bims-moremu 2026-06-14 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–06–14
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging.
The Role of Leukemia Inhibitory Factor in Attenuating Skeletal Muscle Atrophy: Mechanisms to Exercise Interventions.
Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?
Excessive training does not induce mitochondrial dysfunction or impair insulin signalling within skeletal muscle.
Fibroadipogenic progenitor-secreted prostaglandin E2 coordinates stem cell fate via autocrine and paracrine crosstalk in healthy and dystrophic muscle.
Muscle fibre denervation in ageing.
A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.
eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.
microRNA-1: A Master Regulator of Metabolism Governing Skeletal Muscle Hypertrophy.
Homer 2 regulates muscle differentiation with NFATc1.
LaminA/C-dependent cellular senescence signaling promotes skeletal muscle atrophy and abnormalities in Parkinson's disease.
MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.
The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.
Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.
Integrated RNA sequencing and in vivo biosensor imaging define the early pathogenic cascade of Duchenne muscular dystrophy.
Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators.
Physiological and functional characterization for high-throughput optogenetic skeletal muscle exercise assays.
Combination S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy.
The miR-30c-5p/SOCS3 axis is a potential driver of inflammation and metabolic imbalance in Duchenne muscular dystrophy.
Endocannabinoid system and skeletal muscle health: insights from cannabidiol.
Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.
Injectable Hydrogel-Based Delivery of Soluble Cripto Protein Enhances Repair After Skeletal Muscle Injury.
Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy.
BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation.
Deciphering skeletal muscle development: cellular heterogeneity and molecular regulatory networks from single-cell and spatial transcriptomic perspectives.
FAP-intrinsic Hedgehog signaling controls intramuscular adipogenesis, fibrosis, and myofiber regeneration.
Benzothiazole Derivatives as Dual Modulators of PGE2 and GABAergic Signaling in Skeletal Muscle.
Deficiency of G9a boosts muscle regeneration through IL13/Musclin-mediated crosstalk between macrophage and myofiber.
Inflammation reprograms fibro-adipogenic progenitors to sustain immunopathogenic niches in myositis.
Microneedle patch-based delivery of Pyr-Apelin-13 reverses functional and structural deficits in age-related sarcopenia.
Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.
Oxaliplatin triggers adipose and muscle wasting through cancer-independent metabolic and CNS pathways in mouse models.
Hepatokines lipocalin 2 and osteopontin drive muscle atrophy in MASH.
Skeletal-muscle-targeted non-viral delivery of full-length DMD mRNA for Duchenne muscular dystrophy.

Skelet Muscle. 2026 Jun 12.

Enhancers integrate microenvironmental signals in muscle stem cells during regeneration in health, disease, and aging.

Sarah Hachmer, F Jeffrey Dilworth.

  Effective skeletal muscle regeneration requires muscle stem cells (MuSCs) to continuously interpret and respond to signals from their surrounding microenvironment. These niche-derived cues, including inflammatory, extracellular matrix, paracrine, metabolic, and biomechanical signals, direct MuSC progression through quiescence, activation, proliferation, and differentiation by reshaping gene expression programs. Increasing evidence suggests that transcriptional enhancers serve as a key regulatory interface through which environmental information is translated into transcriptional output. Enhancer activity is governed by the coordinated action of lineage-defining transcription factors, histone modifiers, chromatin remodelers, transcriptional coactivators, and architectural proteins that together regulate chromatin accessibility, enhancer-promoter communication, and gene activation. Recent work has shown that enhancer landscapes and three-dimensional genome organization are highly dynamic during muscle regeneration and become altered in aging and disease. In this review, we examine how enhancer-associated mechanisms enable MuSCs to interpret niche-derived signals, highlighting the roles of transcription factor networks, chromatin remodeling complexes, and enhancer-promoter interactions in coordinating gene expression. We further discuss how disruption of enhancer regulation contributes to impaired regeneration in aging and muscular dystrophy, where altered chromatin states and genome organization lead to aberrant transcriptional responses. Understanding how these regulatory elements integrate complex environmental signals will be essential for defining the mechanisms underlying muscle regeneration and may provide new avenues for therapeutic intervention.

Keywords:  Gene Expression; Inflammation; Muscle Stem Cells; Myogenesis; Niche; Regeneration; Transcriptional Enhancers

DOI:  https://doi.org/10.1186/s13395-026-00434-5
Cells. 2026 May 26. pii: 981. [Epub ahead of print]15(11):

The Role of Leukemia Inhibitory Factor in Attenuating Skeletal Muscle Atrophy: Mechanisms to Exercise Interventions.

Na Jiang, Shiyi Wang, Jiaqiao Zhang, Dandan Jia.

  Leukemia inhibitory factor (LIF), a member of the interleukin-6 (IL-6) cytokine family, is a well-characterized myokine with pleiotropic regulatory effects on skeletal muscle. LIF modulates several fundamental cellular processes, including myoblast proliferation, apoptosis, angiogenesis, and energy metabolism. Exercise upregulates LIF expression in skeletal muscle, thereby promoting satellite cell activation, proliferation, myoblast differentiation, and angiogenesis, facilitating physiological muscle hypertrophy, and suppressing myocyte apoptosis and muscle atrophy. In addition, LIF plays a critical role in modulating the inflammatory and extracellular matrix remodeling following exercise-induced muscle damage, thereby supporting efficient muscle repair and regeneration. This review elaborates on the biological mechanisms by which LIF regulates skeletal muscle atrophy and contributes to the enhancement of skeletal muscle function. It also highlights the biological characteristics of myogenic LIF and discusses future directions for basic and applied research on exercise interventions targeting LIF signaling pathways.

Keywords:  exercise; hypertrophy; leukemia inhibitory factor; proliferation; skeletal muscle atrophy

DOI:  https://doi.org/10.3390/cells15110981
Int J Mol Sci. 2026 Jun 02. pii: 5016. [Epub ahead of print]27(11):

Fibro-Adipogenic Progenitor Cell Alterations in Skeletal Muscle: Pathological Dysfunction or Adaptive Reprogramming?

Margarita Y Sorokina, Oksana A Ivanova, Anna A Kostareva, Renata I Dmitrieva.

  In skeletal muscle, there are two main progenitor populations crucial for growth, maintenance, and repair: satellite cells (SCs) and interstitial cells, of which fibro-adipogenic progenitor cells (FAPs) are the best characterized fraction. However, data on how specific diseases or physiological conditions affect the biological properties of FAPs are limited. In this review we analyze data obtained with FAPs purified from skeletal muscle tissue from Duchenne muscular dystrophy (both human patients and mdx mice models), hindlimb functional unloading (rats), and type 2 diabetes (T2DM, human patients). Here we discuss how disuse/disease affect FAP's properties: the adaptive metabolic remodeling; the alterations in adipogenic differentiation in vitro; the possible role of particular subpopulations of FAPs in disease development; the role of FAPs in cell-to-cell interactions during skeletal muscle degeneration and regeneration. Current research has outlined how different physiological and pathological conditions alter FAPs' behavior, highlighting FAPs as a potential target for clinical protocols aimed at treating or mitigating skeletal muscle disorders. Future studies should clarify how FAPs govern cell-to-cell interactions during skeletal muscle degeneration and regeneration, offering critical insights for therapies targeting diverse neuromuscular diseases.

