Luis Cabrera-Alarcón, María Del Mar Muñoz-Hernández, Pablo Hernansanz-Agustín, Andrea Curtabbi, Julio Domenech-Fernandez, Enrique Calvo, Jesús Vázquez, Antonio L Serrano, Pura Muñoz-Cánoves, Gloria Olaso-González, José Antonio Enríquez, María Carmen Gómez-Cabrera.

  Loss of skeletal muscle mass and strength are common manifestations of frailty in older people and are linked to reduced quality of life. However, whether mitochondria are mechanistically linked to frailty and how physical activity, or lack thereof, is involved in age-related functional decline are still unknown. We report that exercise-induced improvements in functional capacity, including reduced frailty in old mice, are dependent on mitochondrial adaptations in skeletal muscle at structural, enzymatic, and functional levels. Our preclinical study included a healthy aging mouse line, a transgenic model of robustness, and a muscle-specific mitochondrial-deficient mutant mice, allowing us to assess both mitochondrial plasticity with aging and the necessity of intact mitochondrial function for exercise-induced adaptations. These findings were corroborated by a cross-sectional human study examining the relationship between skeletal muscle mitochondrial function, age, and physical capacity. We analyzed biopsies from 30 donors (men and women, aged 17 to 99 y) stratified into young and older adults with varying functional statuses. Our results indicate that mitochondrial dysfunction in skeletal muscle is associated with the decline in locomotor muscle function in the elderly, highlighting the potential role of exercise or habitual physical activity in mitigating this phenotype. Notably, we demonstrate that skeletal muscle mitochondria maintain plasticity during aging in mice and humans, and that this preserved adaptability can be leveraged to improve muscle performance and overall functional capacity.

Keywords:  frailty; health span; mitochondrial function; proteomics; sarcopenia

DOI:  https://doi.org/10.1073/pnas.2508286123
Biochem Biophys Res Commun. 2026 Mar 25. pii: S0006-291X(26)00441-9. [Epub ahead of print]815 153677

TRPV2 is essential for calcium signalling in the early stages of myogenesis.

Yanzhu Chen, Kimiaki Katanosaka, Yuki Katanosaka.

  Skeletal muscle responds to stressors such as exercise and muscle injury by adaptive remodelling. The resilience of skeletal muscle involves not only mature muscle fibres but also the adjacent muscle satellite cells (MuSCs). We previously found that transient receptor potential vanilloid type 2 (TRPV2) is expressed in MuSCs and is essential for MuSC proliferation and activation in MuSC-specific conditional knockout mice. These mice show no mechanical-load-induced muscle hypertrophy and delayed injury-induced muscle regeneration. The effect of TRPV2 on Ca2+ signalling during early myogenesis is unknown; however, here, we demonstrate that tranilast, an inhibitor of TRPV2, suppressed IP3R-derived Ca2+ oscillations in early myogenesis. The addition of adenovirus (Ad)-TRPV2 or Ad-Cre recombinase to floxed-TRPV2 cells modulated TRPV2 expression, and demonstrated the TRPV2 dependence of IP3R and MEF2c expression, nuclear translocation of MEF2c, and Ca2+ oscillations. These findings indicate that TRPV2 regulates intracellular Ca2+ signalling during early myogenesis and highlight its potential as a target for the prevention and treatment of muscle disorders.

Keywords:  Ca(2+) signal; IP(3)R; MEF2c; MuSCs; Myogenesis; TRPV2

DOI:  https://doi.org/10.1016/j.bbrc.2026.153677
Physiol Rep. 2026 Apr;14(7): e70853

Sex- and skeletal muscle-specific gene expression response of histone 3 lysine 27-modifying enzymes by voluntary running in mice.

Daniel Gamu, Makenna Cameron, Yasmeen Jalil, Imen Zouaoui, Jada Sangha, Jonathan Kim.

  Skeletal muscle is highly plastic and capable of remodeling its contractile and metabolic properties depending on physical demands. Such remodeling requires modification of chromatin structure to support transcriptional activation and repression of gene programs. Chromatin dynamics depend, in part, on the acetylation and methylation of histone 3 lysine 27 (H3K27), which is controlled by several enzymes that add and remove these histone marks. Several histone post-translational modifications in muscle have been shown to be modulated by exercise. Here, we sought to examine whether major H3K27 regulators themselves are altered by endurance training. Male and female C57BL/6J mice were provided with voluntary running wheels for 6 weeks and compared to sex-matched sedentary controls with locked running wheels. We found that exercise altered gene expression of epigenetic machinery responsible for regulating acetylation and methylation enrichment in both a muscle- and sex-specific manner, including major H3K27 acetyltransferases and core components of the polycomb repressive complex-2. Our findings add to a growing body of evidence implicating H3K27 post-translational modifications, and thereby chromatin dynamics, as a mechanistic component of exercise-induced muscle remodeling.

Keywords:  exercise; histone acetylation/methylation; muscle adaptation; skeletal muscle

DOI:  https://doi.org/10.14814/phy2.70853
Histol Histopathol. 2026 Apr 01. 25071

Telocytes in skeletal muscle: Emerging players in homeostasis and repair/regeneration.

Irene Rosa, Eloisa Romano, Mirko Manetti.

Telocytes (TCs) have recently emerged as novel components of the skeletal muscle interstitium. They are distinguished from other stromal cells by their immunophenotypic profiles and, especially, unique ultrastructural traits. Specifically, TCs feature a small cell body and very long, thin telopodes with a moniliform appearance conferred by the alternation of slender segments (podomers) and small dilated portions (podoms). Experimental evidence suggests that, as part of the skeletal muscle stem cell niche, TCs may be involved in orchestrating satellite cell activation and myogenic differentiation through both direct physical interactions and paracrine signaling. Yet, further in-depth research is needed to uncover specific immunophenotypic signatures for skeletal muscle TCs within the niche, as well as to identify the signaling pathways by which they influence neighboring satellite cells and, possibly, other cellular components of the niche. In the present review, particular emphasis is placed on the putative strategic role of TCs in maintaining skeletal muscle tissue homeostasis, their involvement in muscle pathological alterations, and, most importantly, their possible role in the coordination of the regenerative response following injury. In perspective, the promising therapeutic potential of TC-based strategies to enhance skeletal muscle tissue repair/regeneration and restrain post-injury fibrosis is also discussed.

DOI: https://doi.org/10.14670/HH-25-071
Commun Biol. 2026 Apr 02.

TWEAK-induced alternative NF-κB signaling regulates Cxcl10 and Mymx to promote myoblast-to-myotube fusion and muscle regeneration.

Neena Lala-Tabbert, Allan Humphrey, Diana Ratsun, Nathalie Earl, Martine St-Jean, Eric C LaCasse, Robert G Korneluk.

