bims-moremu 2026-05-03 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–05–03
thirty-two papers selected by
Anna Vainshtein, Craft Science Inc.

Mechanical Overload-Induced Retinoid Metabolism Is Involved in Protein Synthesis in Skeletal Muscle of Female Mice.
The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice.
From mice to muscle: does MitoQ translate to human strength in ageing?
The interaction between exercise and autophagic flux in neurodegenerative muscle loss.
Ribosome dynamics during skeletal muscle repair and regeneration in mice and humans.
Macrophage and fibro-adipogenic progenitor (FAP) communication in skeletal muscle regeneration: Tissue homeostasis and pathogenic remodeling.
Mechanobiological landscape of muscle stem cells.
Low-dose Simulated Galactic Cosmic Radiation Exposure After Hindlimb Unloading Has Long-term Impact on Skeletal Muscle Metabolic Proteins in Female Mice.
Multi-omics reveals molecular signatures of moderate intensity exercise and identifies candidate exercise mimetics in mice.
GRP94 Promotes the Fusion of Mouse C2C12 Myoblasts and the Regeneration of Skeletal Muscle Injuries Through Myomaker.
RIPK3 Inhibition Mitigates Denervated Muscle Atrophy via NOX4-Mediated Mitochondrial Restoration and Inflammation Suppression.
Age-related transcriptional drift and physiological adaptation in long-living Ames dwarf skeletal muscle.
Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles.
Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy.
Ankrd2 may alleviate denervation-induced skeletal muscle atrophy by inhibiting inflammation.
Mitochondrial Activity Localization in the Skeletal Muscle and Its Individual Fibers Across Tetrapods.
Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.
The Effects of Palmitoylethanolamide or Ibuprofen on the Abundance Profile and Synthesis Rate of Proteins in C2C12 Skeletal Myotubes.
Sirtuin 1 as an emerging exerkine in the aging process: unveiling its multifaceted biological roles.
MESH1-mediated coenzyme A degradation drives ferroptosis sensitivity and muscle pathology.
Divergent Roles of Skeletal Muscle 11β-HSD1 in Age-Related and Chronic Kidney Disease-Associated Sarcopenia.
Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies.
Muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICU acquired weakness.
Elevation of Mitochondrial Ca2+ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse Soleus Muscle.
Inflammation-Linked Muscle Atrophy in Limb Girdle Muscular Dystrophy R1 (LGMDR1): Insights into Disease Mechanisms.
Intraperitoneal Administration of Cardiolipin Enhances Mitochondrial Respiration in Skeletal Muscle of Male Mice.
Reduced Skeletal Muscle Perfusion Accompanies Skeletal Muscle Atrophy After Severe Spinal Cord Injury.
Combining SMN2 splicing modifiers with HDAC6 inhibition improves spinal muscular atrophy outcomes.
Strategic role of calpains in modulation of NF-κB activity in skeletal muscle.
Ambient Temperature Shapes Skeletal Muscle Growth and Fiber-Type Plasticity in Mice.
Skeletal muscle as an endocrine and paracrine organ in breast cancer biology: a narrative review.
Nuclear envelope budding enables export of large transcripts in muscle cells.

J Nutr Sci Vitaminol (Tokyo). 2026 ;72(2): 176-181

Mechanical Overload-Induced Retinoid Metabolism Is Involved in Protein Synthesis in Skeletal Muscle of Female Mice.

Tomoya Kitakaze, Aino Nakatsuji, Naoki Harada, Ryoichi Yamaji.

  Although exercise is the most effective strategy for increasing the skeletal muscle mass, the underlying molecular mechanisms remain poorly understood. We previously demonstrated that β-carotene, a provitamin A compound, enhances muscle mass through a retinoic acid receptor γ (RARγ)-dependent pathway. However, the involvement of vitamin A in exercise-induced muscle hypertrophy remains unclear. In this study, we used a mouse model of functional overload to mimic resistance exercise and investigated the role of vitamin A in overload-induced muscle growth. Overload increased the expression of Rdh10, Dhrs9 and Aldh1a2, an enzyme required for active vitamin A synthesis in the skeletal muscle. In contrast, the expression of Aldh1a1, Dhrs3, and Rarb was decreased by the overload. Vitamin A deficiency significantly suppressed overload-induced muscle hypertrophy and protein synthesis. Moreover, local administration of an RAR antagonist to the skeletal muscle reduced overload-induced protein synthesis. These findings suggest that vitamin A contributes to skeletal muscle hypertrophy during muscle overload by promoting protein synthesis via RAR-mediated signaling.

Keywords:  exercise; muscle hypertrophy; overload; protein synthesis; vitamin A

DOI:  https://doi.org/10.3177/jnsv.72.176
bioRxiv. 2026 Apr 13. pii: 2026.04.10.717808. [Epub ahead of print]

The Muscle Tissue Environment Limits Muscle Stem Cells in Aged Mice.

Alicia A Cutler, Tenaya K Vallery, Thomas O Vogler, Jesse Kurland, Thea S Zlatklov, Tiffany Antwine, Nicole Dalla Betta, Tze-Ling Chang, Brad Pawlikowski, Carson H Butcher, Kory J Lavine, David M Ornitz, Kristi S Anseth, Bradley B Olwin.

Frailty arising from loss of muscle function and mass is a significant health concern impacting quality of life and dramatically increasing health care costs as our population ages. Ameliorating frailty derived from reduced muscle function is thus a critical research priority to improve health span. Cell intrinsic defects in muscle stem cells (MuSC), or satellite cells, occur as skeletal muscle ages, reducing the capacity of MuSCs to maintain and repair skeletal muscle and are accompanied by cell nonautonomous changes. Although rejuvenating stem cells in aged tissues or organs has potential to improve muscle aging phenotypes, we found that the extracellular environment in aged mice abrogates rejuvenated muscle stem cell potential. MuSCs from young mice were unable to grow on extracellular matrix derived from aged mice that contains elevated collagen protein levels, establishing a critical role for the environment in contributing to muscle phenotypes in aging. Combining an inducible FGF receptor 1 (FGFR1) to rescue MuSC intrinsic aging defects with a drug to reduce fibrosis partially rescued muscle mass loss in aged mice. We conclude that aging affects tissues, and particularly skeletal muscle tissue, via complex multifactorial processes requiring multifaceted interventions to improve aging phenotypes.

DOI: https://doi.org/10.64898/2026.04.10.717808
J Physiol. 2026 Apr 27.

From mice to muscle: does MitoQ translate to human strength in ageing?

Emilie Y Daroga, Kate A Dunsmore, Tina Y Chen.



Keywords:  MitoQ; ageing; mitochondria; mitoquinone mesylate; reactive oxidative species; skeletal muscle

DOI:  https://doi.org/10.1113/JP291266
Gene. 2026 Apr 25. pii: S0378-1119(26)00198-8. [Epub ahead of print] 150188

The interaction between exercise and autophagic flux in neurodegenerative muscle loss.

Dongdong Wang, Yahui Li.

  Neurodegenerative diseases are increasingly recognized as systemic disorders that extend beyond the central nervous system and profoundly affect skeletal muscle. Muscle weakness and atrophy in these conditions are driven not only by denervation but also by mitochondrial dysfunction, chronic inflammation, and impaired proteostasis. Among the mechanisms underlying muscle deterioration, autophagy has emerged as a critical regulator of cellular quality control. Balanced autophagic flux is essential for the removal of damaged proteins and dysfunctional mitochondria, thereby preserving metabolic homeostasis and neuromuscular junction stability. Conversely, dysregulated autophagy contributes to proteotoxic stress and accelerates muscle degeneration in neurodegenerative disorders. Exercise is a potent physiological stimulus capable of modulating autophagy in skeletal muscle. Preclinical models and emerging clinical evidence indicate that appropriately prescribed exercise can restore impaired autophagic flux, enhance mitochondrial quality control, and improve muscle function in neurodegenerative and aging-related muscle loss. However, the effects of exercise are context- and intensity-dependent, underscoring the need for individualized therapeutic strategies. This review synthesizes current evidence on the interaction between exercise and autophagic regulation in neurodegenerative muscle loss. Exercise as a therapeutic strategy is supported by well-defined molecular and cellular mechanisms, including the regulation of autophagy and mitochondrial quality control.