Keywords:  adipogenesis; duchenne muscular dystrophy; fibro/adipogenic progenitors; metabolic flexibility; myogenesis; skeletal muscle; skeletal muscle unloading

DOI:  https://doi.org/10.3390/ijms27115016
J Physiol. 2026 Jun 11.

Excessive training does not induce mitochondrial dysfunction or impair insulin signalling within skeletal muscle.

Geneviève J DesOrmeaux, Henver S Brunetta, Pierre-Andre Barbeau, Alexandra M Coates, Christopher Pignanelli, Fasih A Rahman, Jamie F Burr, Graham P Holloway.

  Excessive training, also known as overtraining, has been suggested to impair skeletal muscle mitochondrial function and glucose homeostasis, challenging the notion that exercise is inherently beneficial. However, methodological limitations on assessment of mitochondrial bioenergetics while considering exercise-induced mitochondrial biogenesis make the metabolic consequences of overtraining still debatable. Therefore, we investigated skeletal muscle insulin signalling and mitochondrial bioenergetics in skeletal muscle following a 3-week overtraining protocol in healthy highly trained endurance athletes. Proteomics of skeletal muscle revealed an upregulation of proteins related to fatty acid metabolism and mitochondrial content induced by overload training. Functionally, mitochondrial respiratory capacity as well as H2O2 emission were increased in permeabilized muscle fibres. These effects were dependent on mitochondrial content, suggesting preservation of intrinsic mitochondrial oxidative phosphorylation. While sub-maximal mitochondrial H2O2 emission and oxidative stress were increased following excessive training, insulin signalling within skeletal muscle (i.e., Akt phosphorylation) during an oral glucose challenge was improved, suggesting excessive exercise does not induce skeletal muscle insulin resistance. In a further analysis, based on their psycho-physiological performances, participants were identified by who successfully or not developed an overreaching phenotype. This approach revealed a unique proteome signature in individuals who were overreached, marked by a smaller increase in proteins involved in cytoskeleton organization, glycogen metabolism, and protein translation. However, despite such classification, we did not observe reductions in either mitochondrial bioenergetics or insulin signalling within skeletal muscle. Altogether, overtraining in highly active individuals induces mitochondrial biogenesis without impairments in skeletal muscle insulin signalling nor mitochondrial oxidative capacity. KEY POINTS: Proteomics revealed upregulation of fatty acid and mitochondrial proteins by excessive training. Overtraining does not cause mitochondrial dysfunction. Improved insulin signalling in skeletal muscle post-overtraining. Overreached athletes show blunted increase in protein synthesis and metabolism.

Keywords:  glucose; metabolism; overtraining; proteome; skeletal muscle

DOI:  https://doi.org/10.1113/JP289538
Cell Death Differ. 2026 Jun 12.

Fibroadipogenic progenitor-secreted prostaglandin E2 coordinates stem cell fate via autocrine and paracrine crosstalk in healthy and dystrophic muscle.

Thomas Molina, Paul Fabre, Pauline Garcia, Tae-Yeon Kim, Zachary Gurlekian, Lydia Tellier, Lupann Rieger, Julianne Dallaire, Étienne Collette, Rebecca Desaulniers, Karine Greffard, Ornella Pellerito, Serge McGraw, Jean-François Bilodeau, Nicolas A Dumont.

Fibroadipogenic progenitors (FAPs) play a key role in skeletal muscle homeostasis and regeneration. They produce extracellular matrix components and secrete cytokines that regulate muscle stem cell function. The number of FAPs and their activity need to be dynamically regulated to avoid their chronic accumulation and overproduction of fibrosis. However, the intrinsic factors by which FAPs control their cell fate decisions remain elusive. Here, we show that FAPs-secreted prostaglandin-E2 (PGE2) functions as a key autoregulatory factor. Using lipidomics and single cell transcriptomics, we show that FAPs are a main cellular source of PGE2 in resting muscle and during regeneration. FAP-secreted PGE2 exerts paracrine effects that maintain the muscle stem cell pool at steady state and stimulate their proliferation post-injury. Moreover, it functions as an autocrine regulator of FAP fate decisions (apoptosis) and subpopulation dynamics. Acute or chronic administration of non-steroidal anti-inflammatory drugs that inhibit the prostaglandin-synthesizing enzyme COX2 increases FAPs content post-injury. Using Pdgfrα-CreERT2_Cox2flox mice, we showed that conditional ablation of COX2 specifically in FAPs increases FAPs content, fibrosis, and impairs muscle regeneration, which can be rescued by PGE2 administration. Furthermore, we show that PGE2 production in FAPs is impaired in mouse models of Duchenne muscular dystrophy, and we provide a proof-of-concept that PGE2 administration can reduce FAPs numbers, fibrosis accumulation, and increase muscle strength. Overall, we uncover a novel role for PGE2 beyond its function in inflammation and identify a mechanism by which FAPs intrinsically regulate their own cell fate, revealing therapeutic potential for muscle injury and dystrophic conditions.

DOI: https://doi.org/10.1038/s41418-026-01762-1
Clin Sci (Lond). 2026 Jul 15. 140(7): 1243-1263

Muscle fibre denervation in ageing.

Casper Soendenbroe.

  Muscle fibre denervation describes the loss of effective neural input from a motor neuron to one or more muscle fibres. In ageing, denervation is increasingly recognised as an important contributor to progressive declines in muscle strength and functional capacity, yet it remains heterogeneous and difficult to define in humans. This ambiguity reflects both biological complexity and current methodological limitations. The purpose of the present review is to synthesise current human evidence for muscle fibre denervation in ageing, clarify key conceptual distinctions, and evaluate methodological approaches used to assess denervation in humans. Muscle fibre denervation can occur through structural disconnection of the motor neuron from the fibre or through functional impairment of neuromuscular transmission. Evidence for denervation in ageing is derived from histological, molecular, electrophysiological, and circulating biomarker approaches, each capturing distinct and only partially overlapping aspects of neuromuscular integrity. Importantly, no single measure provides a comprehensive assessment of denervation. Experimental models of disuse in humans reveal a functional denervation phenotype, characterised by molecular and electrophysiological changes that partially resemble those observed with ageing. Physical activity appears to mitigate against aspects of muscle fibre denervation; however, the mechanisms underlying these effects remain incompletely understood. Collectively, the available evidence indicates that denervation in ageing is a multifaceted and dynamic process that requires multimodal, longitudinal approaches to define, detect, and ultimately target denervation-related mechanisms to preserve neuromuscular function across the human lifespan.

