bims-moremu 2026-03-29 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–03–29
35 papers selected by
Anna Vainshtein, Craft Science Inc.

Hypothyroidism impairs skeletal muscle regeneration after injury by altering myogenic and nonmyogenic pathways.
Exacerbated Skeletal Muscle Phenotype in Mice with 'Homotypic' Expression of the Tubular Aggregate Myopathy ORAI1 G100S Mutation.
Cellular Senescence in Skeletal Muscle: Myogenic and Non-Myogenic Cell Populations, Mechanisms, and Therapeutic Opportunities.
Mitochondrial Impairment in Unloaded Postural Muscle: Mechanisms Driving Loss of Muscle Function and Mass.
Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).
Fibro-adipogenic progenitor cells from murine SMA muscles are intrinsically adipogenic.
Regulation of skeletal muscle mitochondrial fuel utilization during exercise.
Ribosome Biogenesis and Translational Control in Skeletal Muscle Atrophy and Hypertrophy: Mechanisms and Therapeutic Perspectives.
Progress on cell therapy for skeletal muscle disorders.
DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation.
Hypoxia-Induced GRP78 Activation Disrupts the Fndc5/Irisin Axis to Accelerate Skeletal Muscle Atrophy.
Bile Acid Metabolism Affects Muscle Regeneration in Aging Skeletal Muscle in a Manner Associated with Regulation of ABCB1 Expression.
AKT Signaling Regulates Agrin-Mediated Acetylcholine Receptor Surface Density.
Exercise modulation of the alternative splicing landscape in human tissues.
Nicotinamide and Pyridoxine Supplementation Enhances Muscle Stem Cell Activity and Muscle Regeneration in Humans: A Randomized Placebo-Controlled Clinical Trial of High Force Eccentric Contraction Recovery in Healthy Young Men.
Muscle Atrophy After ACL Reconstruction Involves Molecular Mechanisms Beyond Unloading.
Molecular mechanisms of skeletal muscle atrophy: clinical challenges and future therapeutic strategies.
Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.
Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia.
Methods of muscle atrophy analysis at the single-nucleus level.
Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.
Cannabinoid type 2 receptor regulates skeletal muscle regeneration by NLRP3-GSDMD mediated macrophage pyroptosis after injury.
Females are protected from semaglutide-induced muscle loss in ob/ob mice.
Exercise-Induced Exerkines Modulate Autophagy: Implications for Interorgan Crosstalk in the Hallmarks of Ageing.
CRISPR-Cas9-Mediated Upregulation of Utrophin Ameliorates Duchenne Muscular Dystrophy.
Aging Impairs Intramuscular Collagen Remodeling Responses to Repeated Passive Stretching in Skeletal Muscle.
Molecular Transducers of Physical Activity Consortium (MoTrPAC): Initial Insights into the Dynamic Human Responses to Exercise.
Seeking the Mechanism for Reversal of Enhanced Insulin Sensitivity after Acute Exercise.
Active immunization against myostatin and activin A improves skeletal muscle performance in growth hormone-deficient mice.
Multi-omics analysis reveals sex-specific etiology of human muscle weakness following musculoskeletal injury.
Global MyoG research 2004-2024: a bibliometric analysis of trends and translational implications.
Transcriptomic advances in studies of muscle stem cell aging: From bulk to single-cell and beyond.
Phosphodiesterase 4 (PDE 4) Inhibition Reduces Ischemia-Reperfusion-Induced Leucocyte Infiltration, Apoptosis and Mitochondrial Fission Markers in Mice Skeletal Muscles Four Hours After Ischemia Onset.
Robust immune cell infiltration and macrophage senescence occur within a week of recovery after limb immobilization in older adult skeletal muscle.
Epigenetic inhibition of class I histone deacetylases by MS-275 attenuates diabetic skeletal muscle atrophy via Akt/ARK5-FoxO and myostatin-Smad signaling.

JCI Insight. 2026 Mar 23. pii: e197761. [Epub ahead of print]11(6):

Hypothyroidism impairs skeletal muscle regeneration after injury by altering myogenic and nonmyogenic pathways.

Paola Aguiari, Valentina Villani, Yan-Yun Liu, Gianni Carraro, Gregory A Brent, Laura Perin, Anna Milanesi.

  Thyroid hormone signaling is an essential regulator of skeletal muscle development, function, and metabolism, yet the specific signaling pathways required for muscle regeneration are not yet defined. We used scRNA-seq and the FUCCI (fluorescent ubiquitination-based cell cycle indicator) reporter mouse model to examine how hypothyroidism impacts repair processes after cardiotoxin-induced injury in mice. During regeneration, and up to 2 months after injury, hypothyroid muscles displayed smaller myofibers and a shift to slower oxidative fiber types. scRNA-seq of tibialis anterior muscle during regeneration revealed that hypothyroidism reduced myogenic-lineage diversity. Cell cycle analysis confirmed delayed cell cycle progression at 5 and 14 days after injury, with skeletal muscle stem cells stalled at the G1/S transition, hindering differentiation. Transcriptomic data revealed altered nonmyogenic dynamics, including elevated activated fibro-adipogenic progenitors (FAPs) early in repair and persistent proinflammatory macrophages. Integrative regulon and ligand-receptor analysis further demonstrated that triiodothyronine acted through dual modes: a direct transcriptional control of myogenic cell cycle and oxidative programs and an indirect paracrine remodeling mediated by FAP and immune signaling networks. This study identified what we believe to be novel effects of hypothyroidism on myogenic heterogeneity and impaired tissue repair, offering insights into muscle-wasting mechanisms relevant to hypothyroidism-associated myopathy and sarcopenia.

Keywords:  Cell biology; Endocrinology; Muscle; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.197761
Biomedicines. 2026 Mar 05. pii: 587. [Epub ahead of print]14(3):

Exacerbated Skeletal Muscle Phenotype in Mice with 'Homotypic' Expression of the Tubular Aggregate Myopathy ORAI1 G100S Mutation.

Nan Zhao, Miao He, Robert T Dirksen.

  Background: Tubular aggregate myopathy (TAM) is an autosomal dominant myopathy that results from gain-of-function mutations in the STIM1 and ORAI1 genes, which encode the two key proteins that coordinate store-operated Ca2+ entry in skeletal muscle and other cell types. Knock-in mice heterozygous for a glycine-to-serine point mutation in the ORAI1 pore (ORAI1G100S/+ or GS mice) phenocopy several key aspects of TAM in humans with the analogous mutation including muscle weakness, exercise intolerance, elevated CK levels, hypocalcemia, and the presence of tubular aggregates. Methods: Since homozygous inheritance of the ORAI1-G100S mutation is embryonic lethal, we assessed the impact of homotypic ORAI1-G100S expression in skeletal muscle by crossing GS mice with constitutive, muscle-specific ORAI1 knock-in mice (cORAI1-KO). Results: Compound cORAI1-KO/GS mice exhibit only one active ORAI1 (GS) allele, and thus only express ORAI1-G100S monomers in skeletal muscle ('homotypic' GS mice). Homotypic GS mice exhibit an earlier onset and more severe muscle phenotype than age-matched heterotypic GS mice with both WT and GS alleles. Specifically, homotypic GS mice exhibit TAs at an earlier age, as well as significantly reduced in vivo muscle performance (grip strength, treadmill endurance, and rotarod endurance), maximal specific force production, and respiratory function, compared to those observed for both WT and heterotypic GS mice. Conclusions: These findings indicate that homotypic expression of the ORAI1-G100S mutation in skeletal muscle results in an earlier-onset and more severe muscle phenotype.

Keywords:  ORAI1; calcium signaling; skeletal muscle; store operated calcium entry

DOI:  https://doi.org/10.3390/biomedicines14030587
Am J Physiol Cell Physiol. 2026 Mar 26.

Cellular Senescence in Skeletal Muscle: Myogenic and Non-Myogenic Cell Populations, Mechanisms, and Therapeutic Opportunities.

Konstantinos Papanikolaou, Angad Yadav, Robert T Mankowski, Matthew S Alexander, Jorge L Gamboa, Anna E Thalacker-Mercer, Cory M Dungan, Davis A Englund.

  Skeletal muscle plays a central role in systemic metabolism, physical function, and overall health. Aging and disease diminish the ability of myogenic and non-myogenic skeletal muscle cells to coordinate adaptation and repair, but the mechanisms underlying this decline are not fully understood. Growing evidence implicates cellular senescence, a stress response marked by irreversible cell-cycle arrest and pro-inflammatory signaling, as a key contributor to muscle pathology. In this review, we synthesize current insights into the molecular mechanisms that govern cellular senescence in skeletal muscle, its effects on myogenic and non-myogenic cell populations, and recent technologies that have clarified key aspects of senescence biology. We further explore emerging therapeutic strategies aimed at targeting senescent cells and discuss key knowledge gaps that must be addressed to advance our understanding of senescent myogenic and non-myogenic cells in skeletal muscle.