Myoblast fusion is essential for skeletal muscle growth and repair, yet the upstream signals regulating this process remain incompletely understood. Here, we show that the cytokine TWEAK promotes myotube formation through activation of alternative NF-κB signaling. Transcriptomic profiling of TWEAK-treated myotubes reveals upregulation of Myomixer (Mymx) and the chemokine CXCL10, both critical for fusion. Mechanistically, the NF-κB member RelB directly binds the Mymx and Cxcl10 gene promoters, enhancing their transcription. Genetic or pharmacological disruption of this pathway impairs myoblast fusion in both C2C12 and primary mouse myoblasts, while Mymx overexpression rescues fusion in TWEAK-deficient myoblasts. In mouse models, TWEAK treatment enhances myotube formation during muscle regeneration, whereas loss of TWEAK reduces fusion efficiency. These findings identify TWEAK-alternative NF-κB signaling as a key regulator of muscle cell fusion through direct transcriptional control of Mymx and Cxcl10 and defines targetable pathways to enhance repair in muscle disease.

DOI: https://doi.org/10.1038/s42003-026-09975-3
Endocrinology. 2026 Apr 02. pii: bqag040. [Epub ahead of print]

FGF21 targets pathways which enhance insulin sensitivity in brown adipose, but not skeletal muscle in mice.

Matthew C Juber, Sheps King-McAlpin, Paul Buscaglia, Julien A Sebag, Matthew J Potthoff.

  Acute pharmacological administration of the endocrine hormone fibroblast growth factor 21 (FGF21) enhances insulin sensitivity. This acute insulin-sensitizing effect of FGF21 is mediated through direct signaling to brown adipose tissues. Since skeletal muscle is an important site of insulin-stimulated glucose intake and shares a common progenitor cell with brown adipocytes, we examined whether the beneficial effects of FGF21 administration could be enhanced by making skeletal muscle a FGF21-responsive target tissue. This was accomplished by ectopically expressing the FGF21 co-receptor, β-klotho, in skeletal muscle. Here, we demonstrate that under normal conditions, FGF21 does not enhance insulin-stimulated glucose uptake in skeletal muscle. In addition, generation of FGF21 responsiveness and direct signaling to skeletal muscle also has no effect on FGF21-mediated increases in whole-body or skeletal muscle insulin sensitivity. Instead, FGF21 uniquely signals to brown adipocytes to enhance insulin-stimulated glucose uptake. Therefore, to identify how FGF21 signals to brown adipocytes to enhance insulin sensitivity, we performed comprehensive phospho-proteomics in brown adipocytes in response to FGF21 and/or insulin. Our results indicate that FGF21 administration increases the phosphorylation of several proteins involved in the trafficking of GLUT4 in primary brown adipocytes. These results provide new insights into how FGF21 enhances insulin sensitivity.

Keywords:  FGF21; betaklotho; brown adipose; insulin; sensitivity; skeletal muscle

DOI:  https://doi.org/10.1210/endocr/bqag040
J Physiol. 2026 Apr 03.

Exercise training induces mitochondrial biogenesis, while high-fat diet increases the ability of mitochondria to use long and short-chain fatty acids.

Jessica L Dowling, Rachel M Handy, Nicole M Notaro, Sara M Frangos, David J Dyck, Graham P Holloway.

  Short-chain fatty acids (SCFAs), derived from peroxisomal metabolism and the gut microbiota, have been proposed as key substrates to support mitochondrial oxidative phosphorylation (OXPHOS) in extrahepatic tissues such as skeletal muscle. However, the extent to which mitochondria can oxidize SCFAs (acetate, propionate and butyrate) and the ability of exercise training and a high-fat diet (HFD) to modulate this process remains unclear. Here, we show that SCFA-supported respiration in skeletal muscle is relatively limited (18 ± 6 nmol min-1 mg-1), accounting for only ∼7% of maximal carbohydrate (pyruvate: 252 ± 41 nmol min-1 mg-1) and ∼14% of LCFA (palmitoylcarnitine)-linked respiration. Despite this low capacity, the intrinsic mitochondrial ability to oxidize palmitoylcarnitine, acetate and butyrate increased (P < 0.05: +50%) following HFD consumption, suggesting HFD rewires mitochondria to optimize lipid oxidation. By contrast, exercise training prevented these HFD-induced intrinsic mitochondrial responses. Although intrinsic changes are biologically relevant, skeletal muscle adaptation to metabolic stress also involves mitochondrial biogenesis and an expansion of the mitochondrial proteome. Proteomic analysis and citrate synthase activity revealed that, although HFD independently did not alter mitochondrial protein abundance, exercise training increased mitochondrial proteins, a response amplified in the presence of a HFD. Consequently, although exercise did not directly enhance mitochondrial SCFA-supported respiration, the combined effect of HFD and exercise predicted a greater overall capacity for SCFA oxidation because of increased mitochondrial abundance. Collectively, although SCFAs contribute minimally to mitochondrial respiration in skeletal muscle, combined HFD and exercise synergistically enhance overall OXPHOS capacity across diverse substrates, including SCFAs, primarily through increased mitochondrial protein abundance rather than intrinsic mitochondrial remodelling. KEY POINTS: Peroxisome and gut derived short-chain fatty acids (SCFA) have been proposed as an alternative metabolic fuel source to support skeletal muscle oxidative phosphorylation. The capacity and adaptability of mitochondrial SCFA oxidation remains unknown. SCFA-supported mitochondrial respiration is limited (<15%) compared to carbohydrate (pyruvate) and long-chain fatty acid linked substrates. High-fat feeding increased the intrinsic capacity of mitochondria to utilize palmitoylcarnitine, acetate and butyrate- effects prevented by 4 weeks of exercise training. Combined high-fat diet and exercise training increased skeletal muscle mitochondrial protein content in an additive manner, increasing oxidative capacity and ability to utilize both long- and SCFAs as a fuel source.

Keywords:  exercise; high‐fat diet; mitochondria; short‐chain fatty acids; skeletal muscle

DOI:  https://doi.org/10.1113/JP289545
Cell Death Dis. 2026 Mar 28.

The Sirt2-Nur77 axis regulates muscle stem cell quiescence and senescence via epigenetic-metabolic synergy.

Yanteng Wang, Yichen Yang, Wan Yu, Yue Liu, Wenwei Guan, Yingxi Wang, Na Li, Liu Cao, Difei Wang.

Nur77 expression decreases with age in multiple organs, including the liver, brain, heart, and kidney, whereas Sirt2 increases with age in the mouse cerebral cortex and hippocampus. We identified the central role of the Sirt2-P300/Nur77/K310 acetylation axis in regulating muscle homeostasis and regeneration and its age-related alterations. Consistently, we observed reduced Nur77 and elevated Sirt2 expression in aging skeletal muscle, particularly the anterior tibialis, which is enriched in type IIB and IIA fast-twitch fibers. Mechanistically, Sirt2 promoted Nur77 degradation via K310-specific deacetylation, weakening Myf5 transcriptional activity and altering satellite cell metabolic heterogeneity. Functional tests showed that Sirt2 inhibition (AGK2) or Nur77 activation (CSNB) improved muscle function in aged mice, whereas the K310R mutation led to muscle atrophy and impaired regeneration. These findings suggest the Sirt2-P300/Nur77 axis as a potential therapeutic target for skeletal muscle aging and anti-sarcopenia drug development.