Keywords:  Sarcopenia; aging; denervation; motor unit; neuromuscular junction; skeletal muscle

DOI:  https://doi.org/10.1042/CS20260761
Sci Adv. 2026 Jun 12. 12(24): eadz1953

A decline in skeletal muscle NOX4 abrogates exercise-induced adaptive homeostasis and exacerbates biological aging.

Chrysovalantou E Xirouchaki, Esther García-Domínguez, Eamon Coughlan, Meagan J McGrath, Saveen Giri, Shuwei Liang, Florian Wiede, Anne Bigot, Junichi Sadoshima, Maria C Gomez-Cabrera, Andrew Philp, Marcus Moberg, William Apró, William Roman, Christina A Mitchell, Tony Tiganis.

A decline in nuclear factor erythroid 2-related factor 2 (NFE2L2)-orchestrated adaptive homeostasis and oxidative distress are thought to be key features of aging. In contracting skeletal muscle, the reactive oxygen species-producing enzyme NADPH oxidase 4 (NOX4) is a potent inducer of NFE2L2 adaptive homeostasis. Here, we report that skeletal muscle NOX4 levels decline in aged mice and humans, resulting in abrogated NFE2L2 adaptive homeostasis, increased protein oxidative damage, and decreased muscle function. We show that deleting NOX4 in skeletal muscle exacerbates the physiological decline associated with aging, resulting in overt sarcopenia and frailty, characterized by physical inactivity, increased adiposity, systemic inflammation, whole-body insulin resistance, and advanced liver disease in aged chow-fed mice. The systems-wide physiological decline in aged skeletal muscle NOX4-deficient mice could be corrected by restoring NOX4 using viral approaches or activating NFE2L2 downstream with sulforaphane and reinstating adaptive homeostatic responses otherwise induced by exercise. Our findings provide important insights into the basis for the decline in NFE2L2-orchestrated adaptive homeostasis that accompanies physical inactivity with age and identify key mechanisms by which exercise may promote healthy aging.

DOI: https://doi.org/10.1126/sciadv.adz1953
FASEB J. 2026 Jun 30. 40(12): e71972

eIF3 Orchestrates a Biphasic Stress Response Linking Translational Control to Mitochondrial Integrity in Skeletal Muscle.

Yingying Lin, Jianing Xia, Man Li, Junhao Zhang, Yonghao Mu, Lenian Ling, Minghao Lu, Jiahuan Wang, Kexin Liao, Yefeng Cai.

  Skeletal muscle adaptation to physiological and pathological stressors requires precise coordination of protein synthesis and mitochondrial function. While the roles of canonical translation regulators such as eIF2α and 4E-BP1 in exercise-induced protein synthesis modulation are well established, the contribution of eIF3, the largest eukaryotic initiation factor complex, to muscle stress responses remains poorly understood. Eukaryotic initiation factor 3 (eIF3) regulates mRNA translation and mitochondrial homeostasis, yet how individual eIF3 subunits respond to distinct modes of skeletal muscle stress remains unclear. Here, we systematically characterized eIF3 dynamics and mitochondrial function using two complementary mouse models: acute exhaustive training and dexamethasone (DEX)-induced atrophy. Integrated proteomic, transcriptional, and imaging analyses revealed a biphasic regulatory pattern: DEX treatment caused broad downregulation of eIF3a, eIF3b, eIF3c, eIF3g, and eIF3l, concurrent with comprehensive mitochondrial electron transport chain (ETC) impairment, while acute training selectively decreased eIF3d, eIF3e, eIF3g, and eIF3l but uniquely preserved eIF3f expression alongside adaptive ETC remodeling. This differential response pattern distinguishes eIF3 from other stress-responsive translation factors, as eIF2α phosphorylation typically causes global translation suppression whereas eIF3 dysregulation selectively impairs mitochondrial protein synthesis. Notably, eIF3f preservation under both conditions suggests a compensatory mechanism to maintain translational capacity. siRNA-mediated knockdown of eIF3e or eIF3f in C2C12 myotubes demonstrated their differential effects on mitochondrial protein expression and atrophy signaling, with eIF3f knockdown causing more severe mitochondrial protein suppression. Seahorse XF analysis confirmed that eIF3 subunit loss directly impairs mitochondrial oxygen consumption, while SUnSET assays demonstrated attenuated global protein synthesis upon eIF3e or eIF3f depletion. Furthermore, eIF3 knockdown suppressed mTORC1 signaling (p-mTOR, p-4EBP1, p-S6K, p-S6) and differentially modulated ubiquitin-proteasome activity without altering bulk autophagy. These findings establish eIF3 as a molecular integrator linking translational control to mitochondrial integrity in skeletal muscle physiology, positioning this complex as a potential therapeutic target for conditions ranging from exercise-induced adaptation to muscle wasting disorders.

Keywords:  ETC complex; eIF3; mitochondria; muscle adaptation; skeletal muscle; translation regulation

DOI:  https://doi.org/10.1096/fj.202600161R
Exerc Sport Sci Rev. 2026 Jul 01. 54(3): 127-133

microRNA-1: A Master Regulator of Metabolism Governing Skeletal Muscle Hypertrophy.

Jainil Daredia, Benjamin I Burke, John J McCarthy, Ahmed Ismaeel.

  Downregulation of microRNA-1 (miR-1), the most abundant muscle-enriched microRNA, represents a conserved hallmark of skeletal muscle hypertrophy across species. We propose that mechanical overload-induced reduction in miR-1 expression drives metabolic reprogramming critical for hypertrophic adaptation. This review explores emerging evidence establishing miR-1 as a master regulator of metabolism that governs skeletal muscle growth.

Keywords:  Warburg effect; aerobic glycolysis; extracellular vesicles; mechanical overload; metabolic reprogramming; pyruvate metabolism; resistance exercise training

DOI:  https://doi.org/10.1249/JES.0000000000000384
Cells Tissues Organs. 2026 Jun 08. 1-20

Homer 2 regulates muscle differentiation with NFATc1.

Miki Aizawa, Masakazu Kinoshita, Kunihiro Sakuma.