Keywords:  Autophagic flux; Exercise; Neurodegenerative diseases; Skeletal muscle

DOI:  https://doi.org/10.1016/j.gene.2026.150188
Am J Physiol Cell Physiol. 2026 May 01.

Ribosome dynamics during skeletal muscle repair and regeneration in mice and humans.

Minying Cui, Sebastian Edman, Baptiste Jude, Paulo R Jannig, Oscar Horwath, Emily Shorter, Pieter J Koopmans, Toby L Chambers, Ronald G Jones, Abraham Nilsson, Johanna T Lanner, Thomas Sejersen, Eva Pontén, Kevin A Murach, Jörg Schilcher, Ferdinand von Walden.

  Skeletal muscle repair requires coordinated regulation of inflammation and protein synthesis, but the roles of ribosome biogenesis and protein composition remain poorly defined. To address this, mice underwent femoral artery ligation (FAL) to induce muscle regeneration over 28 days. In humans, tibialis anterior biopsies from traumatic tibial fracture patients were subjected to RNA sequencing. Following FAL, c-Myc mRNA increased transiently, followed by increased ribosomal DNA transcription, leading to elevated total RNA levels. Skeletal muscle-specific ribosomal protein paralog RPL3L was replaced by the ubiquitously expressed RPL3 during the initial phases of recovery, but this shift was reversed by day 28. A substantial transcriptomic response was observed in human muscle injury, with heavy emphasis on MYC-induced anabolism and inflammation. This supports a model in which MYC-driven changes in ribosomal content and composition form a core anabolic module in skeletal muscle repair, potentially representing a targetable axis to enhance recovery after muscle injury.

Keywords:  Ribosome heterogeneity; Skeletal muscle; regeneration; ribosomen biogenesis

DOI:  https://doi.org/10.1152/ajpcell.00184.2026
J Leukoc Biol. 2026 Apr 28. pii: qiag054. [Epub ahead of print]

Macrophage and fibro-adipogenic progenitor (FAP) communication in skeletal muscle regeneration: Tissue homeostasis and pathogenic remodeling.

Seily Shrestha, Abbey Politeski, Sarah A Dick.

  Skeletal muscle regeneration depends on coordinated interactions between macrophages, fibro-adipogenic progenitors (FAPs), and muscle stem cells (MuSCs). Following injury, macrophages transition from pro-inflammatory to anti-inflammatory phenotypes, regulating debris clearance, cytokine secretion, and the activity of FAPs and MuSCs. FAPs transiently support MuSC-mediated regeneration but, if not cleared appropriately, differentiate into fibroblasts or adipocytes, contributing to fibrosis and fatty infiltration. Dysregulated macrophage-FAP crosstalk drives pathological conditions, including Duchenne Muscular Dystrophy (DMD) and age-related sarcopenia, where imbalances in cytokines and growth factors exacerbate maladaptive remodeling. FAP-derived colony-stimulating factor 1 (CSF1) sustains macrophage survival while macrophage-derived signals, including tumor necrosis factor alpha (TNF-α) and transforming growth factor beta (TGF-β), regulate FAP apoptosis, proliferation, and differentiation, shaping the regenerative niche. Single-cell and spatial transcriptomic approaches have revealed extensive heterogeneity among resident and infiltrating macrophages and FAP subsets, uncovering the molecular circuits underlying intercellular communication. Therapeutic strategies targeting cytokines and growth factors show promise in restoring balanced macrophage-FAP signaling, enhancing regeneration, and limiting fibrosis and fatty infiltration. Understanding the temporal dynamics of macrophage-FAP interactions is essential for developing interventions that preserve muscle homeostasis and counteract degenerative disease.

Keywords:  Fibro-Adipogenic Progenitors; Macrophages; Regeneration; Skeletal Muscle

DOI:  https://doi.org/10.1093/jleuko/qiag054
Skelet Muscle. 2026 Apr 29.

Mechanobiological landscape of muscle stem cells.

Kotaro Hirano, Yuji Hara.



Keywords:  Mechanical resilience; Mechano-sensors; Mechano-signaling; Mechanobiology; Mechanosensitive ion channel; Muscle regeneration; Muscle satellite cell; Muscle stem cell; PIEZO1; TRP channel

DOI:  https://doi.org/10.1186/s13395-026-00425-6
Am J Physiol Regul Integr Comp Physiol. 2026 Apr 30.

Low-dose Simulated Galactic Cosmic Radiation Exposure After Hindlimb Unloading Has Long-term Impact on Skeletal Muscle Metabolic Proteins in Female Mice.

Matthew Martone, Brian A Irving, Guillaume Spielmann, Neil M Johannsen, Matthew M Robinson, Jeffery C Chancellor, Heather C M Allaway.

  Background: Spaceflight stressors, including microgravity-induced unloading and galactic cosmic radiation (GCR), acutely disrupt mitochondrial function and contribute to skeletal muscle atrophy. The long-term remodeling of skeletal muscle following combined unloading and radiation exposure remains poorly understood. We investigated protein abundance changes 9-months post-exposure to combined unloading and radiation exposure. Methods: Female, 6-month old, C57Bl/6J mice underwent 5 days of hindlimb unloading (HU) or weight-bearing (WB) conditions, followed by 0Gy, 0.5Gy, or 1.5Gy of simulated GCR exposure using the simplified 5-ion beam exposure (simGCRsim) (n=5/group). The gastrocnemius muscle was collected after 9-months of WB and analyzed by data-independent acquisition mass spectrometry. Differentially abundant proteins were identified and evaluated using pathway enrichment analyses. Results: WB mice exposed to 0.5Gy exhibited increased abundance of electron transport system proteins and mitochondrial transport proteins, suggesting increased mitochondrial activity relative to control mice. HU mice exposed to 0.5Gy displayed decreased glycolytic proteins, increased reliance on oxidative pathways, and reduced antioxidant proteins (glutaredoxins, peroxiredoxin) compared to WB0.5. In HU mice, a higher radiation dose (HU1.5 vs HU0.5) led to the downregulation of 26S proteasome subunits and the upregulation of peroxisomal antioxidant, tricarboxylic acid cycle, and β-oxidation proteins, indicating dose-dependent mitochondrial adaptations. Conclusion: Long-term muscular remodeling after simGCRsim exposure is influenced by both muscle loading status and radiation dose, with prolonged shifts toward oxidative metabolism and altered protein quality control persisting months after exposure. These findings provide new insights into skeletal muscle adaptation to spaceflight stressors and have important implications for astronaut health during and after long-duration missions.

Keywords:  disuse; ionizing radiation; mitochondria; proteomics

DOI:  https://doi.org/10.1152/ajpregu.00014.2026
Redox Biol. 2026 Apr 22. pii: S2213-2317(26)00184-9. [Epub ahead of print]93 104186

Multi-omics reveals molecular signatures of moderate intensity exercise and identifies candidate exercise mimetics in mice.

Hanlin Jiang, Shota Inoue, Junpei Hatakeyama, Hideki Moriyama.