DOI: https://doi.org/10.1038/s41419-026-08645-w
Aging (Albany NY). 2026 Mar 27. 18(1): 213-233

ATF5 is required for the maintenance of mitochondrial homeostasis and skeletal muscle health during aging.

Victoria C Sanfrancesco, David A Hood.

  In skeletal muscle, the mitochondrial network is highly regulated by quality control (MQC) processes including the Integrated Stress Response (ISR) and the mitochondrial Unfolded Protein Response (UPRmt), controlled in part by the transcription factor, Activating Transcription Factor 5 (ATF5). With age, mitochondrial health and function become altered in muscle, but the role of ATF5 in regulating these processes has not yet been evaluated. This study therefore aimed to evaluate the role of ATF5 in mediating mitochondrial quality control and function during aging. To investigate this, we utilized young (4-6 months) and middle-aged (14-16 months; denoted as aged) ATF5 whole-body KO and WT male mice. The normal age-related decline in muscle mass was prevented in the absence of ATF5. This was accompanied by an attenuated rise in important protein degradation regulators, indicating that ATF5 regulates muscle protein turnover with age. Aged ATF5 KO muscle exhibited greater muscle fatiguability than WT counterparts, accompanied by accelerated mitochondrial ROS production. The expression of the co-regulatory ISR/UPRmt transcription factors, CHOP and ATF4, was attenuated in response to acute contractile activity in the absence of ATF5. The lack of ATF5 led to a reduction in the levels of LonP and was accompanied by an increase in mitochondrial:nuclear derived protein imbalance. Collectively, these results suggest that ATF5 functions to maintain mitochondrial quality control and muscle endurance at the expense of muscle mass, and its absence attenuates the normal compensatory stress response to contractile activity with age.

Keywords:  ATF5; aging; mitochondria; skeletal muscle; stress response

DOI:  https://doi.org/10.18632/aging.206365
Adv Exp Med Biol. 2026 ;1505 249-269

The Crucial Role of Exercise in Promoting Adolescent Muscle Development.

Xilong Hu, Haiwang Shi, Rui Duan.

  Skeletal muscle, as one of the largest organ system in the human body, exerts a determining influence on adolescents' mastery of motor skills and their lifelong health. Puberty represents a critical window for muscle development, during which the quality of myogenesis not only shapes athletic potential but also profoundly influences long-term health outcomes in adulthood. Under pathological conditions, such as obesity, an aberrant metabolic environment can compromise muscle function in youth, impede the progression of motor abilities, and increase susceptibility to metabolic disorders. It is well established that scientifically prescribed exercise interventions effectively unlock adolescents' muscle-building potential, thereby laying a solid foundation for enduring physical performance and overall well-being.This chapter offers a systematic overview of the key biological principles that regulate skeletal muscle development during puberty and provides an in-depth analysis of the mechanisms and signaling pathways by which structured exercise drives muscle growth and functional adaptation. In addition, it examines the challenges posed by muscle structural and functional impairments under pathological states and evaluates how targeted exercise regimens can restore and enhance muscle health. By mastering the conceptual framework presented here, coaches and parents will be better equipped to identify early warning signs of impaired muscle development, support individualized training plans that optimize motor skill acquisition while minimizing injury risk, and implement proactive interventions to prevent metabolic dysregulation and age-related muscle decline.

Keywords:  AMPK signaling; CKD; Cystic fibrosis; Exerkine; Fiber type; Obesity; ROS; Satellite cells; Skeletal muscle; mTOR pathway

DOI:  https://doi.org/10.1007/978-981-95-7000-3_13
bioRxiv. 2026 Mar 28. pii: 2026.03.27.711928. [Epub ahead of print]

ATF4 Coordinates Transcriptomic and Structural Adaptations in Aging Muscle.

Amber Crabtree, Mohd Mabood Khan, Estevao Scudese, Calixto Pablo Hernandez Perez, Prasanna Venkhatesh, Andrea G Marshall, Benjamin Rodriguez, Edgar Garza Lopez, Okwute M Ochayi, Estélio Henrique Martin Dantas, Pamela Martin, Matheus Baffi, Fabiana Scartoni, Margaret Mungai, Kit Neikirk, Jennifer Streeter, Renata Oliveira Pereira, Dao Fu Dai, Han Le, Harrison Mobley, Jeremiah Afolabi, Bret C Mobley, Celestine N Wanjalla, Duane Hall, Julia Berry, Oleg Kovtun, Jenny C Schafer, Sean Schaffer, Prasanna Katti, Chantell Evans, Andre Kinder, Joyonna Gamble George, Melanie McReynolds, Annet Kirabo, Sepiso Kenias Masenga, Antentor Hinton.

Aging is associated with a progressive loss of skeletal muscle function, known as sarcopenia; however, the molecular mechanisms coordinating cellular stress responses and structural adaptations remain incompletely understood. The aim of this study was to investigate the role of activating transcription factor 4 (ATF4), a master regulator of the integrated stress response (ISR), in aging muscle using complementary human population and mouse model approaches. Older adults exhibited a marked decrease in aerobic capacity, muscle strength, and endurance when compared with young participants. These results paralleled findings in aged mice, with significant loss of muscle mass across multiple hindlimb muscles. Ultrastructural analysis revealed substantial age-related changes in mitochondrial morphology, including decreased volume, surface area, and branching index, as well as a shift toward smaller, more fragmented, and spherical mitochondria. These structural changes likely impair oxidative capacity and drive a feed-forward cycle of mitochondrial dysfunction and ISR activation. Our findings indicate that ATF4 coordinates transcriptomic and structural adaptations in aging muscle, identifying the ISR pathway as a potential therapeutic target for preserving muscle function in older adults.

DOI: https://doi.org/10.64898/2026.03.27.711928
J Mol Cell Biol. 2026 Mar 31. pii: mjag015. [Epub ahead of print]

NAD+ subcellular partitioning mediated by miR-183 and miR-96 regulates muscle stem cell differentiation.

Mei Ma, Ruisen Ma, Zhuoyang Li, Siyi Shen, Wenqing Kong, Tianyuan Qiu, Zhoumin Niu, Jingjing Chen, Yuting Wu, Yan Li, Zi-Bing Jin, Yuying Li, Hao Ying.