Keywords:  DNA damage; cell cycle; inflammation; muscle wasting; satellite cells

DOI:  https://doi.org/10.1152/ajpcell.00876.2025
Antioxidants (Basel). 2026 Feb 24. pii: 277. [Epub ahead of print]15(3):

Mitochondrial Impairment in Unloaded Postural Muscle: Mechanisms Driving Loss of Muscle Function and Mass.

Kristina A Sharlo, Timur M Mirzoev, Boris S Shenkman.

  Mechanical unloading of skeletal muscle triggers various signaling alterations that result in muscle atrophy and weakness. Mitochondria are essential to muscle health, acting not only as energy suppliers but also as central mediators of molecular regulation. Mitochondrial activity, content, and dynamics are tightly controlled by multiple signaling pathways; conversely, mitochondria-derived messengers, such as reactive oxygen species (ROS), ATP, and mitokines, are involved in the regulation of nearly all aspects of muscle signaling. During mechanical unloading, altered muscle activity leads to mitochondrial dysfunction. However, the initial triggers, underlying mechanisms, and full consequences of this dysfunction remain poorly understood. Nevertheless, mitochondria-targeted therapies have emerged as a promising strategy for mitigating unloading-induced muscle impairments. In this review, we summarize current data regarding the characteristics, causes, and outcomes of unloading-induced mitochondrial dysfunction, specifically focusing on muscle atrophy and functional decline. We highlight novel findings regarding the roles of mitokines and mitochondrial calcium overload, propose a new hypothesis to explain the biphasic dynamics of ATP accumulation during slow-type muscle unloading, and describe emerging therapeutic strategies to counteract these mitochondrial impairments.

Keywords:  ATP; ROS; calcium handling; dry immersion; hindlimb suspension; mechanical unloading; mitochondria; mitokines; muscle atrophy; skeletal muscle

DOI:  https://doi.org/10.3390/antiox15030277
bioRxiv. 2026 Mar 06. pii: 2026.03.04.705181. [Epub ahead of print]

Integrative Multi-omics Analysis of the Human Skeletal Muscle Response to Endurance or Resistance Exercise: Findings from the Molecular Transducers of Physical Activity Consortium (MoTrPAC).

MoTrPAC Study Group

The Molecular Transducers of Physical Activity Consortium (MoTrPAC) was established to systematically characterize the molecular basis of the health benefits of exercise. Here, we present the integrative, multi-omics response of human skeletal muscle to acute endurance (EE) and resistance (RE) exercise. Distinct temporal responses were observed, with changes in ATAC-seq, phosphoproteome, and metabolome occurring before changes in the transcriptome and proteome. These distinct temporal multi-omic dynamics were used to identify transcriptional regulatory hubs converging around MEF2A and NFIC regulation of autophagy, angiogenesis and metabolism. Further, early RE-specific phosphoproteome signatures counteracted epigenetic modifications and downregulated transcripts involved in protein turnover. Additional findings include suppression of HIPK2/3 kinase signatures linked to the acute exercise regulation of sarcomeric proteins TTN, NEB, ANKRD2 and LMOD2. Our data demonstrate distinct temporal regulation across the multi-omic landscape of human skeletal muscle, with EE and RE eliciting common and unique molecular signatures.

DOI: https://doi.org/10.64898/2026.03.04.705181
Proc Natl Acad Sci U S A. 2026 Mar 31. 123(13): e2525423123

Fibro-adipogenic progenitor cells from murine SMA muscles are intrinsically adipogenic.

Yangyi E Luo, Zoe Abe-Teh, Tarek Alsaghir, Katie D Heiden, Kari B Basso, Elisabeth R Barton.

  Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. Although classically viewed as a neurogenic disease, SMA patients exhibit poor skeletal muscle regeneration and increased fatty-fibrotic infiltration. Fibro-adipogenic progenitors (FAPs) are mesenchymal precursor cells that contribute to muscle remodeling and underlie fat and fibrosis formation. Because FAPs transiently express Smn1 during regeneration, FAPs were examined in muscles from adult C/C SMA and control mice to determine if reduced Smn activity altered their properties. We performed a nonbiased screen of FAPs following BaCl2-induced injury using an in situ cell surface proteomic strategy that probed the cellular membrane and environment of FAPs in early regeneration. Proteomic profiling revealed early adipogenic priming in SMA tissues, with increased levels of perilipin-4 and adipocyte lipid-binding proteins. Significantly more adipocytes accumulated in C/C SMA muscles after glycerol injection versus controls. Further, SMA FAPs produced more fat than control FAPs when transplanted into glycerol injured muscles lacking FAPs. RNA sequencing of FAPs isolated after BaCl2 or glycerol injury identified transcriptional enrichment of lipid biosynthesis and dysregulated lipid metabolism in SMA FAPs. Primary FAPs isolated from C/C SMA muscles mirrored heightened adipocyte formation, which was normalized by increasing Smn activity with Risdiplam. Conversely, adipogenesis of primary FAPs from control muscles was enhanced when subjected to siRNA Smn1 knockdown. Together, these findings demonstrate that reduced Smn activity potentiates intrinsic adipogenic bias in FAPs that may contribute to pathological fat deposition in SMA muscle.

Keywords:  fibro-adipogenic progenitors; mesenchymal stem cells; muscle regeneration; spinal muscular atrophy; surface proteomics

DOI:  https://doi.org/10.1073/pnas.2525423123
Trends Endocrinol Metab. 2026 Mar 24. pii: S1043-2760(26)00014-7. [Epub ahead of print]

Regulation of skeletal muscle mitochondrial fuel utilization during exercise.

Likun Yang, Tingting Fu, Hao Yu, Yujing Yin, Zhenji Gan.

  Skeletal muscle exhibits remarkable metabolic plasticity, with mitochondria playing a central role in adapting to energy demands during exercise. These organelles form a dynamic and specialized system capable of remodeling to meet metabolic challenges. Recent studies demonstrate that exercise not only stimulates mitochondrial biogenesis but also engages finely tuned quality-control mechanisms to sustain energy efficiency and performance. A key adaptation is mitochondrial fuel flexibility, the capacity to switch between lipid and carbohydrate oxidation, which underlies endurance and metabolic health. Importantly, efficient lipid utilization, rather than low lipid content, explains why trained muscle can accumulate lipids while remaining insulin sensitive. Here, we review emerging insights into how exercise reprograms skeletal muscle mitochondria to optimize fuel use and highlight implications for metabolic disease.

Keywords:  biogenesis; exercise; fuel utilization; mitochondria; mitochondrial quality control; skeletal muscle

DOI:  https://doi.org/10.1016/j.tem.2026.01.014
Biomolecules. 2026 Mar 10. pii: 406. [Epub ahead of print]16(3):

Ribosome Biogenesis and Translational Control in Skeletal Muscle Atrophy and Hypertrophy: Mechanisms and Therapeutic Perspectives.

Miaomiao Xu, Xiaoguang Liu.

  Maintenance of skeletal muscle mass is essential for mobility, metabolic homeostasis, and clinical outcomes across a wide spectrum of physiological and pathological conditions. While muscle atrophy and hypertrophy have traditionally been interpreted through upstream anabolic-catabolic signaling and proteolytic pathways, accumulating evidence indicates that ribosome biogenesis and translational control represent rate-limiting determinants of muscle plasticity. However, this regulatory layer remains insufficiently integrated into current models of muscle adaptation and disease. In this review, we synthesize recent advances in ribosomal RNA transcription, ribosomal protein dynamics, and translational regulation in skeletal muscle, with particular emphasis on signaling networks governed by mTORC1, c-Myc, AMPK, and FOXO. We highlight ribosome biogenesis as a central hub linking mechanical loading, nutrient availability, inflammatory stress, and metabolic status to protein synthesis capacity. Evidence from human and animal studies demonstrates that impaired ribosome production and translational efficiency precede and predict muscle atrophy in disuse, aging, cancer cachexia, and chronic disease, whereas ribosome expansion is a prerequisite for sustained hypertrophy. Beyond quantitative regulation, we discuss the emerging concept of ribosome heterogeneity as a qualitative layer of translational control that may enable selective mRNA translation during muscle growth, stress adaptation, and degeneration. We further examine ribosome-mitochondria crosstalk as a critical but underexplored mechanism coordinating anabolic capacity with cellular energetics. Finally, we outline therapeutic implications, highlighting exercise, nutritional strategies, and indirect pharmacological interventions that preserve ribosomal competence, and propose ribosome-based biomarkers as promising tools for precision management of muscle-wasting disorders. Collectively, this review positions ribosome biology as a translationally relevant framework bridging molecular mechanisms with therapeutic perspectives in skeletal muscle atrophy and hypertrophy.

Keywords:  ribosome biogenesis; ribosome heterogeneity; skeletal muscle atrophy; therapeutic strategies; translational control

DOI:  https://doi.org/10.3390/biom16030406
Adv Drug Deliv Rev. 2026 Mar 21. pii: S0169-409X(26)00093-1. [Epub ahead of print]233 115859

Progress on cell therapy for skeletal muscle disorders.

Karim Azzag, Rita C R Perlingeiro.