  Exercise is known to promote systemic health and prevent various chronic diseases. However, the molecular mechanisms underlying its beneficial effects remain incompletely understood. Although the health benefits of exercise have been widely studied, most research has treated exercise as a general intervention, without clearly standardizing its intensity. This study focused on a physiologically and molecularly defined moderate intensity, which may uniquely capture the core health-promoting mechanisms of exercise. To characterize the molecularly defined moderate intensity exercise, integrative multi-omics analyses-including transcriptomics, epigenomics, and phosphoproteomics-were performed using skeletal muscle tissue. These analyses revealed that this specifically defined exercise consistently modulated shared molecular pathways across both exercise modalities, especially insulin signaling, FoxO signaling, and circadian rhythm regulation. To explore the translational relevance of the identified molecular signatures, Connectivity Map analysis was used to search for compounds with similar transcriptional profiles. As a secondary outcome, apigenin and doxazosin were found to mimic exercise-associated molecular responses partially. These compounds exerted distinct physiological effects in vivo, including enhanced mitochondrial function and endurance and muscle hypertrophy with musculoskeletal protection. In conclusion, this study primarily elucidates the systemic molecular basis of physiologically and molecularly defined moderate-intensity exercise. The identification of candidate exercise mimetics serves as a potential application of these findings.

Keywords:  Methylome; Phosphoproteome; Transcriptome; apigenin; doxazosin; exercise; skeletal muscle

DOI:  https://doi.org/10.1016/j.redox.2026.104186
Acta Physiol (Oxf). 2026 Jun;242(6): e70236

GRP94 Promotes the Fusion of Mouse C2C12 Myoblasts and the Regeneration of Skeletal Muscle Injuries Through Myomaker.

Jianian Teng, Liangliang Tian, Kun Zhang, Lei Xing, Huaixin Teng, Huili Tong, Jun Song, Shuang Li.

   AIM: The fusion of myoblasts to form multinucleated myofibres is a key step in the regeneration of skeletal muscle following injury. In this study, we elucidate how GRP94 regulates myoblast fusion during skeletal muscle regeneration.
METHODS: Skeletal muscle injury and regeneration models were established in mice, and myogenic differentiation was induced in C2C12 myoblasts in vitro. GRP94 function was inhibited pharmacologically or reduced by downregulating its expression. Muscle regeneration, myoblast fusion, and Myomaker expression were assessed by hematoxylin and eosin staining, Western blotting, and immunofluorescence. The interaction between GRP94 and Myomaker and its regulatory mechanisms were analyzed using immunoprecipitation and ubiquitin-proteasome assays.
RESULTS: Inhibition of GRP94 delayed muscle regeneration in vivo, resulting in smaller regenerating myofibres and reduced myoblast fusion in vitro. GRP94 suppression decreased Myomaker expression, disrupted its subcellular localisation, and impaired its membrane trafficking. Mechanistically, GRP94 interacted with Myomaker, facilitated its post-translational translocation, and protected it from ubiquitin-mediated degradation.
CONCLUSION: GRP94 promotes the post-translational translocation of Myomaker and delays its degradation via the ubiquitin-proteasome pathway. It thereby regulates myoblast fusion and skeletal muscle regeneration, providing new strategies and a basis for the treatment of muscle regeneration disorders and muscle-related diseases.

Keywords:  GRP94; Myomaker; cell fusion; mouse; skeletal muscle

DOI:  https://doi.org/10.1111/apha.70236
J Cachexia Sarcopenia Muscle. 2026 Jun;17(3): e70311

RIPK3 Inhibition Mitigates Denervated Muscle Atrophy via NOX4-Mediated Mitochondrial Restoration and Inflammation Suppression.

Yuntian Shen, Chen Zhang, Zihao Zhao, Jia Yi, Xinlei Yao, Bingqian Chen, Hualin Sun.

   BACKGROUND: Peripheral nerve injury-induced muscle atrophy shares core pathophysiological features with systemic wasting disorders including cachexia and sarcopenia, yet early molecular triggers remain undefined. This study investigates the pathogenic role of receptor-interacting protein kinase 3 (RIPK3) in denervation atrophy.
METHODS: Sciatic denervation was induced in rats for initial time-course transcriptomics and in mice for genetic and pharmacological studies. Assessments in wild-type and RIPK3-knockout mice included transcriptomics (RNA-seq, qPCR), muscle morphology (wet weight ratio, cross-sectional area), histological inflammation (H&E, CD68 immunofluorescence), mitochondrial function (complex I/V activity, ultrastructure and biogenesis/fission regulators), STRING analysis to identify downstream effectors, validated key effectors NOX2 and NOX4 (qPCR/Western blotting) and associated redox status (DHE staining), and analysis of myofibrillar protein content and proteolytic markers (Western blotting). Confirmatory studies included RIPK3 overexpression in C2C12 myotubes and its pharmacological inhibition (GSK872) in mice.
RESULTS: RIPK3 emerged from transcriptomic analysis as an early upregulated mediator in denervated muscle, with protein levels increasing approximately threefold at 36 h post-injury. Genetic ablation of RIPK3 attenuated muscle atrophy, as shown by improved gastrocnemius wet weight ratio (p = 0.0110). This protective effect was directly evidenced by a 40.7% increase in cross-sectional area (p = 0.04). The morphological preservation was accompanied by markedly suppressed expression of key atrophy markers, including MAFbx, MuRF1 and FoxO3a (all p < 0.01), and preserved MHC levels (p = 0.0278). Mechanistically, RIPK3 knockout reduced inflammation, enhanced oxidative phosphorylation (GSEA FDR < 0.001) and partially restored mitochondrial function, evidenced by significantly increased complex I (p = 0.0438) and complex V (p < 0.001) activity, preserved ultrastructure, upregulated PGC-1α and NRF2 (both p < 0.05) and downregulated mitochondrial fission proteins (p-DRP1, MFF, FIS1; all p < 0.01). STRING analysis predicted NOX4 as a key downstream effector, validated by reduced NOX4 protein (-46.6%, p = 0.0366) and a consequent 52.2% decrease in ROS accumulation (p < 0.001). Consistently, RIPK3 overexpression in C2C12 myotubes elevated NOX4 (p = 0.0046) and atrophy markers, whereas pharmacological inhibition of RIPK3 in mice replicated the protective phenotype, increasing muscle wet weight ratio (p = 0.0277) and suppressing NOX4 (p = 0.0398) and proteolytic markers.
CONCLUSIONS: Denervation activates RIPK3 as a master regulator that drives muscle atrophy via NOX4/ROS-induced mitochondrial dysfunction, sustained inflammation and ubiquitin-proteasome activation. Targeting RIPK3 preserves muscle mass and may offer a novel therapeutic strategy for neurogenic muscle atrophy, with possible implications for related wasting disorders.

Keywords:  NOX4; RIPK3; denervation; mitochondrial dysfunction; muscle atrophy

DOI:  https://doi.org/10.1002/jcsm.70311
NAR Mol Med. 2026 Apr;3(2): ugag018

Age-related transcriptional drift and physiological adaptation in long-living Ames dwarf skeletal muscle.

Kingsley Mokube Ekumi, Matthew J Johnston, Michelle Pauley Murphy, Sharlene Rakoczy, Taylor R Painter, Holly M Brown-Borg.

Skeletal muscle aging is accompanied by deterioration in metabolic flexibility, neuromuscular connectivity, and structural integrity, all of which contribute to frailty and the loss of functional independence. Ames dwarf mice exhibit postnatal growth hormone deficiency and an exceptionally long lifespan, providing a unique model for revealing transcriptional programs that support healthy aging. Here, we present the first comprehensive transcriptomic and functional profile of hindlimb skeletal muscle in middle-aged and old-aged Ames dwarf mice. We show that Ames dwarf muscle maintains a transcriptional profile enriched for vascular remodeling, synaptic communication, extracellular matrix organization, and structural resilience while suppressing lipid metabolic pathways and age-associated transcriptional drift. Advanced age in Ames mice is marked by a substantial shift in transcription factors associated with downregulated genes and a temporally coordinated activation of senescence-associated and inflammatory-response signatures that appear to support, rather than impair, tissue maintenance. Functionally, Ames dwarf mice maintain neuromuscular coordination, grip strength, and endurance with age. Collectively, these findings indicate a distinct transcriptional drift in Ames dwarf skeletal muscle that integrates vascular, neuronal, and senescence-related signals to preserve structural and functional resilience. This work implicates molecular mediators, including Apelin, Klotho, and Notch1 that may underlie exceptional healthspan and modulate resistance to frailty.