  The intracellular abundance of NAD+, a vital metabolic cofactor, critically influences muscle stem cell (MuSC) function. However, the spatial regulation of NAD+ and its impact on MuSC function remain unclear. In this study, we demonstrated that the loss of miR-183 and miR-96 leads to inefficient skeletal muscle regeneration upon injury and triggers premature differentiation of MuSC-derived primary myoblasts. The underlying mechanism involves miRNA-mediated regulation through targeting SLC25A51, a mitochondrial transporter for NAD+ that elevates mitochondrial NAD+ while reducing cytoplasmic NAD+ levels. Our results suggest that the reduction in cytoplasmic NAD+ diminishes SIRT1-mediated deacetylation, increasing H4K16ac at the promoters of myogenic genes to promote differentiation. Concurrently, the mitochondrial NAD+ accumulation stimulates the tricarboxylic acid cycle, leading to elevated levels of ATP and citrate. These metabolites allosterically activate the ACLY pathway, which in turn increases acetyl-CoA production, thereby supplying acetyl groups for H4K16ac. Furthermore, SIRT3 knockdown impaired myogenic differentiation and attenuated the increased levels of both ATP and acetyl-CoA in miR-183/96-deficient cells, suggesting that the elevated mitochondrial NAD+ also enhances differentiation via SIRT3-mediated regulation of mitochondrial metabolism and acetyl-CoA production. Our work establishes miR-183 and miR-96 as critical regulators of epigenetic-metabolic networks that influence MuSC differentiation through subcellular partitioning of NAD+, ensuring proper regeneration timing.

Keywords:  NAD+; SLC25A51; miRNA; muscle stem cell; skeletal muscle regeneration

DOI:  https://doi.org/10.1093/jmcb/mjag015
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70264

Fibro-Adipogenic Progenitors Regulate Orofacial Neuromuscular Junction Regeneration via Myostatin.

Ruizhi Li, Ruojing Liu, Yixuan Huang, Yijue Wang, Xu Cheng, Jingtao Li, Shujuan Zou, Xing Yin.

   BACKGROUND: Orofacial and limb muscles differ in embryonic origin and regenerative capacity. Neuromuscular junction (NMJ) regeneration is critical for muscle restoration both histologically and functionally. The relative potential of orofacial and limb muscles to form postsynaptic apparatuses remains elusive. While the role of fibro-adipogenic progenitors (FAPs) in NMJ regeneration has been discussed in limb muscles, it remains unexplored in orofacial muscles.
METHODS: NMJ regeneration was triggered by freeze injury in masseter (MAS) and tibialis anterior (TA) muscles and assessed using histological and functional tests. FAPs transplantation experiments and coculture with muscle stem cells (MuSCs) were performed to investigate their effects on postsynaptic apparatus formation. Transcriptome profiling of FAPs identified the key secretory molecule involved in NMJ regulation. The effect of this molecule was further investigated using in vitro gain- and loss-of-function assays, conditional knockout transgenic mice and pharmacological blockade.
RESULTS: Immunohistochemistry showed extensive fibrosis surrounded by regenerated myofibres in MAS, whereas no fibrosis but regenerated myofibres in TA. Restored myofibre calibre and resolved fibrosis in the regenerated lesion periphery are observed in both muscles, yet regenerated NMJs remained markedly below the intact level at 30 days post-injury (dpi) only in MAS (-52.1%, p < 0.001). Interestingly, transplantation of FAPs isolated from MAS reduced the number of postsynaptic acetylcholine receptors (AChRs) on regenerated myofibres in recipient TA muscle (-61.3%, p < 0.001). Conditioned medium of FAPs isolated from MAS at 7 dpi impaired AChR clustering on myotubes, decreasing the AChR/myotube area ratio (p < 0.001). RNA-seq analysis of 7 dpi MAS and TA FAPs identified myostatin (Mstn) as the key differentially expressed gene. Mstn transcripts in MAS FAPs were 1.7-fold higher than those in TA FAPs (p < 0.001). In vitro knockdown of Mstn in FAPs isolated from 7 dpi MAS reversed its negative effect on AChR clustering, as evidenced by a 4-fold increase in the AChR/myotube area ratio (p < 0.01). The number of nascent AChR clusters in injured MAS of FAP-specific Mstn knockout mice was higher than that of injured floxed controls (2.7-fold, p < 0.001). Pharmacological blockade of MSTN enhanced postsynaptic AChR neogenesis in MAS.
CONCLUSIONS: We demonstrated differential NMJ regeneration in MAS and TA muscle. Injury-activated MAS FAPs impede postsynaptic apparatus formation by secreting pathophysiological levels of MSTN. Lowering MSTN levels in injured MAS might enhance its regeneration through nerve-muscle signalling.

Keywords:  acetylcholine receptor; agrin; masseter; mesenchymal stem cells; muscle stem cells

DOI:  https://doi.org/10.1002/jcsm.70264
bioRxiv. 2026 Mar 27. pii: 2026.03.25.714270. [Epub ahead of print]

The metalloproteinase inhibitor Marimastat improves skeletal muscle regeneration when administered intravenously after myonecrosis induced by the venom of Bothrops asper.

Andrés Zamora, Alexandra Rucavado, Teresa Escalante, José María Gutiérrez, Erika Camacho.

Skeletal muscle regeneration is often impaired after acute muscle damage induced by viperid snake venoms, such as that of Bothrops asper , a medically-relevant species in Latin America. It has been shown that traces of venom that remain in the damaged muscle affect myogenic cells in culture, raising the possibility of inhibition of these toxins during the regenerative process as a way to improve regeneration. Using a mouse model of myonecrosis and regeneration, we evaluated the effects of Varespladib (a phospholipase A 2 inhibitor) or Marimastat (a metalloproteinase inhibitor) on muscle regeneration when administered intravenously 24 h after the onset of myonecrosis, i.e., after muscle damage has occurred. The regenerative process was evaluated 14 and 28 days after venom injection. Results show that Marimastat, or a combination of both inhibitors, improved the extent of skeletal muscle regeneration and reduced the extent of tissue fibrosis when compared to tissue from mice receiving venom and no inhibitors, as judged by qualitative and quantitative histological assessment. Results underscore the deleterious role of traces of venom components in the damaged muscle during muscle regeneration and suggest that the administration of metalloproteinase inhibitors, or a combination of metalloproteinase and phospholipase A 2 inhibitors, even when muscle damage has developed, may be a therapeutic alternative for improving the extent of muscle regeneration.

DOI: https://doi.org/10.64898/2026.03.25.714270
Biosci Biotechnol Biochem. 2026 Mar 28. pii: zbag047. [Epub ahead of print]

Exercise increases transglutaminase 2 expression in skeletal muscle.

Tomoya Kitakaze, Manami Dokan, Yuki Kishi, Naoki Harada, Ryoichi Yamaji.

  Transglutaminase 2 (TG2) promotes skeletal muscle hypertrophy as a myokine. The expression levels of Tg2 mRNA increased with endurance exercise and were positively correlated with the expression level of Pgc-1α4 mRNA. PGC-1α4 increased Tg2 mRNA expression in cooperation with ATF6α. These findings suggest that the expression level of Tg2 mRNA increases during endurance exercise via ATF-6α and PGC-1α4.

Keywords:  ATF-6α; PGC-1α4; exercise; skeletal muscle; transglutaminase 2

DOI:  https://doi.org/10.1093/bbb/zbag047
Am J Physiol Cell Physiol. 2026 Mar 28.

Neuronal growth regulator 1 modulates actin dynamics to control intracellular GLUT4 trafficking.