  Cell therapy remains an attractive therapeutic option for the numerous genetic and non-genetic maladies affecting skeletal muscle. Since skeletal muscle is the largest tissue in the body, delivery has been notoriously challenging, but there have been significant advances, with several ongoing clinical trials of allogeneic and autologous cell transplantation aiming to replace diseased skeletal muscle with healthy and functional myofibers and muscle stem cells. Paracrine cellular approaches intended to enhance regeneration are also ongoing. In this review, we will provide an overview of the progress and current status of these different approaches, and discuss the forecast for future phases as well as the hurdles that need to be circumvented for the widespread application of cell therapy for skeletal muscle disorders.

Keywords:  Cell therapy; Clinical trial; Induced pluripotent stem cells; Muscular dystrophy; Myoblasts; Myogenic progenitors; Transplantation

DOI:  https://doi.org/10.1016/j.addr.2026.115859
JCI Insight. 2026 Mar 23. pii: e200054. [Epub ahead of print]11(6):

DAB2 in LGMD R2: a molecular link between disease progression and lipid dysregulation.

Celine Bruge, Nathalie Bourg, Emilie Pellier, Quentin Miagoux, Manon Benabides, Noella Grossi, Hassan Hayat, Margot Jarrige, Helene Polveche, Valeria Agostini, Anthony Brureau, Stephane Vassilopoulos, Teresinha Evangelista, Gorka Fernández-Eulate, Tanya Stojkovic, Isabelle Richard, Xavier Nissan.

  Limb-girdle muscular dystrophy R2 (LGMD R2) is an autosomal recessive disorder caused by dysferlin deficiency, leading to progressive muscle weakness and wasting. The lack of reliable clinical biomarkers has limited disease monitoring and therapeutic evaluation. Here, we identified Disabled-2 (DAB2) as a molecular and clinical indicator of disease state in LGMD R2. Transcriptomic profiling revealed a significant upregulation of DAB2 in induced pluripotent stem cell-derived (iPSC-derived) myotubes from patients, a finding validated in muscle biopsies from 14 dysferlin-deficient individuals and in dysferlin-deficient Bla/J mice, where DAB2 levels increased with disease progression. Importantly, AAV-mediated expression of full-length dysferlin restored DAB2 levels, supporting its value as a dynamic readout of disease activity for both disease monitoring and therapeutic response. Given the established role of DAB2 in clathrin-mediated endocytosis, particularly in LDL receptor internalization and cholesterol homeostasis, and the pathological lipid accumulation reported in LGMD R2, we investigated its contribution to lipid dysregulation. High DAB2 expression paralleled lipid deposition in patient muscles, iPSC-derived myotubes, and mouse tissue, whereas siRNA-mediated DAB2 knockdown reduced lipid accumulation in LGMD R2 myotubes. Collectively, these findings suggest that DAB2 functions as a mechanistic link between dysferlin deficiency, altered lipid handling, and disease severity, and they highlight its potential as a prognostic marker and therapeutic response measure for LGMD R2.

Keywords:  Biomarkers; Cell biology; Muscle biology; Transcriptomics; iPS cells

DOI:  https://doi.org/10.1172/jci.insight.200054
Cell Stress Chaperones. 2026 Mar 23. pii: S1355-8145(26)00032-5. [Epub ahead of print] 100176

Hypoxia-Induced GRP78 Activation Disrupts the Fndc5/Irisin Axis to Accelerate Skeletal Muscle Atrophy.

Shiqiang Liu, Linyao Xu, Xinru Song, Zhenhao Zhu, Yuxin Zhang, Yumeng Sun, Sharon Nyoja, Qin Wang, Jialin Gao, Lizhuo Wang, Huiyun Xu.

  Hypoxia is a potent inducer of skeletal muscle atrophy, however the underlying molecular mechanisms remain incompletely defined. Irisin, a myokine derived from Fndc5, plays a critical role in maintaining muscle mass and function, while endoplasmic reticulum (ER) stress has been implicated in muscle degeneration. Here, we investigated the interplay between hypoxia-induced ER stress and irisin regulation in skeletal muscle. Transcriptomic analyses and weighted gene co-expression network analysis (WGCNA) identified Fndc5 and Hspa5 (encoding GRP78) as key genes within hypoxia-related modules, displaying a strong negative correlation. In vivo, mice exposed to hypoxia showed reduced Fndc5/irisin expression accompanied by significant GRP78 upregulation. In vitro, chemical hypoxia and pharmacological induction of GRP78 by HA15 consistently suppressed Fndc5/irisin levels and impaired C2C12 myotube formation. Gene-miRNA network analysis suggested a shared post-transcriptional link between HSPA5-centered ER stress and FNDC5-associated atrophy programs under hypoxia, with miR-34a-5p as a candidate regulator. Collectively, these findings demonstrate that GRP78-driven ER stress under hypoxic conditions disrupts irisin production, thereby accelerating skeletal muscle atrophy. This work highlights a mechanistic axis linking ER stress to irisin deficiency in hypoxia-induced muscle wasting and provides new insights into potential therapeutic targets.

Keywords:  Fndc5; GRP78; Hypoxia; Irisin; Muscle Atrophy

DOI:  https://doi.org/10.1016/j.cstres.2026.100176
Int J Mol Sci. 2026 Mar 13. pii: 2649. [Epub ahead of print]27(6):

Bile Acid Metabolism Affects Muscle Regeneration in Aging Skeletal Muscle in a Manner Associated with Regulation of ABCB1 Expression.

Xiaoqing Wu, Yanan Wei, Qian Xue, Xia Li, Lihua Deng, Menghan Li, Yulan Liu, Jingtong Wang.

  The role of bile acid metabolism within the skeletal muscle microenvironment in sarcopenia remains unclear. This study investigated bile acid alterations and the function of the ATP Binding Cassette Subfamily B Member 1 (ABCB1) transporter in muscle microvascular endothelial cells (MMECs) during aging. Using a sarcopenic mouse model stratified by muscle density, we found elevated deoxycholic acid (DCA) and lithocholic acid (LCA) levels but reduced tauroursodeoxycholic acid (TUDCA) levels in muscle, correlating with downregulated ABCB1/P-glycoprotein expression. In vitro, inhibition of ABCB1 in MMECs impaired bile acid efflux, promoted inflammation, and compromised endothelial health. Conditioned medium from these MMECs reduced the viability, proliferation, and differentiation of C2C12 myoblasts, downregulated myogenic factors, and increased atrophy markers. Furthermore, we identified miR-135a-5p as a direct upstream regulator of ABCB1 in MMECs, and demonstrated that it mediates bile acid efflux impairment and subsequent myoblast dysfunction. Our findings reveal a novel "bile acid-MMEC-muscle" axis in sarcopenia, where miR-135a-5p-mediated ABCB1 downregulation in MMECs disrupts the local bile acid milieu and impairs muscle regeneration, highlighting ABCB1 as a potential therapeutic target for aging-related muscle loss.

Keywords:  ABCB1 transporter; bile acid metabolism; muscle microvascular endothelial cells; sarcopenia; skeletal muscle microenvironment

DOI:  https://doi.org/10.3390/ijms27062649
Medicina (Kaunas). 2026 Feb 27. pii: 456. [Epub ahead of print]62(3):

AKT Signaling Regulates Agrin-Mediated Acetylcholine Receptor Surface Density.

Natasha Jaiswal, Nathan Roger Lin, Colton Frank Lehnen, Amaan Tariq, Laura Lynn Lukov, Chi Zhang.

  Background and Objectives: Acetylcholine receptors (AChRs) are ligand-gated ion channels concentrated at the postsynaptic membrane of skeletal muscle fibers, where their abundance is essential for efficient neuromuscular transmission. The serine/threonine kinase AKT is a central signaling node in muscle homeostasis, regulating metabolism, growth, and survival. However, its role in the Agrin-mediated regulation of postsynaptic AChRs remains incompletely defined. Here, we demonstrate a novel role of AKT in regulating Agrin-induced AChR accumulation in differentiated C2C12 myotubes. Materials and Methods: Differentiated C2C12 myotubes were stimulated with Agrin in the presence or absence of the AKT inhibitor MK2206 during either the formation or maintenance phase. AChR clustering was quantified using α-bungarotoxin labeling. Expression of AChR subunits and neuromuscular junction-associated genes was assessed. Proteasome involvement was examined using the inhibitor MG132. Results: Pharmacological inhibition of AKT using MK2206 during either the formation or maintenance phase of Agrin stimulation significantly reduced α-bungarotoxin-labeled AChR intensity. AKT inhibition also attenuated Agrin-induced expression of multiple AChR subunits and neuromuscular junction-associated genes. Importantly, inhibition of proteasome activity with MG132 restored AChR intensity in the presence of AKT inhibition, suggesting that AKT signaling limits proteasome-dependent AChR loss. Conclusions: these findings identify AKT as a regulator of Agrin-mediated AChR accumulation and maintenance in vitro. These findings identify AKT as a critical integrator of metabolic and synaptic signaling required for postsynaptic receptor stability, with implications for neuromuscular disorders and muscle atrophy.