DOI: https://doi.org/10.1093/narmme/ugag018
Nat Commun. 2026 Apr 27.

Sarcopenia promotes tumorigenesis by disrupting NOTCH-SDC2-regulated biogenesis of muscle-derived extracellular vesicles.

Kah Yong Goh, Wen Xing Lee, Qian Gou, Sze Mun Choy, Shi Chee Ong, Priya D Gopal Krishnan, Huaxin Wang, Lewin Raymarc Roldan Turqueza, Qian Hui Tan, Kenon Chua, Shang Li, Jun Nishiyama, Nathan Harmston, Hong-Wen Tang.

Sarcopenia is an age-related condition characterized by loss of skeletal muscle mass and strength and is associated with increased cancer incidence and mortality, yet how muscle decline promotes tumorigenesis remains unclear. Here, we show that skeletal muscle functions as an anti-tumor organ by secreting extracellular vesicles (EVs) that suppress tumor growth. Using Drosophila melanogaster and mouse cancer models, we demonstrate that muscle-derived EVs inhibit tumorigenesis. In contrast, sarcopenic muscle exhibits reduced EV secretion and altered EV cargo, resulting in loss of tumor-suppressive activity. We identify miR-7a-5p as a tumor-suppressive microRNA enriched in EVs from healthy muscle but diminished with aging, where it restrains tumor growth by inhibiting TEAD1 signaling. Mechanistically, muscle EV biogenesis is regulated by a NOTCH-SDC2 pathway that declines with age but is reactivated by exercise. Together, these findings define a muscle-to-tumor communication axis with therapeutic potential.

DOI: https://doi.org/10.1038/s41467-026-72410-y
Skelet Muscle. 2026 May 01.

Stimulation of EGFR signaling in fibro-adipogenic precursors decreases adipogenesis in Duchenne muscular dystrophy.

Jules Guillemaud, Georgiana Panci, Aurélie Fessard, Léa Delivry, William Jarassier, Rémi Mounier, Julien Gondin, Stéphanie Gobert, Bénédicte Chazaud.

   BACKGROUND: Duchenne Muscular Dystrophy (DMD) is characterized by the formation of fibrosis and fat deposits that progressively replace muscle fibers, resulting in the loss of muscle function. Both fibrosis and adipogenesis are operated by fibroadipogenic precursors (FAPs), but the molecular regulation and interactions between the two processes are not fully understood.
METHODS: Adipogenesis was investigated in vivo in the D2-mdx mouse, and in vitro using FAPs isolated from WT (DBA/2) and D2-mdx muscles. Epithelial Growth Factor (EGF) was overexpressed in the D2-mdx muscle via electroporation of an expression plasmid.
RESULTS: We found that the D2-mdx gastrocnemius muscle showed fat deposition from 10 weeks of age and increased until 18 weeks of age, coinciding with fibrosis. Fat deposition was exclusively found within fibrotic areas. In vitro, D2-mdx FAPs proliferated more, and were more prone to adipogenesis than WT FAPs. Cells from both genotypes showed equal fibrogenesis. Analysis of normal muscle snRNAseq data showed that the Epithelial Growth Factor Receptor (EGFR) was primarily expressed by FAPs. Both EGFR expression and EGFR-phosphorylation were decreased in D2-mdx FAPs as compared with WT FAPs. Stimulating FAPs with EGF decreased adipogenesis, more efficiently in D2-mdx FAPs than in WT FAPs. However, EGF stimulation of EGFR had no effect on their fibrogenic differentiation. Finally, in vivo overexpression of EGF in D2-mdx gastrocnemius muscles reduced both adipogenesis and fibrosis, and was associated with an increased muscle force.
CONCLUSIONS: In a DMD context, FAPs are more likely to differentiate into adipocytes than in normal muscle, which is associated with decreased EGFR signaling. Stimulating EGFR signaling decreased adipogenesis in vitro and fat deposition in vivo. The impact of EGFR signaling on fibrogenesis is unclear, the reduced fibrosis observed in vivo may be due to indirect mechanisms. This study identifies EGFR signaling as a new molecular mechanism for controlling adipogenesis in skeletal muscle FAPs.

Keywords:  Adipogenesis; Duchenne Muscular Dystrophy; Epidermal Growth Factor Receptor; Fibroadipogenic precursors

DOI:  https://doi.org/10.1186/s13395-026-00429-2
Turk J Biol. 2026 ;50(2): 94-108

Ankrd2 may alleviate denervation-induced skeletal muscle atrophy by inhibiting inflammation.

Yalin Zhang, Lin Zhang, Li Li, Liqin Zhang, Li Zeng, Jiaying Qiu, Zhengrong Xi, Wenwen Wang.

   Background/aim: Sciatic nerve injury causes a loss of skeletal muscle innervation, reduced motor function, and eventual muscle atrophy. Inflammation and increased protein degradation are key factors contributing to muscle atrophy. Inflammation is activated early during muscle atrophy and can be modulated by various factors. However, the precise role of inflammation in denervation-induced muscle atrophy remains unclear.
Materials and methods: Transcriptome sequencing was used to determine that the inflammatory response occurs early during denervation-induced muscle atrophy. RT-qPCR validation of several inflammatory factors showed rapid upregulation at early stages, followed by gradual downregulation. Weighted gene coexpression network analysis of differentially expressed genes identified gene modules whose expression patterns were correlated with or inversely correlated to the inflammatory phenotype, thereby identifying key regulatory factors. A total of 14 coexpression modules were identified, and expression patterns opposite to those of inflammatory factors were examined to investigate potential regulatory molecules that could inhibit inflammation and protect skeletal muscle.
Results: Ankrd2 was identified in the darkorange module, showing no significant change at 36 h postdenervation, followed by gradual upregulation, which was opposite to the expression of inflammatory factors. An Ankrd2-overexpressing lentivirus was injected into the tibialis anterior muscle, and Ankrd2 overexpression was found to significantly alleviate muscle atrophy. Gene ontology and Kyoto Encyclopedia of Genes and Genomes analyses showed that Ankrd2 overexpression was associated with downregulation of inflammation-related pathways, particularly the NF-κB signaling pathway. Proatrophy genes in both the ubiquitin-proteasome and autophagic-lysosomal systems were also suppressed.
Conclusion: The present study suggests that denervation-induced muscle atrophy is alleviated by Ankrd2, potentially through inhibition of inflammation, highlighting its potential as a therapeutic target.

Keywords:  Ankrd2; NF-κB signaling pathway; denervation; inflammation; skeletal muscle atrophy

DOI:  https://doi.org/10.55730/1300-0152.2793
Biol Cell. 2026 May;118(5): e70066

Mitochondrial Activity Localization in the Skeletal Muscle and Its Individual Fibers Across Tetrapods.

Unmod Senapati, Subhasmita Rout, Sunil Pani, Bijayashree Sahu, Gourabamani Swalsingh, Punyadhara Pani, Benudhara Pati, Prabhat Kumar Rout, Rajesh Kumar Mohapatra, Suryakant Mishra, Naresh Chandra Bal.