Calcineurin-NFAT is an important pathway that regulates skeletal muscle regeneration. Homer 2 that modulates signal transduction in the central nervous system directly binds to NFATc1. However, its role is not fully understood in skeletal muscle regeneration. We aimed to investigate the change of Homer 2 protein levels and expression patterns during muscle regeneration. Male ICR mice (12 weeks) were used in the experiment (n=6/group). Their left TA muscle was damaged via intramuscular injection of 0.5% bupivacaine hydrochloride (100 μL). The TA muscles of both legs were dissected at 2, 4, and 6 days post-injection and were subjected to immunofluorescence staining with Homer 2, NFATc1 and muscle regeneration markers [Pax7 and myogenin]. We calculated their expression frequency by quantifying the immunoreactivity per 500 nuclei. We observed Homer 2 immunoreactivity in TA muscles at 2, 4, and 6 days post-injection. Homer 2 and Pax7, a satellite cell marker, were co-localized in mononuclear cells also in regenerating TA muscles. Many Homer 2-positive mononuclear cells expressed myogenin. The frequency of Homer 2 and NFATc1-positive cells significantly increased at 4 and 6 days rather than 2 days post-injection. Interestingly, co-immunoprecipitation experiments of Homer 2 and NFATc 1 showed markedly increased levels at 4 days. In conclusion, we demonstrated that expression of Homer 2 protein increases in TA muscle regeneration. Homer 2 may act in the muscle regeneration process via the calcineurin-NFAT pathway.

DOI: https://doi.org/10.1159/000552863
Cell Death Dis. 2026 Jun 06.

LaminA/C-dependent cellular senescence signaling promotes skeletal muscle atrophy and abnormalities in Parkinson's disease.

Jaydeep Sharma, Somnath Mondal, Krishna Singh Bisht, Ankit Biswas, Lakshmikanthan Panneerselvam, Tushar Kanti Maiti, Sam J Mathew.

Parkinson's disease (PD) is a neurodegenerative disease affecting the central nervous system with effects on the skeletal muscle that entails detailed characterization. Several PD-associated motor symptoms, such as rigidity, movement delays and postural instability, involve the skeletal muscle. We used the human α-syn A53T mutant mouse model to characterize the PD-associated skeletal muscle abnormalities. These mice exhibit reduced muscle weight, myofiber size and grip strength at PD onset. Gain of slow muscle fibers at the expense of fast fibers, muscle stem cell number alterations, elevated fibrosis and neuromuscular junction degeneration were observed in these mice. Oxidative stress and DNA damage-associated pathways led to reduced levels of the nuclear membrane protein LaminA/C, causing accelerated cellular senescence in the A53T muscle. We identify a molecular pathway of senescence-associated secretory phenotype activating FoxO signaling, resulting in skeletal muscle loss in the A53T mice. Thus, increased oxidative stress and accumulated cellular senescence could underlie the PD-associated musculoskeletal defects, with potential therapeutic significance.

DOI: https://doi.org/10.1038/s41419-026-08962-0
Front Med (Lausanne). 2026 ;13 1838178

MOTS-c partially protects against skeletal muscle deterioration in C26 cachexia.

Nicholas A Jamnick, Patrick D Livingston, Caleb J Gammon, Natalia M Weinzierl, Leah J Novinger, Andrea Bonetto.

   Background: Cancer cachexia is a multifactorial metabolic syndrome marked by progressive skeletal muscle loss, reduced function, and increased mortality. Mitochondrial dysfunction is a key driver of this phenotype. MOTS-c, a mitochondrial-derived peptide that regulates metabolic homeostasis and mimics exercise signaling, may counteract cachexia, but its role remains largely unexplored, and human studies using MOTS-c in subjects with cancer cachexia are needed.
Methods: Differentiated myotubes were treated with MOTS-c (50 μM) to assess intracellular signaling. In vivo, male mice were inoculated with Colon-26 (C26) carcinoma cells and treated daily with MOTS-c (15 mg/kg/2x Day, i.p.) or vehicle. Body weight was monitored daily. At euthanasia, organ and skeletal muscle masses were measured. Molecular analyses focused on FOXO signaling, atrogene expression (MuRF1, Atrogin-1), and mitochondrial biogenesis markers, including PGC-1α.
Results: In vitro, MOTS-c increased PGC-1α mRNA (+84.6%) and AMPK phosphorylation (+103.1%). C26 tumor-bearing mice exhibited significant systemic wasting (~9% body weight loss). Although MOTS-c did not prevent total body weight or fat loss, it significantly preserved skeletal muscle mass, rescuing quadriceps weight (+12% vs. C26 vehicle; p < 0.05) and trending toward protection of gastrocnemius mass and EDL function. Cachexia-induced upregulation of Atrogin-1 (+8.6-fold) and MuRF1 (+16-fold) was attenuated by MOTS-c, accompanied by increased inhibitory pFOXO1 (+80%), reduced pFOXO3a (-39%), and partial restoration of PGC-1α protein (+143%).
Conclusion: Our findings demonstrate that MOTS-c partially protects against skeletal muscle loss in C26 cachexia by modulating FOXO-driven catabolic signaling and promoting mitochondrial biogenesis, supporting its therapeutic potential in cancer cachexia.

Keywords:  MOTS-c; cachexia; colorectal cancer; muscle; protein homeostasis

DOI:  https://doi.org/10.3389/fmed.2026.1838178
Cell Commun Signal. 2026 Jun 12.

The cGAS-STING pathway contributes to cisplatin-induced skeletal muscle atrophy through altered proteostasis and myogenic signaling.

Xiaoguang Liu, Miaomiao Xu, Huan Wang, Haozhe Wang, Hao Wang, Wenjun Fang, Mengqian Li, Jiongxing Huang, Feipeng Chen, Huiguo Wang, Yang Yu, Lin Zhu.

   BACKGROUND: Cisplatin chemotherapy is widely used for cancer treatment but frequently induces skeletal muscle atrophy, which compromises physical function and patient outcomes. The molecular mechanisms underlying this process remain incompletely understood. The cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling pathway, classically involved in innate immune responses, has recently been implicated in cellular stress and tissue dysfunction. Whether cGAS-STING signaling contributes to cisplatin-induced skeletal muscle atrophy remains unclear.
METHODS: We employed both pharmacological and genetic approaches. Wild-type (WT) mice received a single intraperitoneal injection of the STING agonist DMXAA prior to cisplatin administration. Genetic models included global cGAS and STING knockout mice, as well as skeletal muscle-specific cGAS knockout mice. Cisplatin was administered intraperitoneally (3 mg/kg/day) for four consecutive days. Body weight, skeletal muscle mass, myofiber cross-sectional area (CSA), and fiber diameter were assessed. Molecular and transcriptional analyses were performed using Western blotting, quantitative polymerase chain reaction, and RNA sequencing.
RESULTS: Pretreatment with the STING agonist DMXAA exacerbated cisplatin-induced body weight loss and skeletal muscle atrophy. In contrast, genetic deletion of cGAS or STING attenuated the loss of gastrocnemius and tibialis anterior muscle mass. Skeletal muscle-specific cGAS deficiency preserved muscle weight and myofiber diameter following cisplatin exposure. Although CSA was also assessed, no significant difference was observed between groups. Transcriptomic analysis identified 696 differentially expressed genes upon cGAS deletion, with enrichment in pathways related to inflammatory signaling, proteasome function, and autophagy. Further analyses in skeletal muscle-specific cGAS-deficient mice showed reduced expression of muscle atrophy-associated genes (FBXO32 and Murf1), together with preservation of key myogenic regulators after cisplatin treatment. Consistently, NF-κB signaling and interferon-stimulated gene expression were diminished, accompanied by altered Beclin1 responses and partial attenuation of selected autophagy-related genes.
CONCLUSIONS: These findings support a role for cGAS-STING signaling in cisplatin-induced skeletal muscle atrophy, associated with enhanced innate immune and inflammatory signaling, proteolytic and autophagy-related alterations, and impaired myogenic regulation. Targeting the cGAS-STING pathway may represent a potential therapeutic strategy to mitigate chemotherapy-associated skeletal muscle atrophy.