Keywords:  AKT signaling; Agrin; acetylcholine receptor; proteasome pathway; skeletal muscle

DOI:  https://doi.org/10.3390/medicina62030456
bioRxiv. 2026 Mar 04. pii: 2026.03.03.704460. [Epub ahead of print]

Exercise modulation of the alternative splicing landscape in human tissues.

MoTrPAC Study Group

The diverse health benefits of exercise are associated with multi-organ molecular responses. Alternative RNA splicing (AS) is an important determinant of transcriptome and proteome diversity. We profiled the temporal effects of acute endurance and resistance exercise on the AS landscape of human skeletal muscle, adipose tissue, and blood, and studied regulatory mechanisms through integrated multi-omic analyses. We identified 5102 distinct differential AS (DAS) events, with the majority modifying protein-coding sequence (89%) and being independent of altered RNA expression (67%). Endurance and resistance exercise induced differing patterns of AS alterations with divergent temporal trajectories. We inferred the DAS-associated RNA-binding and DNA-binding proteins. In skeletal muscle, where DAS events were the most abundant, DAS genes were enriched for muscle structure- and RNA splicing-related processes, and splicing machinery components were regulated at the protein phosphorylation, RNA, and AS levels. These findings implicate AS regulation as a major mediator of the responses to exercise.

DOI: https://doi.org/10.64898/2026.03.03.704460
Adv Sci (Weinh). 2026 Mar 24. e18471

Nicotinamide and Pyridoxine Supplementation Enhances Muscle Stem Cell Activity and Muscle Regeneration in Humans: A Randomized Placebo-Controlled Clinical Trial of High Force Eccentric Contraction Recovery in Healthy Young Men.

Grith Højfeldt, Joris Michaud, Ann Damgaard, Karoline Karlog, Eugenia Migliavacca, Sonia Karaz, Elham Pazirandeh-Micol, Odd E Johansen, Leonidas G Karagounis, Bjørk W Helge, William Hagemann, Michael Kjaer, Jerome N Feige, Pascal Stuelsatz, Abigail L Mackey.

  Muscle Stem Cells (MuSCs) drive muscle regeneration and slow pathological progression of muscle diseases. In preclinical models, nicotinamide (NAM) and pyridoxine (PN) synergistically increased MuSC proliferation and differentiation, and accelerated muscle regeneration. Herein we tested if NAM/PN could enhance MuSC activity and muscle regeneration in a randomized, placebo-controlled clinical trial. Men aged 18-49 years were supplemented daily with 714 mg NAM and 19 mg PN, or placebo, for 9 days following one session of damaging unilateral eccentric muscle contractions. The primary endpoint was MuSC activity via immunohistofluorescence on biopsy sections from the vastus lateralis muscle. Histological markers of muscle regeneration constituted secondary outcomes, and muscle damage was validated with clinical markers. 39 out of 43 enrolled participants completed the study. Supplementation of NAM/PN was well tolerated and increased blood concentrations of NAM and PN vitamers. 8 days after the contraction protocol, the number of Pax7, MyoD, and myogenin positive cells per damaged fiber was significantly higher in NAM/PN vs placebo groups (+29%-67%). NAM/PN also increased the proportion of regenerating fibers (+37%). Daily oral NAM/PN supplementation after high intensity muscle contractions enhances MuSC activity and accelerates muscle regeneration and repair, providing new opportunities for therapeutic applications in muscle recovery and muscle wasting disorders.

Keywords:  human muscle regeneration; muscle stem cell; muscle therapeutics; nicotinamide; pyridoxine; randomized placebo‐controlled clinical trial

DOI:  https://doi.org/10.1002/advs.202518471
J Appl Physiol (1985). 2026 Mar 26.

Muscle Atrophy After ACL Reconstruction Involves Molecular Mechanisms Beyond Unloading.

Alexander R Keeble, Sara Gonzalez-Velez, Nicholas T Thomas, Allison M Owen, Austin V Stone, Darren L Johnson, Julián Candia, Luigi Ferrucci, Marco Narici, Esther E Dupont-Versteegden, Brian Noehren, Martino V Franchi, Christopher S Fry.

  Anterior cruciate ligament reconstruction (ACLR) leads to profound muscle atrophy and weakness that remain resistant to rehabilitation. Although early recovery typically involves a brief period of limb unloading, the degree to which disuse alone accounts for muscle pathology after ACLR remains unclear. Here, we leveraged publicly-available RNA-seq datasets of muscle biopsies from vastus lateralis obtained seven days after ACLR or ten days after unilateral lower limb suspension (ULLS), each with matched control limbs, to directly compare disuse-driven and ACLR-specific early transcriptional responses. Despite similar periods of reduced loading, substantial transcriptomic divergence was identified using both intersection and interaction bioinformatic analyses. Only 16% of differentially expressed genes (DEGs) were common to both ACLR and ULLS, with ACLR eliciting over 1,000 more DEGs than ULLS. ACLR was characterized by reduced extracellular matrix (ECM) remodeling and robust induction of denervation-responsive genes which were not observed with unloading alone. These findings indicate that unloading contributes only modestly to the early muscle transcriptomic response following ACLR. Identifying potential ACLR-specific molecular effectors of atrophy advances our understanding of its unique pathophysiology that may underlie poorer functional recovery.

Keywords:  ACLR; RNA-sequencing; disuse; quadriceps; skeletal muscle

DOI:  https://doi.org/10.1152/japplphysiol.00088.2026
Biochem Pharmacol. 2026 Mar 20. pii: S0006-2952(26)00246-7. [Epub ahead of print]249 117913

Molecular mechanisms of skeletal muscle atrophy: clinical challenges and future therapeutic strategies.

Jiahuan Gong, Xinlei Yao, Tongxin Shang, Xia Li, Bingqian Chen, Hualin Sun.

  Skeletal muscle atrophy, characterized by loss of muscle mass and function, is a debilitating feature of chronic diseases, aging, and disuse.It fundamentally results from a sustained imbalance where rates of protein degradation surpass those of synthesis.Key drivers include the hyperactivation of proteolytic systems: the ubiquitin-proteasome system (UPS), autophagy-lysosome pathway (ALP), and calpain/caspase cascades. These systems are regulated by intricate signaling networks. The anabolic insulin-like growth factor 1/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway promotes protein synthesis, while catabolic pathways-including Forkhead box O (FOXO), myostatin/activin-Smad, nuclear factor-kappa B (NF-κB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT)-enhance protein breakdown. Recent research implicates oxidative stress, mitochondrial dysfunction, chronic inflammation, endoplasmic reticulum stress, epigenetic alterations, and programmed cell death (e.g., ferroptosis, pyroptosis) in a complex pathogenic network. Translating these mechanistic insights into effective therapies faces significant hurdles: the intricate interplay of molecular pathways, disparities between preclinical models and human disease, and limitations of current interventions. While exercise, pharmacology, and nutrition offer benefits, their applicability and efficacy are often constrained.A host ofemergingstrategies-such as stem cell and exosome therapies, mitochondrial quality control, and epigenetic modulation-remain exploratory. Future progress necessitates a multidimensional approach: employing multi-omics to decipher mechanism heterogeneity and identify biomarkers; developing human-relevant disease models; and pioneering combinatorial and precision therapies. Integrating these efforts is crucial for advancing the prevention and treatment of skeletal muscle atrophy, ultimately improving patient outcomes.

Keywords:  Autophagy; Cachexia; Mitochondrial dysfunction; Oxidative stress; Sarcopenia; Signaling pathways; Skeletal muscle atrophy; Therapeutic; Ubiquitin-proteasome system

DOI:  https://doi.org/10.1016/j.bcp.2026.117913
J Cachexia Sarcopenia Muscle. 2026 Apr;17(2): e70260

Single-Cell RNA-Sequencing Reveals Cachectic Satellite Cell Population in Muscle of Male Mice With Cancer Cachexia.

Alex Brown, Nicolás Collao, Aisha Saleh, Natasha Strong, Michael De Lisio, Nadine Wiper-Bergeron.