  Mitochondria exhibit a complex spatially organized distribution within muscle, tailored to the energy requirements of ATPases and contractile filaments, which exhibit precise intracellular positioning. Mitochondrial distribution varies across longitudinal and transverse axes as well as based on fiber composition within the muscle. The differential mitochondrial capacity can be localized in muscle by succinate dehydrogenase (SDH) activity. Given the distinct energy requirements of the fore-limb and hind-limb muscles, this study aimed to investigate the distribution of mitochondrial activity within individual fibers and their composition within fascicles across different tetrapod taxa. We analyzed pectoralis and gastrocnemius from toad, garden lizard, duck, pigeon, quail, chicken, rat, rabbit, goat, and buffalo. The study revealed unique patterns of mitochondrial activity distribution within the same muscle across various tetrapods. Toad and lizard muscles showed mostly fibers with intermediate SDH-activity (SDHInt) in both muscles. The muscles only from birds and mammals exhibited fibers with negligible SDH-activity termed SDHLow, which might indicate that such fibers are evolutionarily more recent. Interestingly, avian pectoralis showed a very unique fiber composition compared to mammals, which displayed a mosaic pattern of different fibers. Among mammals, slow-grazers (buffaloes, goats) had higher percentages of SDHHigh and SDHInt fibers, whereas sprint-runners (rats, rabbits) possessed a high abundance of SDHLow fibers. These findings provide evidence for localized mitochondrial enrichment as an adaptation strategy to create muscle group heterogeneity. SUMMARY STATEMENT: This study characterizes the spatial distribution of mitochondrial activity in skeletal muscle across tetrapods, from the single-fiber scale to the fascicular level.

Keywords:  fiber type; metabolism; mitochondria; skeletal muscle; succinate dehydrogenase; tetrapods

DOI:  https://doi.org/10.1111/boc.70066
EMBO Rep. 2026 Apr 27.

Mitochondrial protein import stress causes lysosomal damage and progressive tissue atrophy.

Nicholas A Brennan, Xiaowen Wang, Arnav Rana, Sanaea Z Bhagwagar, Jason Horton, Patricia M Kane, Xin Jie Chen.

Mitochondrial and lysosomal abnormalities co-occur in aging-related diseases with progressive tissue atrophy. It remains unclear whether these two pathogenic pathways affect tissue homeostasis independently, convergently or epistatically. We show that mitochondrial protein import stress causes vacuolar damage in yeast, manifested by V-ATPase disassembly, and vacuolar deacidification and fragmentation. In a mouse model of mitochondrial protein import stress induced by overloading of the nuclear-encoded ANT1 protein, we observe progressive muscle atrophy independent of bioenergetic defects. Like in yeast mutants with severe vacuolar damage, genes involved in amino acid uptake/biosynthesis, one-carbon metabolism, lysosomal biogenesis and iron homeostasis are activated in the skeletal muscle of Ant1-transgenic mice. The affected muscles accumulate glycogen, lipofuscin and poorly processed multivesicular bodies. Despite activation of lysosomal repair and lysophagic pathways, autophagic flux is severely stalled. During aging, various proteolytic cathepsins are increasingly released from the lysosomal lumen into the cytosol. Together with proteasomal activation, this may contribute to unbalanced proteostasis, reduced myofiber size and skeletal muscle atrophy. Our study therefore discovered an evolutionarily conserved mitochondria-to-lysosome proteotoxic axis that affects tissue mass homeostasis during aging.

DOI: https://doi.org/10.1038/s44319-026-00774-9
FASEB Bioadv. 2026 Apr;8(4): e70108

The Effects of Palmitoylethanolamide or Ibuprofen on the Abundance Profile and Synthesis Rate of Proteins in C2C12 Skeletal Myotubes.

Paige L Cole, Connor A Stead, Jatin G Burniston, Daniel J Owens.

  Palmitoylethanolamide (PEA) and ibuprofen (IBU) exert anti-inflammatory effects that may influence skeletal muscle adaptation; however, their impact on muscle proteome dynamics remains unclear. Dynamic proteome profiling was performed in differentiated C2C12 myotubes treated for 36 h with D2O and either vehicle control (VC), PEA (10 μM), or IBU (100 μM). Protein-specific fractional synthesis rates (FSR; 1541 proteins) and relative protein abundances at 36 h (3085 proteins) were quantified and compared between treatments and VC. Relative to VC, PEA increased synthesis rates of 101 proteins (p < 0.05), whereas 2 proteins exhibited reduced synthesis. IBU increased synthesis rates of 165 proteins and reduced 7 proteins relative to VC. Both PEA and IBU increased total ribosomal protein synthesis (~80% relative to VC) and increased the abundance of 40S ribosomal subunit proteins (~18% relative to VC at 36 h). In addition, IBU treatment was associated with greater abundance of proteins involved in muscle contraction and extracellular matrix organization, reduced abundance of proteins associated with carbohydrate metabolism (21 proteins), and increased abundance of proteins linked to lipid metabolic pathways (17 proteins), relative to VC. In contrast, PEA-induced abundance differences were largely restricted to ribosomal proteins. These findings demonstrate that PEA and IBU enhance ribosomal protein turnover relative to control, whereas IBU elicits broader treatment-associated proteome remodeling.

Keywords:  deuterium oxide; non‐steroidal anti‐inflammatory drugs; protein turnover; proteomics; skeletal muscle

DOI:  https://doi.org/10.1096/fba.2025-00286
Biogerontology. 2026 Apr 28. pii: 94. [Epub ahead of print]27(3):

Sirtuin 1 as an emerging exerkine in the aging process: unveiling its multifaceted biological roles.

Patrício Lopes de Araújo Leite, Larissa Alves Maciel, Rita Cristine Barboza Patricio, Geovanna Lopes Carneiro Pereira, Antônio Sérgio de Oliveira Lamounier, Samuel da Silva Aguiar, Caio Victor Sousa, Ivo Vieira de Sousa Neto, Herbert Gustavo Simões.

  Sirtuin 1 (SIRT1) was initially identified as an enzyme that deacetylates histones and suppresses gene activity. Since then, its roles have expanded considerably, and it is now recognized as a multifunctional protein conserved across various organisms. Despite increasing interest, it remains essential to clarify how exercise-induced changes in SIRT1 counteract multiple hallmarks of aging, as well as the full scope of SIRT1's impact on different physiological systems. This review highlights recent findings on the short- and long-term effects of exercise on SIRT1 signaling in both rodents and humans during aging. We explore the molecular pathways activated in various tissues, providing insight into the specific biological functions of SIRT1 within aging cells. Optimal levels of SIRT1 help maintain homeostasis and a biochemical environment conducive to healthspan, influencing biological processes such as mitochondrial dynamics, metabolic pathways, tissue remodeling, autophagy, inflammatory responses, and redox balance. This indicates that SIRT1, a pleiotropic molecule, orchestrates multiple responses throughout aging. SIRT1 may act as a dynamic sensor for exercise benefits and protect against aging by maintaining genomic integrity. Different exercise protocols (acute and chronic) and modalities (aerobic, resistance, and combined training) can increase mRNA levels, activity, or protein levels of SIRT1 in various vital organs (adipose tissue, hippocampus, heart, liver, bone, and skeletal muscle) of aged animals and older adults, promoting health. Taken together, these observations support the notion that SIRT1 functions as a potential exerkine, and understanding its role in exercise-induced adaptations offers new insights into non-pharmacological strategies to enhance longevity.

Keywords:  Aging; Physical exercise; Senescence; Sirtuins

DOI:  https://doi.org/10.1007/s10522-026-10442-z
J Clin Invest. 2026 Apr 25. pii: e202212. [Epub ahead of print]

MESH1-mediated coenzyme A degradation drives ferroptosis sensitivity and muscle pathology.