Seo-Young Yun, Soojin Lee.

  NEGR1 (neuronal growth regulator 1) has been genetically linked to metabolic and neuropsychiatric disorders; however, its cellular function in insulin-responsive tissues remains poorly understood. Here, we investigated the role of NEGR1 in regulating actin cytoskeletal dynamics and insulin-stimulated GLUT4 trafficking in skeletal muscle. We found that loss of Negr1 reduced GLUT4 abundance selectively in predominantly glycolytic skeletal muscles in vivo. Despite preserved insulin-induced Akt phosphorylation, insulin-stimulated GLUT4 translocation was markedly impaired in both Negr1-deficient and NEGR1-overexpressing muscle cells. Mechanistically, Negr1 deficiency was associated with enhanced PAK-cofilin signaling and excessive intracellular F-actin accumulation that likely impedes GLUT4 vesicle trafficking. In contrast, NEGR1 overexpression did not increase total F-actin content but induced abnormal peripheral actin organization, resulting in constitutive GLUT4 surface localization and elevated basal glucose uptake. Consistent with these findings, both loss and overexpression of NEGR1 disrupted insulin-induced Rac1-dependent actin remodeling without affecting Akt signaling. Collectively, these results identify NEGR1 as a critical modulator of actin homeostasis required for proper insulin-stimulated GLUT4 trafficking and glucose uptake in skeletal muscle, providing mechanistic insight into the metabolic abnormalities associated with NEGR1 dysregulation.

Keywords:  Actin dynamics; GLUT4 trafficking; Insulin signaling; NEGR1; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpcell.00084.2026
bioRxiv. 2026 Mar 27. pii: 2026.03.24.714065. [Epub ahead of print]

Insulin-independent glucose uptake in skeletal muscle by coupled SGLT and Na,K-ATPase transport.

Natalie J Norman, Tatiana L Radzyukevich, Peter W Chomczynski, Michal Rymaszewski, Izabela Fokt, Waldemar Priebe, Lucas Schmidt, Tiffany Zhu, Bryan Mackenzie, Julio A Landero, Judith A Heiny.

Exercise is a cornerstone therapy for diabetes because working skeletal muscles take up glucose at dramatically greater rates than postprandial insulin-stimulated glucose uptake and, notably, do so without a requirement for insulin. This remarkable ability of working muscles is preserved in diabetes, when muscles become resistant to insulin. However, the mechanism of insulin- in dependent glucose uptake by working muscles is not fully understood. Here we describe a previously unrecognized glucose uptake pathway in muscle, which we refer to as "mSGLT" based on shared properties with the Sodium Glucose Linked Transporter family. In contrast to the abundant GLUT4 transporter, mSGLT is not regulated by insulin, requires Na,K-ATPase-α2 activity, and transports the hexose α-methyl-D-glucoside (αMDG), a glucose derivative that is handled by SGLTs but not GLUT4. The mSGLT pathway and GLUT transport pathways are independent and additive. In addition to exercise, mSGLT imports glucose under other conditions of adrenergic stimulation, which inhibits pancreatic insulin release and reduces the insulin sensitivity of muscle. SGLT2-specific antibodies recognize a protein in muscle of similar size to the kidney SGLT2; this protein localizes to the muscle t-tubules, together with Na,K-ATPase-α2 and MAP17, the regulatory subunit of SGLT2. However, skeletal muscles do not express a full-length transcript of S lc5a2 (SGLT2), and SGLT2-specific inhibitors do not inhibit mSGLT with high affinity. The novel transporter may be a muscle variant of Slc5a2 that results from post-transcriptional or post-translational mechanisms. mSGLT and its regulation offer potential muscle-specific therapeutic targets for treating hyperglycemia and other conditions when insulin-stimulated glucose disposal into muscle is impaired.

DOI: https://doi.org/10.64898/2026.03.24.714065
Front Cell Dev Biol. 2026 ;14 1772623

Redox regulation in aging muscles: exercise as a key modulator to combat sarcopenia and frailty.

Hua Guo, Xueqin Jiang, Wang Zhiming, Yang Gui, Zhanguo Su.

   Background and Context: Aging is characterized by progressive decline in skeletal muscle function, which can lead to sarcopenia (loss of muscle mass and strength) and frailty (increased vulnerability to stressors), with oxidative stress-arising from an imbalance between reactive oxygen species (ROS) production and antioxidant defenses-playing a central role. This narrative review synthesizes evidence on how exercise modulates redox homeostasis to mitigate these conditions in older adults.
Objectives: To explore the sources and consequences of oxidative stress in aging muscle, examine exercise's role in restoring redox balance, evaluate its impact on sarcopenia and frailty, and identify relevant biomarkers and future research directions. We achieve this by exploring key sources through representative studies, examining molecular mechanisms via pathway analyses, evaluating intervention effects using RCTs and meta-analyses, and identifying biomarkers and gaps through critical synthesis.
Methods: This narrative review involved a comprehensive literature search in databases such as PubMed, Web of Science, and Scopus, focusing on studies from 2000 to 2025 on oxidative stress, exercise, sarcopenia, and frailty in adults aged 60+. Inclusion criteria prioritized peer-reviewed articles, meta-analyses, and RCTs; exclusion applied to non-English or irrelevant studies. Over 100 articles were selected qualitatively for synthesis.
Key Findings: Aerobic and resistance exercises reduce oxidant markers (e.g., MDA decreased by 10%-20% in meta-analyses) and enhance antioxidants (e.g., SOD increased by 15%-30%), upregulating pathways like Nrf2, AMPK, and PGC-1α. Multicomponent programs improve muscle strength (e.g., 20%-40% gains in RCTs) and frailty scores (e.g., reductions in Fried Frailty Phenotype by 1-2 points). However, heterogeneous responses exist, with some studies showing neutral effects on certain markers.
Conclusion: Exercise emerges as a non-pharmacological intervention to attenuate oxidative stress-driven muscle aging, promoting healthy aging. Future studies should focus on personalized regimens and long-term biomarkers for clinical translation.

Keywords:  antioxidant defense; exercise; mitochondrial biogenesis; muscle aging; oxidative stress

DOI:  https://doi.org/10.3389/fcell.2026.1772623
Crit Rev Food Sci Nutr. 2026 Mar 29. 1-18

Exercise-derived exosomes mediate crosstalk between skeletal muscle, adipose tissue, and bone: mechanisms of inter-organ communication and tissue adaptation.

Mengran Qin, Zhichao Huang, Yan Wang, Jianxiong Ma.