   BACKGROUND: Cancer cachexia leads to decreases in body mass, lean mass and fat mass, decreased therapeutic potential and ~20% of cancer-related deaths. While several studies have demonstrated changes to components of the muscle microenvironment with cancer cachexia, none have comprehensively assessed changes to cellular dynamics across the duration of cachexia development.
METHODS: Single-cell RNA-sequencing was performed on hindlimb muscles of male mice with 2-, 2.5- and 3.5-week subcutaneous Lewis-lung carcinoma tumours. Cell population changes were confirmed with flow cytometry.
RESULTS: Body mass (-0.51 g; p = 0.0014) and lean mass (-0.85 g; p = 0.0134) were decreased at 2.5 weeks and were significantly lower than sham. Increases in fat mass were attenuated starting at 2 weeks (0.70 g; p = 0.0408) compared to sham (1.55 g), and muscle cross-sectional area decreased at 3.5 weeks (-14.81%; p = 0.0022) compared to sham. We report a novel cachexia-associated satellite cell subcluster, comprising 71.1% of the population at 3.5 weeks, corresponding with a +20.33% increase in cell size (p = 0.0266) and +19.73% increase in the proportion of activated PAX7+MYOD+ cells after 24 h cultured on individual myofibres (p = 0.0226). This cachexia-associated subcluster was also present in C26 tumour-bearing mice and had a unique gene expression signature compared to other muscle wasting disorders. The cachexia-associated subcluster was enriched for signalling pathways (IL-17, TNF, p53, NF-κB, FoxO, adipocytokines, NOD-like receptor, MAPK and JAK-STAT) implicated in satellite cell dysfunction in cancer cachexia. Prior to the emergence of cachexia-associated satellite cells, increases in CD11b+ (+928.01%; p < 0.0001), Ly6Clow (+1080.85%; p < 0.0001), Ly6Chigh (+920.33%; p = 0.0002), F4/80+CD206- (+299.22%; p = 0.0039), F4/80+CD206+ (+1466.40%; p < 0.0001) immune cell populations were observed at 2 weeks compared to sham and returned to baseline by 2.5 weeks. There was also an increase in PDGFRα+ fibro-adipogenic progenitors at 2 weeks (+53.44%; p = 0.0398) and decreased CD31+ endothelial cells at 2 weeks (-57.37%; p = 0.0014) and 3.5 weeks (-39.78%; p = 0.0213) compared to sham, with no change in ITGA7+ satellite cells (p = 0.4271). Cell communication analyses revealed a decline in cell communication with cancer cachexia in all cells except for monocytes/macrophages, and a decrease in cell adhesion-related signalling in cachexia-associated satellite cells, which is important for satellite cell differentiation, and may help to explain differentiation defects with cachexia.
CONCLUSIONS: We describe a novel satellite cell subcluster unique to cachexia. We also identified increased immune cell and fibroadipogenic progenitor content and decreased endothelial cell content that precede muscle wasting with cancer, suggesting a role for these cell populations in satellite cell dysfunction and muscle atrophy in this condition.

Keywords:  cancer cachexia; muscle atrophy; muscle satellite cells; single‐cell RNA sequencing; skeletal muscle

DOI:  https://doi.org/10.1002/jcsm.70260
Res Sq. 2026 Mar 20. pii: rs.3.rs-8857997. [Epub ahead of print]

Inflammaging-induced TRAF3 degradation impairs AMP biosynthesis to drive sarcopenia.

Jinbo Li, Yaning Xing, Jinxiao Fan, Xing Li, Tian Jin, Congcong Zhang, Lilong Dong, Xiaokuan Zhang, Zhihui Liu, Pinliang Li, Qingfeng Yang, Tao Wu, Brendan Boyce.

Inflammaging is a recognized driver of age-related pathologies, yet its specific mechanistic link to sarcopenia remains poorly understood. Here, we identified a significant reduction of TNF receptor-associated factor 3 (TRAF3) in myoblasts exposed to aged serum and in skeletal muscles from both aging mice and humans. Genetic deletion of TRAF3 in myocytes or satellite cells induced early-onset sarcopenia and impaired regeneration, independent of non-canonical NF-κB signaling. Mechanistically, TRAF3 maintains energy homeostasis by stabilizing the key metabolic enzyme, adenylosuccinate lyase (ADSL), and its loss impairs AMP biosynthesis and ATP production. Muscle-specific TRAF3 restoration or AMP supplementation rescued sarcopenic phenotypes in TRAF3-deficient mice. Notably, neutrophil-derived transforming growth factor β1 (TGFβ1) caused IAP-mediated ubiquitination and degradation of TRAF3 in aged mice--a process reversible by the IAP inhibitor SM-164. Inducible neutrophil-specific TGFβ1 deletion prevented age-related sarcopenia. Our study establishes that TRAF3 is a key protective factor in muscle aging, and its loss mechanistically links inflammaging to bioenergetic deficits, suggesting new strategies to prevent age-related muscle wasting.

DOI: https://doi.org/10.21203/rs.3.rs-8857997/v1
Mech Ageing Dev. 2026 Mar 21. pii: S0047-6374(26)00030-8. [Epub ahead of print]231 112178

Methods of muscle atrophy analysis at the single-nucleus level.

Mercedes Grima-Terrén, Megan Rommelfanger, Silvia Campanario, Andrés Cisneros, Aina Calls-Cobos, Ignacio Ramírez-Pardo, Joan Isern, Antonio L Serrano, Eusebio Perdiguero, Pura Muñoz-Cánoves.

  Muscle atrophy and functional decline are shared manifestations of aging and neuromuscular pathologies. Deciphering the molecular mechanisms underlying muscle decline in these conditions has been slow, partly due to the difficulties of molecularly characterizing muscle fibers (the most abundant cell type in skeletal muscle). In contrast to single-cell RNA sequencing (scRNA-seq), which cannot resolve multinucleated fibers, single-nucleus RNA sequencing (snRNA-seq) enables gene expression profiling from isolated nuclei of hard-to-dissociate solid tissues, providing a key advantage for studying skeletal muscle. This paper presents a detailed protocol for proper tissue dissociation and nuclei isolation from skeletal muscle, optimized for downstream transcriptomic analysis. Additionally, we outline a basic bioinformatics pipeline applicable to snRNA-seq data from skeletal muscle, focusing on transcriptomic comparisons between homeostatic and atrophic muscle states.

Keywords:  Atrophy; Single-nucleus; Skeletal muscle

DOI:  https://doi.org/10.1016/j.mad.2026.112178
Front Cell Dev Biol. 2026 ;14 1761278

Sirt1 coordinates the mitochondrial UPR and myocellular proteostasis to preserve muscle integrity during muscle atrophy in zebrafish.

Qing Chen, Yu-Lun Chang, Miao-Wen Hung, Po-Lin Lee, Chen Hsin, Yi-Fan Lin.

   Introduction: The decline of mitochondrial homeostasis and proteostasis, the two key cell quality control mechanisms, is the hallmark of aging and age-related diseases. One of the most notable examples is the age-related progressive loss of muscle mass, quality, and strength --a condition known as sarcopenia. In atrophic muscle, mitochondrial dysfunction and proteostasis impairment frequently occur together, indicating a potential association between the decline of mitochondrial homeostasis and proteostasis. However, the mechanism by which these two modes of cell quality control are coordinated remains poorly understood.
Methods: We employed dexamethasone-induced muscle atrophy models in both larval and adult zebrafish to investigate the role of cell stress responses in muscle maintenance. Mitochondrial stress was assessed by measuring the mitochondrial unfolded protein response (UPRmt) activity using qRT-PCR and reporter analyses. Proteostasis impairment was evaluated by detecting insoluble polyubiquitinated protein aggregates via Western blotting. Muscle integrity was examined histologically in larval and adult tissues. We performed these assays in sirt1 loss of function conditions (genetic mutation and pharmacological inhibition). Furthermore, to elucidate the mechanism by which Sirt1 regulates proteostasis and muscle preservation, we inhibited the mitochondrial fatty acid oxidation (mFAO) using etomoxir.
Results: Inhibition of Sirt1 markedly exacerbated muscle deterioration and proteostasis impairment under dexamethasone-induced muscle atrophy in zebrafish. Mechanistically, Sirt1 is required for activation of the UPRmt, which in turn promotes expression of the mFAO gene cpt1b. Pharmacological inhibition of Cpt1 using etomoxir phenocopied the defects in muscle integrity and proteotoxic stress observed following Sirt1 inhibition. Importantly, enhancement of proteostasis via hormetic heat shock partially rescued the etomoxir-induced muscle defects.
Discussion: We have demonstrated that muscle atrophic stress induced by dexamethasone treatment activates the UPRmt in zebrafish. The UPRmt is part of the activity of a cell stress regulator, Sirt1, to promote mitochondrial function and preserve muscle integrity during muscle atrophy. Notably, suppressing the UPRmt via Sirt1 inhibition leads to protein aggregation and the ultimate loss of muscle mass, indicating a link between mitochondrial function and proteostasis. We have further shown that mitochondrial metabolism plays a role in proteostasis regulation, as pharmacological inhibition of the mFAO exacerbates dexamethasone-induced proteotoxicity. Collectively, our findings have uncovered a previously uncharacterized regulatory mechanism linking UPRmt signaling to myocellular proteostasis, and highlight the activity of Sirt1, which coordinates these two key cell quality control mechanisms, in muscle preservation during muscle atrophy.

Keywords:  SIRT1; UPRmt; mitochondrial dysfunction; mitochondrial homeostasis; muscle atrophy; myocellular proteostasis; proteostasis

DOI:  https://doi.org/10.3389/fcell.2026.1761278
Cell Death Discov. 2026 Mar 27.

Cannabinoid type 2 receptor regulates skeletal muscle regeneration by NLRP3-GSDMD mediated macrophage pyroptosis after injury.

Xinjie Li, Haomiao Yuan, Shuyang Mu, Jiaqing Pan, Fuyuan Zhang, Shukui Du, Jin Liu, Anran Qu, Yingfu Sun, Linlin Wang, Ping Huang, Rui Zhao, Dawei Guan.