Chao-Chieh Lin, Joshua Rose, Alexander A Mestre, Chien-Kuang C Ding, Ssu-Yu Chen, Sze Mun Choy, Kah Yong Goh, Weiyi Jiang, Wen Xing Lee, Qizhou Jiang, Yanting Chen, Tianai Sun, Jianli Wu, Yueqi Chen, Yunju Oh, Pyeonghwa Jeong, Jiyong Hong, Kenon Chua, Michael C Fitzgerald, Guo-Fang Zhang, Hong-Wen Tang, Pei Zhou, Jen-Tsan Chi.

  Coenzyme A (CoA) facilitates fatty acid synthesis, energy production, gene regulation, and antioxidant function. While CoA biosynthesis is well-characterized, the mechanisms governing CoA degradation remain poorly understood. Here, we identify the Metazoan Homolog of SpoT, MESH1, as a CoA phosphatase that dephosphorylates CoA at the 3' position of the ribose ring to form dephospho-CoA (dp-CoA). Recent studies have shown that CoA, similar to glutathione (GSH), is a cysteine-derived metabolite that protects cells against ferroptosis. Ferroptosis induced by blocking cystine import depletes CoA biosynthesis, while CoA restoration rescues cells from ferroptosis. We found that MESH1 knockdown preserved CoA levels by preventing its degradation, contributing to ferroptosis protection, indicating the bifunctional role of MESH1 in regulating CoA and previously reported NADPH. Mechanistically, MESH1 knockdown elevates CoA levels, maintaining functional mitochondrial thioredoxin system, thereby preventing mitochondrial lipid peroxidation. In Drosophila, we found that dMesh1 overexpression leads to ferroptosis-mediated muscle atrophy, which can be rescued by increasing CoA and NADPH levels. Taken together, these findings establish MESH1 as a key phosphatase that governs ferroptosis sensitivity by coordinating CoA and NADPH homeostasis, unveiling a novel link between CoA degradation, mitochondrial integrity, and muscle health.

Keywords:  Amino acid metabolism; Cell biology; Molecular biology; Muscle; Muscle biology

DOI:  https://doi.org/10.1172/JCI202212
Eur J Endocrinol. 2026 Apr 30. pii: lvag075. [Epub ahead of print]

Divergent Roles of Skeletal Muscle 11β-HSD1 in Age-Related and Chronic Kidney Disease-Associated Sarcopenia.

Michael S Sagmeister, Ana Crastin, Bradley Welsh, Louise Firkins, Ben Cassidy, Thomas Nicholson, Sophie J Hopkin, Nadezhda Wall, Angela E Taylor, Julius E Kieswich, Muhammad M Yaqoob, Gareth Lavery, Myriam Chimen, Helen M McGettrick, Asif J Iqbal, Leigh Breen, Simon W Jones, Lorraine Harper, Rowan S Hardy.

   BACKGROUND: Chronic kidney disease (CKD) is associated with increased incidence of sarcopenia and muscle weakness in aging patients. The glucocorticoid activating enzyme11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) within skeletal muscle in these patients has been implicated in driving this process. We hypothesised that skeletal muscle 11β-HSD1 is elevated in CKD and aging where it would represent a promising therapeutic target.
METHODS: We measured 11β-HSD1 activity in quadriceps biopsies from 17 CKD patients (eGFR <30 ml/min) and 14 age-matched controls (mean age 71±5 years). Muscle strength, mass, and gait speed were assessed in relation to tissue 11β-HSD1 activity. Primary human myotubes were treated with patient-derived sera to evaluate regulatory drivers. Murine models of CKD (adenine diet) and aging (21 months) in wild-type (WT) and 11β-HSD1 knockout (11βKO) animals were examined to model therapeutic targeting.
RESULTS: Muscle 11β-HSD1 activity was not elevated with CKD, but increased with age (r=0.559, p=0.001), predicting lower grip strength (p=0.008). Markers of inflammation, including c-reactive protein and IL-6 strongly predicted 11β-HSD1 activity. Pro-inflammatory mediators such as TNFα, directly upregulated 11β-HSD1 activity in myotubes, whilst sera from CKD donors did not. Whilst mice with 11βKO deletion were not protected from CKD driven muscle atrophy, 11βKO animals showed marked protection against age related muscle loss.
CONCLUSIONS: Skeletal muscle 11β-HSD1 activity is not induced by CKD itself, but increases significantly over aging, where it is a predictor of muscle weakness. Its targeted deletion, preserves muscle mass in aged mice, supporting its efficacy in preventing sarcopenia in an aging CKD population.

Keywords:  Aged; Cortisol; Glucocorticoid; Muscle strength; Muscular Atrophy; Renal insufficiency

DOI:  https://doi.org/10.1093/ejendo/lvag075
J Pathol. 2026 May 01.

Unraveling the spatial landscape of dystrophinopathies: a transcriptomic approach to Becker and Duchenne muscular dystrophies.

Laura Gm Heezen, Qirong Mao, Stefan Nicolau, Claudio Novella Rausell, Julia van der Weerd, Jan Kueckelhaus, Rasya Gokul Nath, Jordi Diaz- Manera, Hermien E Kan, Erik H Niks, Maaike van Putten, Annemieke Aartsma-Rus, Kevin M Flanigan, Ahmed Mahfouz, Pietro Spitali.

  Dystrophinopathies are caused by pathogenic variants in the DMD gene, resulting in partial (Becker) or complete loss (Duchenne) of dystrophin. Becker (BMD) and Duchenne muscular dystrophy (DMD) are characterized by progressive muscle wasting, fatty replacement, fibrosis, and loss of function. To study histopathological changes, we used Visium spatial transcriptomics to profile skeletal muscle biopsies of patients affected by dystrophinopathy (n = 8) and healthy controls (n = 4). We estimated the proportion of cell types and their spatial localization across samples applying a deconvolution strategy using previously published single-nucleus RNA-sequencing data. We identified genes enriched in fat patches and cell types such as fibroadipogenic progenitors (FAPs) in areas of active pathology. Using expression data of ligand-receptor pairs, we highlight cell-cell communications leading to fibrotic and adipogenic lesions. Finally, analysis of gene expression gradients in areas of adjacent muscle and fat, allowed the identification of genes associated with muscle areas committed to becoming fat. © 2026 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Keywords:  cell–cell communication; dystrophinopathy; fibroadipogenic progenitors; histopathology; single‐nucleus RNA sequencing; spatial transcriptomics

DOI:  https://doi.org/10.1002/path.70067
Am J Physiol Endocrinol Metab. 2026 Apr 29.

Muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICU acquired weakness.

Tom S O Jameson, Benjamin T Wall, Tomáš Urban, Adéla Krajčová, Bob Bakalář, Michal Fric, Kateřina Jiroutková, Valér Džupa, Jan Gojda, Craig Porter, Barbora Miznerová, František Duška, Francis B Stephens.

  The association of perturbed skeletal muscle metabolism with ICU acquired weakness (ICUAW) is not clear. The objective of the present study was to characterise temporal changes in skeletal muscle mitochondrial function, ATP concentration, and substrate utilisation during and up to 6 months post ICU admission in critically ill patients, and to delineate mechanisms underpinning ICUAW by comparing the expression of genes involved in skeletal muscle mitochondrial function and substrate utilisation in the critically ill patients to control groups that had either undergone elective surgery or leg immobilisation (i.e. muscle disuse). The study design was a randomised controlled trial of functional electrical stimulation-assisted cycle ergometry (FESCE) vs. standard care, with skeletal muscle mitochondrial respirometry defined a priori in a nested sub-group of patients as the primary outcome. Mitochondrial respirometry did not change 7 days or 6 months after ICU admission and was not impacted by FESCE. However, a 20% reduction in muscle ATP content by day 7 of ICU stay persisted after 6 months and tended to associate with ICUAW (P=0.078, R2=0.582). Moreover, a 40% lower muscle glycogen and 2.5-fold greater muscle lactate were observed earlier at day 1 compared to elective surgery patients. These changes reflected expression of genes related to glycogen metabolism when disuse was accounted for, and of which a greater expression of the gene encoding glycogen phosphorylase (PYGM) was predictive of mortality. We conclude that muscle glycogen metabolism is rapidly dysregulated in critical illness, which may have implications for muscle ATP resynthesis and ICUAW.