Keywords:  CGAS–STING pathway; Chemotherapy-induced skeletal muscle atrophy; Cisplatin toxicity; Skeletal muscle wasting; Therapeutic target

DOI:  https://doi.org/10.1186/s12964-026-02989-8
Int Rev Cell Mol Biol. 2026 ;pii: S1937-6448(25)00114-5. [Epub ahead of print]403 85-121

Autophagy in cancer cachexia: From mechanisms to therapeutic opportunities.

Riccardo Ballarò, Fabio Penna, Marc Beltrà.

  Cancer cachexia is a multifactorial syndrome characterized by body weight loss, muscle wasting, and systemic metabolic alterations, significantly contributing to patient morbidity and mortality. A key feature of cachexia is the excessive degradation of muscle proteins and mitochondria, largely mediated by autophagy. Although hyperactivation of autophagy has been widely recognized as a hallmark of cancer cachexia, its precise role in exacerbating muscle atrophy through enhanced proteolysis and mitochondrial disposal remains a subject of ongoing debate. This review provides a comprehensive overview of previous milestones and recent advancements in understanding autophagy's role in cancer cachexia, with particular focus on its impact on skeletal muscle and liver, as well as its contribution to tumor metabolic flexibility. Additionally, the review explores emerging therapeutic strategies aimed at modulating autophagy, including exercise, exercise mimetics, and novel molecules to selectively target specific branches of autophagy. By synthesizing current evidence, this review highlights the need for further research into the mechanisms underlying autophagy dysregulation in cancer cachexia and the potential for autophagy-based interventions to improve patient outcomes.

Keywords:  Autophagy; Cancer cachexia; Diet therapy; Exercise; Liver metabolism; Mitophagy; Muscle wasting; Tumor metabolism

DOI:  https://doi.org/10.1016/bs.ircmb.2025.08.008
Transl Res. 2026 Jun 11. pii: S1931-5244(26)00119-2. [Epub ahead of print]

Integrated RNA sequencing and in vivo biosensor imaging define the early pathogenic cascade of Duchenne muscular dystrophy.

Elena Cannone, Martina La Spina, Barbara Gnutti, Chiara Tesoriero, Silvia Castagnaro, Chiara Tobia, Luca La Via, Patrizia Sabatelli, Cesare Faldini, Giuseppe Fiume, Andrea Vettori, Dario Finazzi, Massimo Gennarelli, Chiara Magri, Marco Schiavone.

  Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by loss of dystrophin, and characterized by progressive muscle wasting, with massive replacement of muscle fibers with adipose tissue. Yet, the early molecular events that initiate pathology remain poorly defined. Here, we combined longitudinal RNA sequencing of sapje dystrophic zebrafish (a single-mutation vertebrate model of human DMD characterized by a severe phenotype), transcriptomic profiling of human DMD myoblasts and myotubes, and functional in vivo imaging using pathway-specific zebrafish biosensors to reconstruct the cascade of events triggered by dystrophin deficiency. We observed that the earliest stages of disease are characterized by marked downregulation of genes controlling cytosolic Ca2+ homeostasis, mitochondrial function and organization, and Pax3/Mef2a/Srf-mediated transcriptional programs essential for satellite cell maintenance and muscle differentiation. These early deficits precede robust but ineffective regenerative and metabolic compensatory responses, accompanied by extracellular matrix remodeling and TGFβ activation. At advanced stages, both sapje zebrafish and human DMD myotubes converge on profound mitochondrial dysfunction, impaired cell-cycle control, and chronic inflammation signaling. Live imaging of sapje zebrafish biosensors validated these transcriptomic signatures, revealing reduced Notch, Bmp, Shh, Hif-1a and Wnt signaling, along with aberrant TGFβ activity and disrupted mitochondrial dynamics in vivo. Together, these findings identify a conserved temporal sequence linking early Ca2+ dysregulation to mitochondrial failure, satellite cell hyperactivation, and fibrotic remodeling, providing mechanistic insights and therapeutic targets for early intervention in DMD patients.

Keywords:  Duchenne muscular dystrophy; RNA sequencing; human myoblasts; human myotubes; live imaging; zebrafish; zebrafish biosensors

DOI:  https://doi.org/10.1016/j.trsl.2026.06.007
Cells. 2026 Jun 05. pii: 1041. [Epub ahead of print]15(11):

Ribosome Biogenesis as a Putative Bottleneck to Skeletal Muscle Hypertrophy: Mechanisms, Human Evidence, and Practical Modulators.

Mario Muñoz López, José Francisco López-Gil, Xabier Ramírez de la Piscina Viúdez, Eneko Baz-Valle, José Francisco Tornero Aguilera.

   BACKGROUND: Skeletal muscle hypertrophy has traditionally been attributed to transient spikes in translational efficiency governed by the mTORC1 signaling cascade. However, contemporary molecular evidence reveals that sustained macroscopic growth is strongly associated with the physical expansion of the translational machinery itself. The activation of RNA Polymerase I and the subsequent synthesis of new ribosomes represent a critical biological correlate for long-term protein accretion.
OBJECTIVE: This comprehensive review critically examines ribosome biogenesis as the primary structural bottleneck shaping human skeletal muscle adaptation, differentiating acute signaling efficiency from chronic translational capacity.
SYNTHESIS: We dissect the molecular orchestration of nucleolar expansion and critically address the pervasive methodological pitfalls plaguing the current literature. Specifically, we highlight the moving denominator paradox, demonstrating how flawed bulk RNA normalization strategies systematically underestimate true ribosomal accretion in actively growing tissue. By synthesizing in vivo human evidence, we delineate how age, concurrent training, and training volume modulate this structural capacity. We further establish the high-responder phenotype as a function of successful nucleolar adaptation. Finally, we explore advanced molecular frontiers, including epigenetic chromatin remodeling, ribosomal heterogeneity as an emerging frontier, non-coding RNA regulation, and nuclear mechanotransduction via the YAP/TAZ axis.
CONCLUSIONS: Acute anabolic signaling is merely permissive. Permanent hypertrophic adaptation fundamentally relies on overcoming the translational capacity bottleneck. Shifting the scientific and applied focus toward the architectural expansion of the nucleolus will fundamentally redefine practical hypertrophy programming and clinical interventions for sarcopenia.