  Inter-organ communication among bone, skeletal muscle, and adipose tissue is essential for maintaining metabolic homeostasis and musculoskeletal integrity. Dysregulation of this crosstalk is closely associated with aging-related and metabolic diseases, including osteoporosis, sarcopenia, and obesity. With population aging and the rising prevalence of metabolic disorders, elucidating the mechanisms underlying bone-muscle-adipose interactions has become a critical focus in biomedical research. Emerging evidence highlights exercise-derived exosomes as key mediators of intercellular communication. These extracellular vesicles transport specific microRNAs and bioactive molecules that modulate signaling pathways across bone, skeletal muscle, and adipose tissue, thereby coordinating systemic metabolism and tissue remodeling. Exercise has been shown to regulate the biogenesis, release, and molecular cargo of exosomes, enhancing the synergistic function of these tissues and alleviating age-associated metabolic dysfunction and degeneration. Notably, exercise-induced exosomal miRNAs exhibit therapeutic potential by targeting pathways involved in inflammation, mitochondrial function, and anabolic-catabolic balance. This review summarizes current advances in the role of exercise-derived exosomes in bone-muscle-adipose crosstalk during aging and metabolic diseases, discusses their potential as novel therapeutic targets or biomarkers, and outlines key challenges and future research directions. These insights aim to provide a theoretical basis and practical guidance for the development of exercise-based interventions and aging-related disease therapies.

Keywords:  Aging; exercise; exosomes; metabolism; organ interaction

DOI:  https://doi.org/10.1080/10408398.2026.2646268
J Muscle Res Cell Motil. 2026 Mar 30. pii: 11. [Epub ahead of print]47(2):

Effects of culture media glucose concentration on LHCN-M2 skeletal muscle cell viability, differentiation and metabolic phenotype: a proof-of-concept study.

Ryan Brett, Leanne Hodson, Derek Renshaw, Mark C Turner.

  In vitro skeletal muscle culture models provide important insight into the cellular mechanisms which underpin skeletal muscle physiology and metabolism in health and disease. The establishment of a model that can be cultured in physiological concentrations of glucose is an important factor in its translatability to more complex models and systems. Using the human skeletal muscle cell line, LHCN-M2 myoblasts, we aimed to determine the effects of different concentrations of glucose in culture media on cell viability, proliferation, ATP production and differentiation. LHCN-M2 myoblasts were cultured in NORM (1 g· L- 1) or HIGH (3.8 g· L- 1) glucose growth media, and cell viability, ATP production, and proliferation were measured. Immunofluorescence microscopy was used to determine LHCN-M2 differentiation into multinucleated myotubes with increasing concentrations of human serum (0.5%, 1% and 2% v/v). There were no differences in the viability, proliferation or basal ATP production rates of LHCN-M2 cells grown in NORM compared to HIGH glucose (P > 0.05). Morphological analysis revealed that myotube area was greater when differentiated in 2% compared to 0.5% human serum (P = 0.02), but myotube number and fusion index were unaffected (P > 0.05). These findings demonstrate that LHCN-M2 cells are capable of proliferating and differentiating into multinucleated myotubes under normal glucose concentrations in the culture media. Further work is required to determine the implications of media glucose concentration on the wider metabolic function and phenotype of LHCN-M2 myoblasts cells and myotubes.

Keywords:  Cell health; Cell lines; Human skeletal muscle; Metabolism; Mitochondrial function; Physiologically relevant; Proliferation

DOI:  https://doi.org/10.1007/s10974-026-09729-y
Sci Rep. 2026 Apr 01.

Dietary restriction and aerobic exercise alleviate obesity-related skeletal muscle impairment via the miR-130/PPARγ axis and IGF-1/Akt/mTOR signaling activation.

Qiyi Zhang, Tianqi Liu, Xiaoxiong He.

  This study investigated the effects of dietary restriction (DR) combined with aerobic exercise training (ET) on high-fat diet (HFD)-induced obesity and associated skeletal muscle impairment in male Sprague-Dawley rats, as well as the underlying mechanisms. An 8-week DR + ET intervention effectively increased the cross-sectional area and protein content of the soleus muscle. Both DR and ET alone promoted the activation of the IGF-1/Akt/mTOR signaling pathway and reduced the protein expression of peroxisome proliferator-activated receptor γ (PPARγ), a target of miR-130 in adipocytes, in HFD-induced obese rats. However, no additional benefit was observed with combined DR + ET treatment. Consistent with these findings, miR-130 expression was upregulated in the skeletal muscle of obese rats compared with those fed a normal diet, and this increase was significantly attenuated by DR, ET, or DR + ET, with DR + ET showing the strongest inhibitory effect. To further explore the role of miR-130 in skeletal muscle cells, L6 and C2C12 cells were transfected with miR-130 mimics. Overexpression of miR-130 markedly suppressed proliferation and differentiation in these cells, accompanied by reduced creatine kinase activity and decreased myogenin expression-both key markers of myogenic differentiation. Moreover, miR-130 overexpression inhibited the luciferase activity of a reporter vector containing the PPARγ-3'-UTR, and this inhibition was abolished by mutation of the PPARγ-3'-UTR, indicating a direct regulatory mechanism affecting protein synthesis in skeletal muscle. In summary, DR and ET each alleviated obesity-related skeletal muscle impairment by activating IGF-1/Akt/mTOR signaling and suppressing miR-130 expression, but their combination did not produce synergistic effects.

Keywords:  Aerobic exercise; Dietary restriction; Obesity; Skeletal muscle

DOI:  https://doi.org/10.1038/s41598-026-46630-7
Curr Opin Clin Nutr Metab Care. 2026 May 01. 29(3): 277-286

Anabolic resistance in cancer cachexia: a role for sex and chemotherapy.

Tanner Jenkins, Quan Zhang, James A Carson.

   PURPOSE OF REVIEW: The purpose of this review is to highlight recently published research that can provide insight into how either sex or chemotherapeutics can impact cancer regulation of muscle anabolic resistance. Critical knowledge gaps are emphasized that are linked to cancer and treatment disruptions to muscle anabolic signaling. We speculate and propose a rationale for estrogen's protective effect against cancer-induced muscle anabolic resistance in females. Furthermore, there is growing evidence that many cancer treatments have the potential to exacerbate muscle anabolic resistance in both males and females. We present current evidence and speculate on how nutritional interventions could serve as key modulators of cancer-induced anabolic resistance in these conditions.
RECENT FINDINGS: Recently published studies have reinforced that sex impacts the regulation of cancer cachexia in several established preclinical models, with males often developing more severe cachexia when compared to females. Importantly, recent research has established these sex differences at the transcriptomic level. Recent research has also strengthened the link between hypogonadism as a driver of cancer cachexia in preclinical models. Furthermore, chemotherapy has the potential to exacerbate muscle anabolic resistance.
SUMMARY: There is a growing body of literature that provides a strong rationale for further investigation into the impact of sex and chemotherapy on the cancer regulation of muscle anabolic resistance.

Keywords:  chemotherapy; sex; skeletal muscle

DOI:  https://doi.org/10.1097/MCO.0000000000001219
Tissue Cell. 2026 Mar 26. pii: S0040-8166(26)00192-8. [Epub ahead of print]101 103499

Exosomes: Molecular messengers shaping muscle physiology and growth.

Ayoola Ebenezer Afe, Xiaorong Guo, Farhad Badshah, Kui Li, Rong Zhou.