Skeletal muscle repair after injury requires coordinated immune responses. The cannabinoid type 2 receptor (CB2R) has been implicated in this process; however, its molecular mechanism in regulating inflammation and muscle regeneration, particularly whether it involves modulating macrophage pyroptosis-a specific pro-inflammatory cell death-remains elusive. This study proposes and validates a novel mechanism: CB2R activation protects skeletal muscle by inhibiting the PI3K/AKT/NF-κB signaling axis, thereby suppressing NLRP3 inflammasome-mediated pyroptosis in macrophages and ultimately fostering a pro-regenerative microenvironment. Using a mouse contusion model and conditioned medium assays, we demonstrate that CB2R deficiency exacerbates macrophage pyroptosis, elevates inflammatory mediators, and impairs muscle repair. This effect is driven by hyperactivation of the PI3K/AKT/NF-κB pathway, as blocking this pathway alleviated the inflammatory response and restored the expression of muscle regeneration markers. Furthermore, inflammatory signals released from CB2R-deficient macrophages directly impaired the development of muscle cells in the conditioned medium-based assay. Our findings uncover a novel non-cell-autonomous mechanism whereby CB2R supports skeletal muscle regeneration by restraining macrophage-driven inflammation and maintaining a repair-permissive environment, providing new insights into skeletal muscle repair from the perspective of the regenerative microenvironment and further expand the current understanding of muscle regeneration following injury. This work provides a robust mechanistic rationale for repurposing CB2R agonists as promising therapeutic strategies for muscle injury.

DOI: https://doi.org/10.1038/s41420-026-03077-z
bioRxiv. 2026 Mar 05. pii: 2026.03.03.709376. [Epub ahead of print]

Females are protected from semaglutide-induced muscle loss in ob/ob mice.

Subhasmita Rout, Takuya Karasawa, Shinya Watanabe, Amandine Chaix, Micah J Drummond, Katsuhiko Funai, Ran Hee Choi.

Obesity is a major contributor to cardiometabolic disease, and pharmacological therapies such as semaglutide are increasingly used to induce weight loss. However, the commonly used diet-induced obesity model in C57BL/6J mice is limited by relative resistance to weight gain in females, complicating the study of sex-specific effects. Here, we used leptin-deficient ob/ob mice, which develop severe early-onset obesity in both sexes, to investigate sex-specific responses to semaglutide on skeletal muscle mass, function, and mitochondrial metabolism. The ob/ob mice were treated daily with semaglutide or vehicle for three weeks, followed by assessments of body composition, muscle and organ mass, muscle contractile function, and mitochondrial efficiency. Semaglutide induced comparable reductions in body weight and food intake in both sexes but elicited distinct sex-specific changes in body composition. Male mice exhibited losses in both skeletal muscle and organ mass, whereas female mice preferentially lost fat and organ mass while preserving skeletal muscle. Despite these divergent structural adaptations, muscle force generation remained intact in both sexes. Collectively, these findings reveal pronounced sexual dimorphism in skeletal muscle and metabolic remodeling during pharmacologically induced weight loss, highlighting the importance of considering biological sex when evaluating the metabolic and therapeutic effects of anti-obesity interventions.
Article Highlight: C57BL/6J mice are limited by relative resistance to weight gain in females, complicating the study of sex-specific effects. So, we wanted to determine the sex-specific effect of semaglutide on skeletal muscle function, and mitochondrial metabolism in ob/ob mice. We assessed body composition and ex-vivo muscle force following the treatment and found that the female ob/ob mice are protected from semaglutide-induced skeletal muscle mass loss. These findings demonstrate sex-specific effects of semaglutide, highlighting the need to consider biological sex in GLP-1RA-based therapies.

DOI: https://doi.org/10.64898/2026.03.03.709376
Int J Mol Sci. 2026 Mar 18. pii: 2746. [Epub ahead of print]27(6):

Exercise-Induced Exerkines Modulate Autophagy: Implications for Interorgan Crosstalk in the Hallmarks of Ageing.

Qi Deng, Jielun Huang, Cenyi Wang, Jiling Liang.

  Population aging and widespread sedentary lifestyles have increased the prevalence of chronic non-communicable diseases, many of which are linked to progressive disruptions of cellular homeostasis. Autophagy, a conserved cellular degradation and recycling pathway, plays a central role in maintaining metabolic flexibility, proteostasis, and organ function. However, aging and physical inactivity impair autophagic regulation, thereby contributing to the development of sarcopenia, cardiovascular diseases, metabolic disorders, and neurodegenerative diseases. Physical exercise is a non-pharmacological intervention that can restore autophagic activity and confer systemic health benefits in multiple preclinical and clinical contexts. Increasing evidence indicates that these benefits are mediated not only by local tissue adaptations but also by complex inter-organ communication. Central to this process are exercise-induced bioactive factors, collectively termed exerkines, including myokines, cardiokines, adipokines, hepatokines, osteokines, and circulating miRNAs. Rather than acting independently, exerkines form an integrated signaling network that fine-tunes autophagic flux across multiple tissues. Exerkine-mediated regulation of autophagy involves key pathways such as AMPK/mTOR, FoxO, SIRT1, ULK1, and TFEB, thereby coordinating energy metabolism, mitochondrial quality control, inflammation, and protein turnover in skeletal muscle, heart, liver, adipose tissue, bone, and the central nervous system. This review summarizes current evidence on representative exerkines and their roles in autophagy-dependent inter-organ crosstalk, highlighting the exercise-exerkine-autophagy axis as a promising target for preventing and managing chronic diseases.

Keywords:  autophagy; exercise; exerkines; miRNAs; sarcopenia

DOI:  https://doi.org/10.3390/ijms27062746
Mol Ther. 2026 Mar 24. pii: S1525-0016(26)00211-X. [Epub ahead of print]

CRISPR-Cas9-Mediated Upregulation of Utrophin Ameliorates Duchenne Muscular Dystrophy.

Maëlle Ralu, Simon Guiraud, Sumitava Dastidar, Paola Galbiati, Emilia Sadaoui, Fetta Mazed, Fatima Amor, Anne de Cian, Isabelle Richard, Kamel Mamchaoui, Giuseppe Ronzitti, Francesco Saverio Tedesco, Mario Amendola.

Duchenne muscular dystrophy is a lethal neuromuscular disorder caused by loss of dystrophin. Upregulating utrophin, a dystrophin paralogue, is a promising gene therapy approach. Here, we present a CRISPR-Cas9-based strategy to enhance utrophin expression by disrupting repressor binding sites. Using a Cas9/gRNA ribonucleoprotein complex we disrupted several such sites in DMD myoblasts and identified micro-RNA Let-7c binding site as effective in relieving repression of the UTRN gene. Interestingly, Cas9-generated indels were as effective as the complete removal of Let-7c binding site in upregulating UTRN expression, with minimal off-target effects. In a three-dimensional tissue-engineered human skeletal muscle model of DMD, this editing strategy resulted in significant utrophin upregulation and functional improvements of calcium dysregulation and muscle contraction. Finally, in mdx mice, local or systemic delivery of recombinant adeno-associated viruses encoding Cas9 and gRNA targeting the Let-7c binding site resulted in utrophin upregulation and amelioration of muscle histopathology and function. These findings provide the foundations for a mutation-independent, potentially universal gene editing therapeutic strategy for DMD.

DOI: https://doi.org/10.1016/j.ymthe.2026.03.025
Int J Mol Sci. 2026 Mar 18. pii: 2753. [Epub ahead of print]27(6):

Aging Impairs Intramuscular Collagen Remodeling Responses to Repeated Passive Stretching in Skeletal Muscle.

Yuji Kanazawa, Kenichiro Miyahara, Tatsuo Takahashi, Ryo Miyachi, Mamoru Nagano, Satoshi Koinuma, Naoya Iida, Takao Inoue, Yasufumi Shigeyoshi.

  Aging is associated with changes in intramuscular collagen structure and metabolism, which may impair mechanical adaptability and regenerative capacity. We investigated the effects of aging and repeated passive stretching on intramuscular collagen remodeling in the tibialis anterior muscles of mice. The tibialis anterior muscles of young and aged mice were exposed to repeated passive stretching, and the localization of collagen and collagen-related factors was evaluated. Baseline gene expression of collagens I and IV was significantly reduced in aged muscles and was not restored by stretching. Repeated passive stretching increased the area and intensity of collagen I immunoreactivity in both young and aged mice but produced little change in collagen IV. Stretch-induced dynamic changes in lysyl oxidase-positive cells in the extracellular matrix (ECM) were evident in young mice but were markedly attenuated in aged mice. In addition, matrix metalloproteinases (MMP2 and MMP9) mRNA and protein expressions did not differ between groups. No significant age- or stretch-dependent changes were observed in the localization of advanced glycation end products. These findings suggest that although the increase in fibrillar collagen in response to stretching is maintained with aging, the regulatory mechanisms controlling ECM stabilization, particularly those related to cross-linking dynamics, may be impaired.

Keywords:  aging; extracellular matrix; lysyl oxidase; matrix metalloproteinase; stretching

DOI:  https://doi.org/10.3390/ijms27062753
bioRxiv. 2026 Mar 05. pii: 2026.03.02.705347. [Epub ahead of print]

Molecular Transducers of Physical Activity Consortium (MoTrPAC): Initial Insights into the Dynamic Human Responses to Exercise.