Keywords:  Functional electrical stimulation; Glycogen metabolism; ICU acquired weakness; Mitochondrial respirometry; Skeletal muscle

DOI:  https://doi.org/10.1152/ajpendo.00022.2026
Cells. 2026 Apr 17. pii: 713. [Epub ahead of print]15(8):

Elevation of Mitochondrial Ca2+ Above a Plateau Level Impairs Force Production and Accelerates Fatigue in Mouse Soleus Muscle.

Joseph Bruton, Kent Jardemark.

  Soleus muscle fibres display modest changes in tetanic force and [Ca2+]i during repeated contractions. In this study, we investigate whether increasing mitochondrial Ca2+ load during repeated contractions could induce premature fatigue. Intact, single fibres were dissected from the soleus muscles of adult mice. Mitochondrial Ca2+ was measured with rhod-2 in intact fibres. Fatigue was induced by 70 Hz, 350 ms tetani given at 2 s intervals in the absence and presence of 10 µM CGP-37157, a potent inhibitor of the mitochondrial Na+-Ca2+ exchanger. In soleus fibres fatigued in the absence of CGP-37157, tetanic force was significantly reduced by about 30% at the end of the fatiguing stimulation, while mitochondrial [Ca2+] increased to a maximum after about 50 tetani and returned to its resting level within 20 min after the end of the stimulation. In the presence of CGP-37157, the maximal mitochondrial [Ca2+] increase was more than twice that in control fibres. In addition, fatigue developed more rapidly and force remained depressed after the end of the stimulation. No difference in mitochondrial membrane potential or ROS production was seen between control and CGP-37157 conditions. We conclude that while modest increases in mitochondrial Ca2 may be beneficial, excessive mitochondrial Ca2 loading depresses muscle function.

Keywords:  Ca2+; mitochondria; skeletal muscle

DOI:  https://doi.org/10.3390/cells15080713
Curr Issues Mol Biol. 2026 Mar 30. pii: 361. [Epub ahead of print]48(4):

Inflammation-Linked Muscle Atrophy in Limb Girdle Muscular Dystrophy R1 (LGMDR1): Insights into Disease Mechanisms.

Sukanya Banerjee, Bishan Dass Radotra, Manni Luthra-Guptasarma, Manoj K Goyal.

   BACKGROUND: Muscle atrophy is a major feature of Limb Girdle Muscular Dystrophy R1 (LGMDR1) patients, but its underlying molecular mechanisms have not been fully explored. While the ubiquitin-proteasome system (UPS) is known to be involved in muscle protein degradation, inflammation commonly observed in LGMDR1 patients may further activate the UPS. This study aimed to explore the role of inflammation in the muscle atrophy of LGMDR1 patients.
METHODS: Muscle biopsies from six confirmed LGMDR1 patients (with CAPN3 variants and reduced calpain-3 protein expression) were analyzed for atrophy-related markers, MuRF1 and Atrogin-1, using qRT-PCR and Western blotting. The expression of cytokines, TNF-α, IL-1β, and IL-6 was analyzed by qRT-PCR from muscle biopsies and by ELISA from serum samples. The NFκB, FOXO1, and FOXO3 gene expression was analyzed using qRT-PCR and Western blotting from muscle biopsies.
RESULTS: Elevated TNF-α levels were associated with increased UPS activity, reflected by upregulated NFκB, FOXO1, MuRF1, and Atrogin-1 expression in LGMDR1.
CONCLUSION: Our findings indicate that increased TNF-α expression is associated with muscle wasting in LGMDR1 patients by targeting UPS pathway mediators that activate ubiquitin ligases-MuRF1 and Atrogin-1. These findings suggest that targeting TNF-α signaling and its downstream factors may help develop therapeutic interventions to prevent muscle atrophy in LGMDR1 patients.

Keywords:  LGMDR1; TNF-α signaling; inflammation; muscle atrophy; ubiquitin-proteasome system

DOI:  https://doi.org/10.3390/cimb48040361
J Exp Pharmacol. 2026 ;18 598396

Intraperitoneal Administration of Cardiolipin Enhances Mitochondrial Respiration in Skeletal Muscle of Male Mice.

Amanda Laplante, Andreas Bergdahl.

   Purpose: Cardiolipin is a phospholipid located in the inner mitochondrial membrane and is released following myocardial ischemia-reperfusion injury. While cardiolipin has documented effects in several tissues, its impact on skeletal muscle function and mitochondrial respiration remains unclear. The purpose of this study was to investigate the effects of exogenously elevated cardiolipin on aerobic capacity and mitochondrial respiratory function in skeletal muscle using a mouse model.
Methods: Male C57BL/6 mice were randomized into an experimental group (n = 11) receiving cardiolipin injections and a control group (n = 12) receiving a placebo solution. Mice were injected twice weekly for 6 weeks with 0.1 mL of cardiolipin (0.5 mg/mL) or placebo. Voluntary running distance was monitored throughout the intervention. Aerobic capacity was assessed at baseline, week 3, and week 6 by measuring time to exhaustion during treadmill running at a constant speed of 16 m min-1. Following the intervention, mice were euthanized, the vastus lateralis muscle was excised, and mitochondrial respiratory capacity was evaluated using high-resolution respirometry. Mitochondrial density was assessed by immunoblotting.
Results: Mice receiving cardiolipin exhibited increased skeletal muscle oxygen consumption compared with controls. No differences in mitochondrial density were observed between groups, suggesting that the enhanced oxygen consumption was not associated with increased mitochondrial content but may instead reflect alterations in mitochondrial respiratory efficiency.
Conclusion: Exogenously elevated cardiolipin is associated with enhanced skeletal muscle mitochondrial respiratory function without altering mitochondrial density, which may indicate improved mitochondrial efficiency. These findings provide novel insight into the potential role of cardiolipin in skeletal muscle energy metabolism and aerobic performance. Future studies should explore the combined effects of cardiolipin administration and exercise training on skeletal muscle respiratory capacity and further investigate the underlying mechanisms.

Keywords:  ATP production; OXPHOS; aerobic capacity; cardiolipin; respiratory efficiency

DOI:  https://doi.org/10.2147/JEP.S598396
J Appl Physiol (1985). 2026 Apr 30.

Reduced Skeletal Muscle Perfusion Accompanies Skeletal Muscle Atrophy After Severe Spinal Cord Injury.

Zachary S Clayton, Branden L Nguyen, Hui Jean Kok, Michael C Reynolds, Christine F Conover, Russell D Wnek, Kinley H Buckley, Jayachandra R Kura, Dana M Otzel, Yangyi E Luo, Elisabeth R Barton, Darren T Beck, Danielle J McCullough, Joshua F Yarrow.