  Exosomes, a subset of extracellular vesicles, are key mediators of intercellular communication and important regulators of skeletal muscle biology. However, the mechanisms by which they influence muscle growth, metabolism, and interactions with adipose tissue remain underexplored, particularly in livestock and regenerative medicine. This review integrates recent advances elucidating the roles of exosomal cargos, such as microRNAs, proteins, and lipids, in regulating myogenesis, regeneration, fiber-type specification, intramuscular fat deposition, and energy metabolism. It also details the mechanisms by which exosomes modulate key signaling pathways, including the PI3K/Akt/mTOR, TGF-β, Notch, and Wnt/β-catenin pathways, as well as the exosome-mediated cross-talk linking muscle and adipose tissues in metabolic and structural regulation. Furthermore, we examine the potential of engineered exosomes as targeted delivery vehicles to modulate muscle composition, enhance meat quality, and promote tissue regeneration. By integrating mechanistic insights with emerging translational advances, this review highlights the prospective applications of exosome biology in both biomedical research and agricultural biotechnology.

Keywords:  Adipogenesis; Atrophy; Exosome; Extracellular vesicles; Hypertrophy; Myogenesis

DOI:  https://doi.org/10.1016/j.tice.2026.103499
Physiol Genomics. 2026 Mar 28.

Transcriptional Remodeling of Human Skeletal Muscle Following Sleep Restriction in Postmenopausal Women.

Hari Naga Sai Kiran Suryadevara, R Caitlin Hebert, Jaroslaw Staszkiewicz, Eric Ravussin, Kara L Marlatt, Prachi Singh, Sujoy Ghosh.

  Sleep is a critical regulator of metabolic health, but its impact on skeletal muscle remains underexplored. Given the muscle's pivotal role in glucose metabolism, energy homeostasis, and immune signaling, understanding how insufficient sleep affects global transcriptomic responses in skeletal muscle is of significant interest. In a randomized crossover design, skeletal muscle biopsies were collected from healthy postmenopausal women following four nights of habitual or restricted sleep (40% reduction). RNA-seq was performed on 7 paired samples and analyzed using differential expression (DE), gene correlation, pathway enrichment, and transcription factor motif analysis. Global DE analysis revealed modest transcriptomic shifts, with 9 genes consistently altered across multiple DE methods. Gene set enrichment analysis showed upregulation of oxidative phosphorylation and myogenesis pathways and downregulation of immune and inflammatory signaling during sleep restriction. Differential correlation analysis identified substantial reorganization in gene co-expression networks, particularly within RNA degradation and ribosomal pathways. Transcription factor and motif analyses suggested YY1 as a possible key mediator of transcriptional reprogramming during sleep restriction. Motif analysis confirmed enrichment of YY1 binding sites among differentially correlated genes, further implicating its role in linking circadian disruption, metabolic stress, and immune modulation. Sleep restriction for 4-nights triggers subtle but biologically meaningful changes in skeletal muscle transcriptomes. The simultaneous upregulation of mitochondrial and structural genes, alongside downregulation of immune-related genes, reflects a complex adaptive response. YY1 appears to be a central regulatory node linking sleep loss to muscle dysfunction, with implications for metabolic resilience, inflammation, and tissue repair.

Keywords:  Sleep restriction; correlation analysis; motif analysis; skeletal muscle; transcriptomics

DOI:  https://doi.org/10.1152/physiolgenomics.00269.2025
bioRxiv. 2026 Mar 23. pii: 2026.03.20.713228. [Epub ahead of print]

Distinct postsynaptic morphogenetic strategies across Drosophila embryonic muscles during neuromuscular junction formation.

Melissa Ana Inal, Daichi Kamiyama.

Precise synaptic connectivity emerges through coordinated interactions between neurons and their target cells during development. At the Drosophila embryonic neuromuscular junction (NMJ), postsynaptic muscle fibers actively participate in this process by extending dynamic, actin-rich protrusions termed myopodia that interact with approaching motor growth cones. Previous work focusing on muscle 12 (M12) revealed that myopodia cluster at nascent neuron-muscle contact sites, suggesting that specialized postsynaptic architectures may facilitate synaptic partner selection. However, whether similar morphogenetic strategies operate across the diverse set of embryonic muscles has remained unclear. Here, we establish a genetic imaging toolkit that enables minimally invasive visualization of defined muscle subsets throughout the embryo. Using muscle-specific and stochastic GAL4 drivers to label muscle membranes in vivo , we systematically compare myopodial organization across multiple muscle fibers, including M12, M14, M6, and M7. We find that postsynaptic morphology varies substantially between muscles. M12 displays robust myopodial clustering associated with a prominent sheet-like membrane structure, which we term the muscle lamella, whereas M6 and M14 frequently form myopodial clusters but do not evidently exhibit this structure. In contrast, M7 shows markedly reduced clustering frequency and smaller clusters. These observations reveal previously unrecognized heterogeneity in postsynaptic organization among neighboring muscles during early neuromuscular development. Together, our findings demonstrate that myopodial clustering represents a broadly deployed but differentially organized strategy by which muscles engage motor axons during synaptic partner selection. The imaging toolkit established here provides a foundation for systematic analysis of neuron-muscle interactions across the embryonic musculature and reveals that distinct muscles employ diverse morphogenetic strategies during NMJ assembly.

DOI: https://doi.org/10.64898/2026.03.20.713228
Am J Physiol Cell Physiol. 2026 Apr 03.

Mitochondrial Localization Around Central Nuclei in Regenerating Skeletal Muscle Following Eccentric Contraction in Rat Model.

Reiya Murakami, Ayaka Tabuchi, Takayoshi Kobayashi, Kazuyoshi Yagishita, Daisuke Hoshino, David C Poole, Yutaka Kano.

  This study aimed to characterize the spatial distribution and ultrastructural changes of mitochondria in regenerating muscle following ECC-induced injury, utilizing photothermal microscopy (PTM) and transmission electron microscopy (TEM). ECC was applied to the gastrocnemius muscles of male rats (13 weeks old, 284.8 ± 8.9 g), and regenerating muscles were harvested seven days post-injury. PTM, featuring a high-sensitivity optical system, was employed to visualize the wide-range and three-dimensional distribution of mitochondria within the white gastrocnemius muscle region. Concurrently, TEM was used for quantitative analysis of mitochondrial ultrastructural morphology, including cristae density. In regenerating muscle, the regular lattice-like network observed in normal tissue was disrupted and replaced by fragmented, randomly distributed mitochondria. Notably, both PTM and TEM analyses revealed a high concentration of mitochondria specifically around "central nuclei", a hallmark of regenerating muscle (i.e. within 0.1- 1.0 µm: Normal 1.8 ± 2.0% vs. Regeneration 5.5 ± 3.6%, p < 0.0001, by TEM data). Detailed morphological analysis further demonstrated that mitochondria in the immediate vicinity of the central nucleus (< 0.1 µm) had significantly lower cristae density (inner and outer membranes ratio, 1.10 ± 0.43) compared to those in distal regions (> 2.0 µm) (1.80 ± 0.65, p < 0.0001), indicating that they may be structurally immature. In conclusion, during the muscle regeneration process, mitochondria specifically localize around the central nucleus. Given their low cristae density, these potentially represent newly synthesized (biogenesis-derived) mitochondria. This perinuclear accumulation is thought to function as a critical energy source for the nuclear transcriptional and translational activities required for muscle differentiation, while also serving as a hub for organelle coordination during the regeneration process.