Keywords:  RNA Polymerase I; mechanotransduction; nucleolus; resistance training; ribosome biogenesis; skeletal muscle hypertrophy; translational capacity

DOI:  https://doi.org/10.3390/cells15111041
Bioeng Transl Med. 2026 May;11(3): e70101

Physiological and functional characterization for high-throughput optogenetic skeletal muscle exercise assays.

Ronald H Heisser, Angel Bu, Laura Schwendeman, Tamara Rossy, Pavankumar Umashankar, Vincent Butty, Ritu Raman.

  Exercise promotes human mobility by tuning the function of skeletal muscle, and recent studies highlight exercise's broader impacts on human health via muscle's paracrine and endocrine roles beyond force generation. In vitro models of tissue engineered skeletal muscle enable precise investigation of adaptation to exercise, with emerging approaches for optogenetic muscle stimulation providing a less invasive alternative to traditional techniques for electrical stimulation. In this study, we present a high-throughput muscle culture and optical exercise protocol for scalable in vitro exercise studies. First, we characterize optical rheobase for 2D muscle monolayers, finding that optical intensities as low as 5 μW mm-2 can trigger functional contraction. We then leverage RNA sequencing to map changes in muscle gene expression in response to various optical exercise regimens, highlighting how changing stimulation parameters impact myogenic and broader physiological and pathological transcriptional responses. Our platform and results establish a practical foundation for high-throughput in vitro exercise studies of skeletal muscle.

Keywords:  exercise; optogenetics; skeletal muscle; tissue engineering

DOI:  https://doi.org/10.1002/btm2.70101
JCI Insight. 2026 Jun 09. pii: e204852. [Epub ahead of print]

Combination S100A1 and ARC gene therapy as a treatment for DMD cardiomyopathy.

David W Hammers, Cora C Hart, Eli A Zerpa, Karen I Laurent, Young Il Lee, Margaret M Sleeper, H Lee Sweeney.

  Duchenne muscular dystrophy (DMD) is a lethal pediatric striated muscle disease caused by loss of dystrophin for which there is no cure. Cardiomyopathy is the leading cause of death amongst individuals with DMD, and effective therapeutics to treat DMD cardiomyopathy are a major unmet clinical need. This work investigated adeno-associated viral (AAV) gene therapy approaches to treat DMD cardiomyopathy by overexpression of the calcium binding proteins S100A1 and apoptosis repressor with caspase recruitment domains (ARC). Using the severe D2.mdx mouse model of DMD, we identified that S100A1 gene therapy improves the diastolic dysfunction associated with DMD cardiomyopathy, whereas ARC gene therapy prolongs survival. The combination of both S100A1 and ARC in a single bicistronic vector improves the long-term cardiac outcome and histopathology of D2.mdx mice, development of heart failure caused by micro-dystrophin expression, and exhibits safety via intracoronary delivery in a canine model of DMD. In addition to robust cardiac benefits, S100A1-ARC gene therapy benefits D2.mdx skeletal muscle function and histopathology when driven by a striated muscle promoter. Together, these findings indicate that S100A1-ARC gene therapy represents an effective treatment for DMD cardiomyopathy and may have therapeutic benefits in treating other forms of cardiomyopathy and muscle pathologies.

Keywords:  Cardiology; Cardiovascular disease; Gene therapy; Muscle biology; Neuromuscular disease

DOI:  https://doi.org/10.1172/jci.insight.204852
Front Cell Dev Biol. 2026 ;14 1841851

The miR-30c-5p/SOCS3 axis is a potential driver of inflammation and metabolic imbalance in Duchenne muscular dystrophy.

Yayu Wang, Xiuyi Ai, Yue Chang, Shu Zhang, Pei Zhang, Shiwen Wu.

   Background: Duchenne muscular dystrophy (DMD) constitutes a severe, incurable disorder inherited in an X-linked manner, characterized by continuous skeletal muscle degeneration, chronic inflammatory responses, and profound metabolic alterations. Although miRNA-mRNA regulatory networks are thought to contribute to DMD pathogenesis, their key drivers remain insufficiently defined.
Methods: In this study, we integrated bulk RNA-seq (GSE38417, GSE109178), small RNA-seq (GSE157668), and single-cell RNA-seq (GSE213925) data and combined differential expression analysis, target gene prediction, functional pathway enrichment mapping, and protein-protein interaction network analysis to screen candidate miRNA-mRNA axes, which were subsequently validated in mdx mice, C2C12 myoblasts, and primary skeletal muscle cells.
Results: We identified 100 differentially expressed miRNAs (DEMs) in DMD muscle, with miR-30c-5p being the most downregulated and possessing the highest number of predicted targets. Integrated analysis revealed SOCS3 as a key upregulated hub gene targeted by miR-30c-5p. ScRNA-seq showed elevated SOCS3 expression in myocytes from DMD muscle, where SOCS3+ cells exhibited enriched inflammatory pathways and suppressed metabolic processes. In mdx mice, miR-30c-5p expression showed a pronounced reduction (P < 0.001). In contrast, SOCS3 expression increased at both the transcriptional (P < 0.001) and translational (P < 0.01) levels. Functional experiments further showed that overexpression of miR-30c-5p reduced SOCS3 expression, whereas inhibition of miR-30c-5p increased SOCS3 levels in C2C12 cells and primary skeletal muscle cells. Dual-luciferase reporter assay further supported direct binding of miR-30c-5p to the SOCS3 3'UTR. In mdx-derived primary skeletal muscle cells, miR-30c-5p restoration was also accompanied by reduced TNF-α and increased IL-10 levels, and rescue experiments supported that these anti-inflammatory effects were at least partly SOCS3-dependent.
Conclusion: These findings suggest that the miR-30c-5p/SOCS3 axis is associated with inflammation- and metabolism-related alterations in DMD and warrants further investigation.

Keywords:  Duchenne muscular dystrophy; SOCS3; inflammation; metabolic dysfunction; miR-30c-5p; single-cell RNA sequencing

DOI:  https://doi.org/10.3389/fcell.2026.1841851
Mol Metab. 2026 Jun 09. pii: S2212-8778(26)00080-3. [Epub ahead of print] 102396

Endocannabinoid system and skeletal muscle health: insights from cannabidiol.

Anaïs Deglos, Nicolas Saroul, Stéphane Walrand, Olivier Le Bacquer.