  The goal of this study was to gain insight into an understudied physiological mechanism that may influence skeletal muscle atrophy following spinal cord injury (SCI). Specifically, we quantified skeletal muscle blood flow (BF) rates in paralyzed hindlimbs throughout the acute to subacute recovery period in a severe contusion SCI model. Secondary objectives were to characterize temporal changes in circulating and tissue-level markers of capillary density and vascular dysfunction, and vascular-related gene expression within hindlimb skeletal muscle. We hypothesized that SCI would reduce skeletal muscle BF and be accompanied by increases in circulating markers of vascular dysfunction, along with reductions in skeletal muscle capillary density and vascular-related gene expression. Four-month-old Sprague-Dawley male rats underwent T9 laminectomy (SHAM surgery) or severe contusion SCI. Hindlimb skeletal muscle mass, absolute BF rates, and mass-corrected BF rates were lower at 1-, 2-, and 4-weeks in SCI vs SHAM, with the most distinct BF differences present in the soleus (~50% lower, p<0.001). Bulk RNA-sequencing revealed that genes related to coagulation, blood vessel maintenance, and endothelial cell health were lower in soleus muscle after SCI, with most differences occurring at 1-2 weeks. Circulating PECAM-1, a marker of vascular dysfunction, was higher 2-3 weeks post-SCI (p<0.05), while no differences in soleus capillary density were detected. Our results reveal reduced limb perfusion and signs of vascular dysfunction in paralyzed hindlimb skeletal muscle during the acute post-SCI period in a rodent severe SCI model. Future studies examining mechanisms of vascular dysfunction after SCI or testing interventions to improve vascular function should consider this timeframe.

Keywords:  Disuse; Paralysis; RNA-sequencing; Skeletal muscle atrophy; Skeletal muscle blood flow; Spinal cord injury; Vascular health

DOI:  https://doi.org/10.1152/japplphysiol.00090.2026
Brain. 2026 May 02. pii: awag148. [Epub ahead of print]

Combining SMN2 splicing modifiers with HDAC6 inhibition improves spinal muscular atrophy outcomes.

Alexis Osseni, Rasha Slika, Laurent Coudert, Agnès Conjard-Duplany, Laure Weill, Edwige Belotti, Eleni Siopi, Yann-Gaël Gangloff, Delphine Sapaly, Sabrina Bendris, Zoé Clerc, Gaëlle Bruneteau, Carole Vuillerot, Pascal Leblanc, Frédéric Charbonnier, Laurent Schaeffer.

  Spinal muscular atrophy (SMA) is a severe neuromuscular disorder caused by SMN gene defects. It leads to motor neuron death and muscle weakness. Without treatment, most affected children don't survive past age two. Recently, new gene therapies help SMA children survive, but treated patients now face ongoing muscle atrophy and functional deficits, creating a novel clinical presentation. Over the last years, treatments of various animal models of neuromuscular disorders have shown the ability of inhibitors of the non-conventional histone deacetylase 6 (HDAC6) to reduce muscle atrophy. This study examines HDAC6 inhibition's impact on muscle cell differentiation and tests in vivo if combining it with new standard SMA treatments improves muscle and overall condition in SMA mice. Here, we report that HDAC6 controls myotube formation and maturation in vitro. In particular, HDAC6 inhibition increases the size of SMA patients-derived muscle primary myotubes. In vivo, when combined with ASOs inducing exon-7 inclusion in SMN2 RNA, HDAC6 systemic inhibition strongly improved muscle strength, mass, function, and longevity of SMA-like mice model. These findings provide evidence that selective inhibition of HDAC6 improves myogenic progression. Hence, HDAC6 inhibitors are good candidates to ameliorate persisting symptoms of SMA patients treated with the new standard of care.

Keywords:  HDAC6; SMA-like mouse model; human primary SMA cells; skeletal muscle; spinal muscular atrophy; tubastatin A

DOI:  https://doi.org/10.1093/brain/awag148
Mol Biol Rep. 2026 Apr 28. pii: 677. [Epub ahead of print]53(1):

Strategic role of calpains in modulation of NF-κB activity in skeletal muscle.

Ritu Ladwal, Rajesh Dabur.



Keywords:  Apoptosis; C-FLIP; CARP; Calpains; Inflammation; IκBα; NF-κB

DOI:  https://doi.org/10.1007/s11033-026-11864-1
Cells. 2026 Apr 13. pii: 685. [Epub ahead of print]15(8):

Ambient Temperature Shapes Skeletal Muscle Growth and Fiber-Type Plasticity in Mice.

Yajie Dong, Wen Sun, Yanjun Dong, Yiran Xu, Linli Xue, Jiayin Lu, Yi Yan, Xiaomao Luo, Haidong Wang, Juan Wang.

  Skeletal muscle development and physiological homeostasis are profoundly influenced by environmental cues. Among these factors, ambient temperature represents a critical determinant of growth performance and metabolic adaptation in mammals. However, the effects of different ambient temperature ranges on skeletal muscle characteristics and on responses across multiple visceral tissues remain poorly understood. In this study, five ambient temperature conditions (16 °C, 20 °C, 24 °C, 28 °C, and 32 °C) were established to investigate their physiological impacts in a mouse model. Our results demonstrate that ambient temperature markedly influences growth performance and skeletal muscle phenotype. Notably, mice housed at 20 °C showed relatively preserved grip strength and a shift in myofiber cross-sectional area distribution, although these findings did not consistently indicate superior skeletal muscle development across all indices. Further analysis revealed that ambient temperature significantly modulated the expression profiles of myosin heavy chain (MyHC) isoforms in skeletal muscle. Specifically, cold exposure was associated with an upregulation of the slow-twitch-related MyHC I, whereas heat stress correlated with an elevation of the fast-twitch-related MyHC IIb. Functional assessments indicated that exposure to colder or hotter conditions was associated with impaired muscle performance, as reflected by reduced grip strength at 16 °C, 28 °C, and 32 °C, and decreased endurance capacity at 28 °C and 32 °C. Histological analyses of major visceral organs revealed no obvious structural alterations in the heart, liver, spleen, lung, or kidney across temperature conditions. However, exposure to thermal extremes (16 °C and 32 °C) significantly reduced intestinal villus height, suggesting compromised intestinal integrity under temperature stress. Collectively, these findings indicate that ambient temperature is associated with multi-tissue changes in skeletal muscle characteristics, functional performance, and intestinal morphology. This study provides new insights into how environmental temperature modulates tissue adaptation and physiological homeostasis in mammals.

Keywords:  ambient temperature; fiber type plasticity; intestinal morphology; skeletal muscle remodeling

DOI:  https://doi.org/10.3390/cells15080685
Discov Oncol. 2026 Apr 25.

Skeletal muscle as an endocrine and paracrine organ in breast cancer biology: a narrative review.

David J Carpenter, Chris Peluso, Kunhong Xiao, Jared Rosenberg, Peter L Lee, Colin E Champ.



Keywords:  Body composition; Breast cancer; Exercise; Nutrition; Quality of life; Resistance training; Survivorship

DOI:  https://doi.org/10.1007/s12672-026-05027-8
Cell. 2026 Apr 24. pii: S0092-8674(26)00386-7. [Epub ahead of print]

Nuclear envelope budding enables export of large transcripts in muscle cells.

Sofia Zaganelli, Janet B Meehl, Robert G Abrisch, Gia K Voeltz.

  Nuclear envelope (NE) budding (NEB) has emerged as an alternative route for nuclear export of viral particles that are too large to pass through the nuclear pore complex. Yet the significance of this unconventional export pathway for large endogenous cargoes in mammalian cells has remained largely unexplored. Here, we use a combination of electron and fluorescence microscopy to demonstrate that NEB events occur following myoblast differentiation into myotubes and concomitant with the expression of extremely long muscle-specific transcripts. We show that NE buds are derived from the inner nuclear membrane, contain internal vesicles, and are specifically enriched with long sarcomeric transcripts. We identify a role for the protein UAP56-interacting factor (UIF) in regulating mRNA cargo targeting into NE buds and show that this pathway requires the endosomal sorting complex required transport III (ESCRT-III) membrane remodeling machinery. Our findings uncover a non-canonical pathway for large transcript nuclear export in muscle cells and provide insight into its mechanism.

Keywords:  ESCRT; RNA trafficking; membrane remodeling; nuclear envelope budding; nuclear export; sarcomeric transcripts

DOI:  https://doi.org/10.1016/j.cell.2026.03.050