Keywords:  Central nuclei; Eccentric contraction; Mitochondrial biogenesis; Photothermal microscopy; Skeletal muscle regeneration

DOI:  https://doi.org/10.1152/ajpcell.00115.2026
Cell Death Differ. 2026 Apr 03.

Activation of α7nAChR reduces inflammation and apoptosis, promoting muscle regeneration through the AKT-FOXO1 pathway.

Xiaolu Jin, Ya Zhou, Luning Sun, Li Li, Chaozhu Zheng, Zhongliang Shan, Chao Ding, Dongdong Huang, Qipeng Zhang, Rongrong Fan, Guan Sun, Meihong Shen, Hongwei Wang, Zhiqiang Huang.

Denervation induces severe muscle atrophy characterized by inflammatory responses and tissue degradation, with limited effective therapeutic options. This study investigates the role of the α7 nicotinic acetylcholine receptor (α7nAChR) in denervation-induced muscle atrophy and evaluates electroacupuncture (EA) as a potential treatment strategy. Using a sciatic nerve transection mouse model, we observe that denervation decreases α7nAChR expression, activates proteolytic pathways. We find that α7nAChR degradation is associated with the activation of inflammatory cytokines and the caspase pathway. In α7nAChR knockout mice, we demonstrate that α7nAChR modulates mitochondrial metabolism and fiber-type composition. It exerts protective effects by activating the AKT-FOXO1 pathway, thereby reducing inflammation and apoptosis, processes that are critical for muscle regeneration. Additionally, treatment with PNU120596 or EA restores α7nAChR function and alleviates muscle atrophy. Our findings suggest that targeting α7nAChR offers a promising therapeutic approach for muscle wasting following denervation, with potential implications for clinical management and future intervention strategies.

DOI: https://doi.org/10.1038/s41418-026-01738-1
J Biophotonics. 2026 Mar;19(3): e70256

Understanding Bioenergetics of Myogenic Differentiation of Human Mesenchymal Stem Cells Using Label-Free Imaging.

Vrushali Khedekar, Gayathri S Kamath, Indrani Talukdar, P Nandakumar, Geetha K Varier.

  Mesenchymal stem cells are essential for tissue repair, making them a prime focus for regenerative medicine and cell-based therapies. However, their full therapeutic potential for treating muscle disorders remains constrained by an incomplete understanding of the mechanisms underlying myogenic differentiation. We characterized the metabolic reprogramming that occurs during the differentiation of human mesenchymal stem cells into the myogenic lineage. We employed wide-field fluorescence microscopy to image endogenous NADH and FAD fluorescence, quantifying the redox ratios (FAD/(NADH + FAD)) to assess changes in cellular metabolism. This revealed distinct shifts in the redox state accompanying the progression of differentiation, indicating a significant transition toward a glycolytic pathway in differentiated myotubes. These findings provide quantitative insights into the metabolic alterations underpinning myogenic differentiation and help in the optimization of stem cell-based approaches for muscle regeneration.

Keywords:  endogenous fluorophores; energy metabolism; glycolysis; oxidative phosphorylation; stem cell differentiation

DOI:  https://doi.org/10.1002/jbio.70256
Trends Mol Med. 2026 Mar 31. pii: S1471-4914(26)00063-8. [Epub ahead of print]

Muscle-to-CNS signaling in physiological homeostasis, aging, and disease.

Chia-Lung Chuang, Mamta Rai, Fabio Demontis.

  The central nervous system (CNS) orchestrates homeostatic responses and organismal behaviors by integrating cues from the whole body. Like other peripheral tissues, skeletal muscle can signal to the brain, and this occurs via muscle-secreted signaling factors (myokines/myometabolites). In this review article, we examine exercise-induced myokines and myometabolites that improve cognitive capacity and impede neurodegeneration and, conversely, detrimental myokines secreted by diseased muscles that negatively impact brain function. Cellular processes modulated by myokines in the CNS include proteostasis, angiogenesis, neurogenesis, synaptic plasticity, cell senescence, and neuroinflammation, resulting in the modulation of diverse behaviors, such as motor control, memory, foraging, and sleep. Collectively, muscle-to-brain signaling emerges as an important influencer of CNS function and aging, with the prospect of utilizing myokine-/myometabolite-based therapies for treating neurodegeneration.

Keywords:  aging; exercise; interorgan signaling; muscle-to-brain; myokines; neurodegeneration

DOI:  https://doi.org/10.1016/j.molmed.2026.03.006
Front Biosci (Landmark Ed). 2026 Mar 17. 31(3): 46704

Transcription Factor Acetylation and Cell Fate Control: A Molecular Switch in Hematopoiesis and Myogenesis.

Pegah Ghavidel, Yassine Abdelmalki, Marie-Claude Sincennes.

  Transcription factor acetylation is a critical yet often overlooked regulator of cell fate. Although traditionally studied in the context of histone modifications, many acetyltransferases and deacetylases also modify transcription factors directly, thereby controlling lineage-specific transcriptional programs. At the molecular level, acetylation fine-tunes transcription factor activity by modulating DNA binding, protein stability, cofactor interactions, and nucleo-cytoplasmic trafficking. These molecular effects frequently intersect with other post-translational modifications, establishing acetylation as a versatile molecular switch of transcriptional output. These molecular effects scale into cellular outcomes that determine identity and plasticity. In pluripotent stem cells, defined acetylation events on core regulators stabilize the pluripotency network and prime lineage-specific enhancers. In hematopoiesis, transcription factor acetylation modulates transitions from stem and progenitor states to committed lineages, while in myogenesis, it governs progenitor differentiation and regenerative capacity. Importantly, differential acetylation of distinct lysine residues can yield context-dependent outcomes, underscoring the precision and adaptability of this modification in controlling cell identity. Recognizing transcription factor acetylation as a central axis of epigenetic regulation reframes our understanding of lineage specification and cellular plasticity. Beyond developmental biology, it provides a mechanistic rationale for therapeutic strategies that target acetylation dynamics, not only altering chromatin states but also reprogramming transcription factor function. This review synthesizes current knowledge of transcription factor acetylation in hematopoietic and myogenic contexts, highlighting its significance as a bridge between molecular mechanisms and cellular identity, and as a promising target in disease intervention.

Keywords:  acetylation; acetyltransferases; chromatin; gene expression; hematopoiesis; histone deacetylase inhibitors; muscle development; post-translational; protein processing; stem cells; transcription factors

DOI:  https://doi.org/10.31083/FBL46704