  The endocannabinoid (EC) system is a complex network comprising endogenous ligands, enzymes responsible for their synthesis and degradation, and various receptors (including CB1 and CB2). Present in many peripheral tissues, including skeletal muscle, EC system is now recognized to influence key physiological processes such as insulin sensitivity, mitochondrial metabolism, protein homeostasis and muscle development. Alterations in this system are associated with a variety of pathologies, including obesity, type 2 diabetes, sarcopenia, cachexia and muscle dystrophies. In this context, cannabidiol (CBD), a phytocannabinoid devoid of psychoactive properties, is attracting growing interest as a potential therapeutic agent. This article provides an analysis of the mechanisms by which the EC system, and more specifically the CB1 receptor, influences skeletal muscle development and function, while exploring emerging data on the potential benefits of CBD in various pathological conditions affecting skeletal muscle.

Keywords:  atrophy; cachexia; cannabidiol; endocannabinoids; mitochondria; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1016/j.molmet.2026.102396
bioRxiv. 2026 Jun 07. pii: 2026.06.03.729837. [Epub ahead of print]

Copper transport to mitochondria by SLC25A3 contributes to skeletal myoblast differentiation and is required for survival of differentiated myotubes.

Alexandra M Perez, Jason D Fivush, Bailey M Cordill, Nathan Ferguson, Yu Zhang, Allison T Mezzell, Ushodaya Mattam, Omar Chaudhry, Karleigh G Porter, Saanvi Maadaadi, Dina Secic, Megan Bischoff, Karthickeyan Chella Krishnan, Rhett Kovall, Tom Cunningham, Maria Czyzyk-Krzeska, Katherine E Vest.

Differentiation of skeletal muscle is associated with increased mitochondrial biogenesis and reliance of oxidative phosphorylation (OXPHOS). The terminal enzyme complex in the electron transport chain, cytochrome c oxidase (COX), requires copper for its assembly and activity, and copper delivery to mitochondria is essential for OXPHOS. However, when mitochondrial copper becomes essential during skeletal myoblast differentiation is not known. Here, we show that genetic deficiency of the mitochondrial copper and phosphate carrier SLC25A3 induced prior to myoblast differentiation leads to the formation of smaller myotubes, but SLC25A3 deficiency induced in mature myotubes leads to cell death and detachment. Both phenotypes are recapitulated upon genetic knockdown of COX17, a critical assembly protein for both COX copper cofactors, or by chemical inhibition of COX. Importantly, myotube death caused by SLC25A3 deficiency is rescued by copper supplementation or expression of an SLC25A3 variant that transports copper but not phosphate. Taken together these data support a model wherein copper transport by SLC25A3 and copper delivery to COX is critical for survival in mature myotubes.

DOI: https://doi.org/10.64898/2026.06.03.729837
ACS Biomater Sci Eng. 2026 Jun 12.

Injectable Hydrogel-Based Delivery of Soluble Cripto Protein Enhances Repair After Skeletal Muscle Injury.

Rachel Lev Gur, Orit Bar-Am, Galit Saar, Ombretta Guardiola, Eli Peled, Gabriella Minchiotti, Dror Seliktar.

  Injectable protein therapies offer a minimally invasive approach for enhancing skeletal muscle regeneration, yet their clinical translation has been limited by poor in vivo stability, rapid diffusion, and insufficient temporal bioavailability at the injury site. Here, we report a thermoresponsive, fully injectable Pluronic F127-fibrinogen (FF) hydrogel that enables temporally synchronized delivery of a soluble form of Cripto, a GPI-anchored co-receptor that promotes myogenic regeneration by counteracting myostatin signaling. Cripto is physically entrapped within the FF precursor and undergoes in situ gelation at physiological temperature, allowing localized delivery without chemical modification or pre-fabrication. The FF hydrogel sustains Cripto release for up to 28 days while preserving receptor-binding activity. In a cardiotoxin-induced skeletal muscle injury model, bolus Cripto delivery failed to enhance regeneration, whereas FF-mediated delivery significantly improved muscle repair, as evidenced by increased centrally nucleated myofibers, enlarged fiber cross-sectional area, and elevated desmin expression. Importantly, FF biodegradation overlapped with the biologically permissive regeneration window, synchronizing protein bioavailability with muscle repair. Together, these findings identify injectable FF hydrogels as a practical and generalizable platform for temporally controlled protein delivery in skeletal muscle regeneration.

Keywords:  hydrogel biodegradation; muscle injury; myostatin inhibition; protein therapeutics; regenerative biomaterials; tissue engineering

DOI:  https://doi.org/10.1021/acsbiomaterials.6c00084
J Transl Med. 2026 Jun 06.

Bacteroides-derived endocannabinoid-like commendamide attenuates skeletal muscle ferroptosis in vitro: implications for Duchenne muscular dystrophy.

Noemi Di Muraglia, Martina De Vito, Elisabetta Panza, Ester Pagano, Rosa Maria Vitale, Fabiana Piscitelli, Rosaria Villano, Raffaele Capasso, Vincenzo Pota, Caterina Pace, Salvatore Dongiovanni, Vincenzo Di Marzo, Fabio Arturo Iannotti.

   OBJECTIVE: The gut microbiota regulates skeletal muscle physiology, with an increasingly recognised role in Duchenne muscular dystrophy (DMD), the most severe X-linked myopathy. Unlike previous studies, we focussed on the genus Bacteroides and its metabolites, assessing their abundance in DMD mice and patients to clarify their potential contribution to the disease.
METHODS: The relative abundance of Bacteroides species was analysed in fecal samples from dystrophic mdx mice and DMD patients, compared with age-matched healthy controls, using PCR-based tecniques. Synthetic and analitical chemistry approaches followed by cell-based assays, in silico and bioinformatic analyses, were employed to identify an unknown mechanism of action of the Bacteroides-derived metabolites.
RESULTS: DMD patients and mdx mice exhibited a significant reduction in commensal Bacteroides species, including Bacteroides vulgatus, known producers of SCFAs and commendamide, an endocannabinoid-like molecule with largely uncharacterized biological functions. In skeletal muscles of mdx mice, we observed biochemical features consistent with increased susceptibility to ferroptosis. In murine C2C12 cells and primary human myotubes exposed to the ferroptosis inducer erastin, commendamide conferred significant protective effects, which were further enhanced in the presence of SCFAs. Additionally, we discovered that commendamide acts as an endogenous activator of PPARα and PPARγ, with PPARα preferentially promoting the transcription of the antioxidant genes Gpx4 and Nrf2.
CONCLUSION: These findings provide new insights into the gut-muscle axis in DMD, suggesting that the depletion of Bacteroides vulgatus and its metabolites may contribute to skeletal muscle degeneration. In vitro evidence demonstrates that commendamide, through PPARα signaling; and SCFAs, enhances antioxidant mechanisms. Overall, these results support further investigation of microbiota-derived metabolites as postbiotic candidates for DMD therapy.