MoTrPAC Study Group

The goal of the Molecular Transducers of Physical Activity Consortium (MoTrPAC) is to examine the physiological and molecular basis for health benefits in response to acute and chronic exercise. Prior to COVID-19 suspension, healthy, sedentary participants (N=206, 18-74y) were randomized to endurance exercise (N=80), resistance exercise (N=81), or non-exercise control (N=45) interventions. The prescribed vigorous acute endurance and resistance exercise bouts induced physiological and metabolic perturbations relative to resting homeostasis. The supervised chronic (3d/wk, 12wk) endurance or resistance training programs robustly improved several physiological parameters (i.e., VO 2 peak, muscular strength). Temporal biospecimen (blood, muscle, and adipose) collections and processing coupled to the acute exercise bouts were highly successful. In most cases, over 90% success was achieved for blood, muscle, and adipose samples. Endurance and resistance exercise induced distinct acute and chronic physiological responses, which provide a framework to interrogate the molecular basis for health adaptations to these two popular exercise modalities.
Abstract Figure:

DOI: https://doi.org/10.64898/2026.03.02.705347
Exerc Sport Sci Rev. 2026 Mar 26.

Seeking the Mechanism for Reversal of Enhanced Insulin Sensitivity after Acute Exercise.

Haiyan Wang, Gregory D Cartee.

  A single endurance exercise session can elevate subsequent insulin-stimulated glucose uptake by skeletal muscle. Refeeding a high-carbohydrate diet postexercise accelerates the reversal of exercise-enhanced insulin-stimulated glucose uptake. We hypothesize that increased glucose flux through the hexosamine biosynthetic pathway mediates the reversal of postexercise-enhanced insulin-stimulated glucose uptake observed with high dietary carbohydrate intake. Summary: We hypothesize that high-carbohydrate intake postexercise favors greater flux through the hexosamine pathway which speeds reversal of exercise-improved insulin sensitivity.

Keywords:  exercise; glucose transport; glycogen; hexosamine biosynthetic pathway; insulin resistance; skeletal muscle

DOI:  https://doi.org/10.1249/JES.0000000000000385
Geroscience. 2026 Mar 24.

Active immunization against myostatin and activin A improves skeletal muscle performance in growth hormone-deficient mice.

Mishfak A M Mansoor, Sarah A Ashiqueali, Md Tanjim Alam, Fabrizzio Lijeron-Herrera, Xiang Zhu, Jash Trivedi, Amanda Lasseter, Augusto Schneider, Lisa Flores, Hu Wang, Xianlin Han, Yuji Ikeno, Jefferey B Mason, Brett Thibodeaux, Michal M Masternak.

  Sarcopenia is a significant age-related hurdle in older adults due to immobilization, prolonged bed rest, loss of resilience, and diminished quality of life. Despite its high prevalence, there are no FDA-approved drugs for sarcopenia to date, underscoring the critical need to explore novel therapeutics. Here, we explore an active immunization strategy to suppress the activity of negative regulators of muscle growth, specifically myostatin and activin A. Importantly, our primary objective was to determine whether long-term MSTN/Act A inhibition can enhance muscle performance independently of hypertrophy, under conditions of impaired GH/IGF-1 signaling. Using a long-lived growth hormone (GH)-deficient murine model, we investigated whether myostatin and activin A immunization improves muscle strength, independently of changes in muscle mass. We showed that, while in the presence of GH, this immunization increases lean mass and grip strength improvement. Notably, in the GH-deficient mice, grip strength is independent of muscle mass gain. Myostatin inhibition modulated transcriptomic shift in the gastrocnemius muscle, allowing for remodeling of the skeletal muscle and an increase in energy expenditure. Consistent with these findings, aged mice subjected to the same immunization schedule exhibited improved grip strength, along with alterations in lipid metabolism within the gastrocnemius muscle. Altogether, these results suggest that this inhibition strategy alters the contractility of the skeletal muscle, allowing for enhanced performance and offering a promising therapeutic strategy for muscle wasting.

Keywords:  Growth hormone; Myostatin and activin A; Sarcopenia

DOI:  https://doi.org/10.1007/s11357-026-02207-w
BMC Med. 2026 Mar 26.

Multi-omics analysis reveals sex-specific etiology of human muscle weakness following musculoskeletal injury.

Alexander R Keeble, Allison M Owen, Nicholas T Thomas, Sara Gonzalez-Velez, Camille R Brightwell, Tyler Barnes, Douglas E Long, Philip A Kern, Caitlin E Conley, Austin V Stone, Darren L Johnson, Yuan Wen, Brian Noehren, Christopher S Fry.

   BACKGROUND: Musculoskeletal injuries comprise a growing source of disability worldwide, and the recovery of muscle strength following injury is a critical determinant of patient reported outcomes. Females experience exacerbated muscle atrophy, poorer outcomes, and higher re-injury rates, necessitating a comprehensive interrogation of sex-specific skeletal muscle differences. Our purpose in the current study was to perform an unbiased transcriptomic profiling of muscle samples to identify putative sex-specific molecular targets to enhance recovery in patients who underwent anterior cruciate ligament reconstruction (ACLR).
METHODS: We performed cellular phenotyping, bulk and single nucleus RNA-sequencing on muscle biopsy samples obtained from thirty-six participants (18 M, 18F). Muscle samples were obtained from the ACLR and contralateral limb with follow-up tissue collection of the injured limb also occurring at seven days and four months post-ACLR. Transcriptomic analyses illuminated putative molecular mechanisms through which sex influences muscle recovery following acute injury.
RESULTS: Females exhibited greater muscle atrophy relative to males at 4 months post-ACLR compared to the uninjured limb. Bulk and single nucleus paired-limb transcriptomic analyses revealed the emergence of sex-specific myonuclear signaling cascades that demonstrate impaired reactive oxygen species scavenging in females. Females exhibited attenuated SOD2 expression that was associated with increased indices of oxidative stress and protein damage. Within females, angiogenesis signaling was also impaired and associated with capillary rarefaction after reconstructive surgery.
CONCLUSIONS: These findings reveal inherent sex-based differences in muscle pathology that likely necessitate unique clinical treatments following musculoskeletal injury.

Keywords:  ACL; Anterior cruciate ligament reconstruction; Capillary; Reactive oxygen species; Skeletal muscle

DOI:  https://doi.org/10.1186/s12916-026-04818-8
Exp Biol Med (Maywood). 2026 ;251 10929

Global MyoG research 2004-2024: a bibliometric analysis of trends and translational implications.

Luoming Hu, Weizhong Zhuang, Weimin Chen, Song Yang, Shuo Chen, Xin Wang, Qiang Gao, Jimei Chen.

  Myogenin (MyoG) is a core myogenic transcription factor that orchestrates myoblast differentiation and myofiber maturation and has been increasingly implicated in skeletal muscle degeneration and rhabdomyosarcoma, yet its global research landscape has not been systematically characterized. In this study, we performed a bibliometric analysis of MyoG-related publications from 2004 to 2024 retrieved from the Web of Science Core Collection. A total of 402 articles authored by 2,402 researchers from 1,148 institutions across 165 countries and regions were analyzed using VOSviewer, CiteSpace and R-based bibliometric tools. We quantified annual publication output, identified leading countries, institutions, authors and journals, and reconstructed collaboration, co-citation and keyword co-occurrence networks to delineate thematic evolution. The global pattern showed a multipolar structure dominated by the United States and China, with European institutions forming an additional hub and emerging countries contributing with growing but comparatively lower impact. Research hotspots exhibited a clear progression from early work on molecular mechanisms (DNA binding, MyoD family interactions, chromatin remodelling) toward regenerative biology (satellite cell regulation, muscle regeneration) and, more recently, disease-oriented studies focused on muscle atrophy, Duchenne muscular dystrophy and rhabdomyosarcoma. Landmark co-cited studies established MyoG as an indispensable regulator of skeletal muscle differentiation and highlighted its expanding relevance in pathological remodelling and therapeutic targeting. Future work is expected to concentrate on decoding MyoG-centred regulatory networks in degenerative muscle disease, integrating single-cell and spatial transcriptomics with functional genomics and multi-omics, and developing MyoG-based diagnostic and targeted therapeutic strategies. Despite the intrinsic limitations of single-database and citation-based approaches, this study provides a panoramic overview of two decades of MyoG research and offers a structured framework to guide future basic and translational investigations in muscle biology and oncology.

Keywords:  bibliometric analysis; muscle atrophy; myogenin (MyoG); regenerative medicine; rhabdomyosarcoma

DOI:  https://doi.org/10.3389/ebm.2026.10929
Cell Res. 2026 Mar 25.

Transcriptomic advances in studies of muscle stem cell aging: From bulk to single-cell and beyond.

Soochi Kim, Seung Pil Pack, Thomas A Rando.

Advances in transcriptomic technologies have progressively transformed the questions we can ask and answer about muscle stem cells (MuSCs) during aging. Early microarray and bulk RNA sequencing studies established foundational population-level signatures of aged MuSCs, including attenuation of myogenic and metabolic programs as well as induction of inflammatory and stress-associated transcription. However, these averaged readouts obscured cell-to-cell variability and rare functional states. The transition to single-cell and single-nucleus RNA sequencing marked a turning point by resolving MuSC heterogeneity and revealing that MuSC aging is not purely stochastic. Instead, aged MuSC pools show reproducible changes in state composition, delayed or altered myogenic lineage progression, and selective vulnerability of specific functional subsets. Emerging spatial transcriptomic approaches, although still limited by sensitivity and cell-type discrimination in muscle, are beginning to place these MuSC states into their native tissue context, directly linking transcriptional states, niche organization, and age-associated remodeling. In parallel, integrative multi-omic designs that pair transcriptomics with chromatin accessibility and metabolic measurements have strengthened mechanistic connections among age-associated gene programs, epigenetic remodeling, and metabolic state shifts. Finally, computational frameworks - including trajectory inference, dynamic modeling, and machine learning - are increasingly applied to high-dimensional transcriptomic data to predict aging trajectories and identify candidate rejuvenation targets. In this Perspective, we trace the evolution of transcriptomic technologies through the lens of MuSC aging and highlight how increasing resolution has reframed core models of MuSC decline and plasticity.

DOI: https://doi.org/10.1038/s41422-026-01240-w
Muscles. 2026 Mar 03. pii: 19. [Epub ahead of print]5(1):

Phosphodiesterase 4 (PDE 4) Inhibition Reduces Ischemia-Reperfusion-Induced Leucocyte Infiltration, Apoptosis and Mitochondrial Fission Markers in Mice Skeletal Muscles Four Hours After Ischemia Onset.

Anne-Laure Charles, Liliane Tetsi, Giulia Quiring, Cindy Barnig, Margherita Giannini, Alain Meyer, Anne Lejay, Claire Lugnier, Bernard Geny.

  Peripheral arterial disease is a leading cause of amputation and/or death worldwide. Phosphodiesterase 4 (PDE 4) inhibitors demonstrated beneficial effects in ischemia-reperfusion (IR) settings, but whether PDE 4 inhibition protects skeletal muscle against IR deleterious effects is unknown. We therefore performed limb IR (two hours each) in twenty-one male Swiss mice (12-16-week-old) treated or not with Rolipram (1 mg/kg i.p. 30 min before ischemia and 5 min before reperfusion). The muscles were analyzed 4 h after the onset of ischemia. IR significantly increased leucocyte infiltration (93.13 ± 6.886 vs. 150.1 ± 18.38 cells/mg of muscle, p < 0.05) and apoptosis (Bax/Bcl2 ratio, +239%, p < 0.05), together with enhanced mitochondrial fission transcripts (+224% for Drp1, p < 0.01 and +368%, p < 0.0001 for Fis1), and decreased mitochondrial respiration and antioxidant defense. PDE 4 inhibition reduced leucocyte infiltration (150.1 ± 18.38 vs. 55.58 ± 13.83; p < 0.01) and apoptosis (+67%, NS) in association with reduced fission markers (+91% for Drp 1 and +111%, p < 0.05, for Fis 1). Muscle mitochondrial respiration did not improve. In conclusion, PDE 4 inhibition using Rolipram partly protected skeletal muscles against IR-induced deleterious effects. These data support further studies investigating the usefulness of leucocytes modulation in lower-limb IR and a potential beneficial effect of PDE 4 inhibition in peripheral arterial disease.

Keywords:  PDE 4; apoptosis; cyclic nucleotide phosphodiesterase (PDE) inhibition; fission; inflammation; ischemia–reperfusion; leucocytes; mitochondria; muscle; oxidative stress

DOI:  https://doi.org/10.3390/muscles5010019
J Physiol. 2026 Mar 27.

Robust immune cell infiltration and macrophage senescence occur within a week of recovery after limb immobilization in older adult skeletal muscle.

Chad M Skiles, Zachary J Fennel, Paul-Emile Bourrant, Elena M Yee, Robert J Castro, Hannah A Zabriskie, Melina Itinose, Mark A Supiano, Ryan M O'Connell, Micah J Drummond.

  Immune cells are critical for modulating inflammation and extracellular matrix remodelling for effective muscle regrowth following disuse atrophy. However, disrupted macrophage function and accumulation of cellular senescence may limit muscle recovery in ageing. The present study aimed to compare changes in the cellular dynamics of muscle macrophages, cellular senescence and collagen content during early recovery following 14 days of unilateral limb immobilization in young (n = 18; ∼24 years) and older male and female adults (n = 18; ∼69 years). Participants underwent 14 days of immobilization followed by 7 days of re-ambulation. Muscle biopsies were collected at baseline, post-immobilization, and at 2 and 7 days of recovery. During re-ambulation, older adults exhibited elevated immune cell infiltration (haematoxylin and eosin, CD45+), higher CD68+ CD206+ macrophage content and greater muscle collagen deposition (Sirius Red) compared to their young counterpart. Furthermore, cellular senescence (SA-β-galactosidase+) was elevated, including a high number of macrophages co-labelled with p21 in older skeletal muscle during recovery. At 7 days of recovery, the amount of macrophage infiltration was positively associated with cellular senescence, whereas the senescent macrophage cell population was significantly correlated to the Sirius Red percent area. Our findings suggest that an age-altered immune cell response and the accumulation of senescent macrophages may disrupt collagen remodelling during early muscle recovery following disuse. KEY POINTS: Age-related impairments in muscle recovery following disuse remain a significant challenge. Immune cells, particularly macrophages, play critical role in muscle remodelling. Muscle macrophage characteristics during the early phase of recovery following disuse in older adults remain unclear. We compared changes in immune cell content, cellular dynamics, cellular senescence, and collagen content during recovery (2 days and 7 days) following 14 days unilateral limb immobilization in young (18-35 years) and older male and female adults (≥60 years). During muscle recovery, older adults (vs. young), increased muscle collagen content concurrent with an infiltration of macrophages. This response was characterized by a distinct predominance of CD68+ CD206+ macrophages and a parallel increase in senescent macrophages. Our findings suggest that an altered immune cell response and accumulation of senescent macrophages may disrupt tissue remodelling during muscle recovery in aged muscle.

Keywords:  ageing; disuse atrophy; fibrosis; immunosenescence; inflammation

DOI:  https://doi.org/10.1113/JP290346
Front Endocrinol (Lausanne). 2026 ;17 1788603

Epigenetic inhibition of class I histone deacetylases by MS-275 attenuates diabetic skeletal muscle atrophy via Akt/ARK5-FoxO and myostatin-Smad signaling.

Youngho Son, Hye-Eun Byeon, Sung-E Choi, Youngha Kim, Yu Jung Heo, Soon Beom Kwon, Jaemyung Choi, Seung Jin Han, Jayoung Jeon, Hae Jin Kim, Nami Lee, Kwan-Woo Lee.

   Background: Sarcopenia is highly prevalent in individuals with diabetes and is associated with impaired physical function and increased mortality. Diabetes-associated skeletal muscle atrophy is driven by chronic inflammation, dysregulated anabolic-catabolic signaling, and activation of ubiquitin-proteasome-mediated protein degradation. Emerging evidence suggests that histone deacetylases (HDACs) act as epigenetic regulators of metabolic and inflammatory pathways; however, their role in diabetic sarcopenia remains incompletely understood.
Methods: Male db/db mice were used as a model of diabetes-associated muscle atrophy and treated with MS-275 (entinostat), a selective class I HDAC inhibitor, for 4 weeks. Skeletal muscle mass and fiber cross-sectional area were assessed by magnetic resonance imaging and histological analysis. Inflammatory responses, myostatin signaling, and Akt/ARK5-FoxO-mediated catabolic pathways were evaluated using immunohistochemistry, quantitative PCR, ELISA, and western blotting.
Results: MS-275 treatment significantly restored skeletal muscle mass and myofiber size in db/db mice. These effects were accompanied by marked reductions in macrophage infiltration, pro-inflammatory cytokine expression, and NF-κB activation. MS-275 also suppressed circulating myostatin levels and attenuated downstream Smad2/3 signaling. Furthermore, MS-275 restored Akt and ARK5 phosphorylation and promoted FoxO1/3 phosphorylation, resulting in decreased expression of the muscle-specific E3 ubiquitin ligases MuRF1 and atrogin-1.
Conclusion: Our findings demonstrate that epigenetic inhibition of class I HDACs by MS-275 attenuates diabetes-associated skeletal muscle atrophy by coordinately suppressing inflammatory signaling and myostatin-driven catabolic pathways while restoring Akt/ARK5-FoxO signaling. These results suggest that class I HDACs are key epigenetic regulators of diabetic muscle wasting and that targeting their activity provides important mechanistic insights for preserving skeletal muscle mass in diabetic sarcopenia.

Keywords:  AKT/FoxO signaling; SMAD signaling; db/db mouse; diabetic sarcopenia; epigenetic regulation; histone deacetylase; myostatin; skeletal muscle atrophy

DOI:  https://doi.org/10.3389/fendo.2026.1788603