Keywords:  Commendamide; Duchenne muscular dystrophy (DMD); Ferroptosis; Gut microbiota; PPAR receptors; Short chain fatty acids (SCFAs)

DOI:  https://doi.org/10.1186/s12967-026-08407-4
J Immunol. 2026 Jun 07. pii: vkag101. [Epub ahead of print]215(6):

BACH1 orchestrates macrophage state transitions to coordinate regenerative inflammation.

Noemí Caballero-Sánchez, Petros Tzerpos, Krisztian Bene, Laszlo Halasz, Dóra Bojcsuk, Gergely Nagy, Maysaa A Ali, Timea Cseh, Szilard Poliska, Matthew J Borok, Jordan Scherer, Frederic Relaix, Enrique Saez, Zsolt Czimmerer, Andreas Patsalos, Laszlo Nagy.

  Efficient tissue regeneration requires the precise coordination of inflammatory and regenerative programs, principally mediated by monocyte-derived macrophages. However, the transcriptional wiring and epigenomic processes behind complex macrophage subtype specification and transition between the different states are not known. Here we have identified the transcriptional repressor BACH1 as a critical, cell-intrinsic regulator of monocyte-derived macrophage specification during skeletal muscle regeneration. Using a myeloid-specific BACH1 knockout mouse model, we demonstrate that BACH1 deficiency disrupts the temporal coordination of monocyte-to-macrophage differentiation, leading to aberrant macrophage subsets with concurrent opposing pro- and anti-inflammatory features. Single-cell RNA-sequencing profiling reveals that BACH1 controls a core transcriptional network, including Nfkb1, Cebpb, and interferon signaling, governing inflammatory resolution and functional macrophage specialization. Mechanistically, BACH1 loss accelerates macrophage differentiation but also affects its core cellular identity, resulting in sustained, rather than declining inflammatory programs including upregulation of Il1b and thus, defective tissue remodeling. These immune alterations compromise the paracrine landscape during regenerative inflammation and impair muscle stem cell differentiation. Our findings establish BACH1 as a molecular tuner or controller that integrates early innate immune signaling with regenerative output, positioning it as a central node linking transcriptional control, immune fate decisions, and tissue repair.

Keywords:  BACH1; inflammation; muscle repair; regenerative inflammation; transcription factor

DOI:  https://doi.org/10.1093/jimmun/vkag101
Front Cell Dev Biol. 2026 ;14 1827120

Deciphering skeletal muscle development: cellular heterogeneity and molecular regulatory networks from single-cell and spatial transcriptomic perspectives.

Xingdong Wang, Yongming Zhang, Huimin Wei, Gerelt Zhao, Ren Mu.

  The development of skeletal muscle is a biological process of great complexity and high regulation whereby there is a spatiotemporal coordination of interactions amongst various cell and molecular events. Recent advances in scRNA-seq and ST have enabled systematic dissection of skeletal muscle dynamics at single-cell resolution, thereby revealing the underlying molecular regulatory processes. This review provides an overview of existing evidence on molecular components of cellular heterogeneity of skeletal muscle development, which synergistically stabilize transcription factor network, epigenetic regulation, and metabolic reprogramming in cell fate regulation. By systematically comparing findings across species-including humans, mice, pigs, and chickens-we highlight both evolutionarily conserved mechanisms and species-specific regulatory features. This combination of scRNA-seq, ST, and multimodal data enables us to understand the microenvironment as a spatial regulator of muscle stem cell (MuSC) behavior: the composition of the niche, intercellular communication, and mechanical cues. These discoveries not only elucidate the fundamental principles of skeletal muscle development but also provide a theoretical basis for therapeutic strategies against muscle-related diseases and for improving economically important traits in livestock breeding.

Keywords:  animal breeding; cell fate determination; regulatory networks; single-cell RNA sequencing; skeletal muscle development; spatial transcriptomics

DOI:  https://doi.org/10.3389/fcell.2026.1827120
bioRxiv. 2026 Jun 02. pii: 2026.05.29.727896. [Epub ahead of print]

FAP-intrinsic Hedgehog signaling controls intramuscular adipogenesis, fibrosis, and myofiber regeneration.

Xinyue Liu, Vincent He, Benedict Deepesh, Alessandra Norris, Daniel Kopinke.

Fibro/adipogenic progenitors (FAPs) are multipotent stromal cells that support myofiber regeneration, but can also give rise to intramuscular adipose tissue (IMAT) and fibrotic scar tissue. While the Hedgehog pathway suppresses FAP adipogenesis and promotes myofiber repair through ligand Desert Hedgehog, the key cell type that senses this signal has remained unclear. Here, we demonstrate through FAP-specific deletion of the Hedgehog signal transducer Smoothened that FAPs are the primary Hedgehog-responding cells during muscle regeneration. Loss of Smoothened in FAPs increases IMAT, causes persistent fibrosis, reduces the Hedgehog-dependent effectors TIMP3 and GDF10, and impairs myofiber regeneration. FAPs lacking Smoothened also fail to support in vitro myoblast differentiation and fusion as efficiently as control FAPs, showing that Hedgehog signaling helps establish a pro-myogenic FAP state early after injury. Pharmacological Hedgehog activation via the Smoothened agonist SAG fails to rescue adipocyte accumulation or myofiber regeneration when FAPs lack Smoothened. Together, these findings provide direct genetic evidence that FAPs are the primary cellular mediators of Hedgehog signaling in muscle and establish FAP Hedgehog signaling competence as a key determinant of regenerative outcome and a target for restoring muscle repair in disease.

DOI: https://doi.org/10.64898/2026.05.29.727896
bioRxiv. 2026 Jun 03. pii: 2026.05.30.728982. [Epub ahead of print]

Benzothiazole Derivatives as Dual Modulators of PGE2 and GABAergic Signaling in Skeletal Muscle.

Marian N Aziz, Kamal Awad, Jian Huang, Zhiying Wang, Venu Varanasi, Marco Brotto, Carl J Lovely.

Benzothiazoles are attractive scaffolds for small-molecule modulators of neuronal signaling. However, their impact on skeletal muscle and GABAergic pathways remains poorly understood. We synthesized a focused library of benzothiazole derivatives via oxidative electrophilic substitution and profiled their activity in C2C12 skeletal muscle cells, assessing cytotoxicity, proliferation, myogenic differentiation, and GABA-related signaling using cell-based assays, real-time PCR, and transcriptomics. Omics-guided analyses revealed that selected benzothiazole derivatives differentially modulate myogenic differentiation and prostaglandin E2, and simultaneously bidirectionally regulate GABAergic and glutamatergic signaling genes, including synaptic subunits and transporters. Notably, a lead derivative downregulated Gabrg2, a GABA-A receptor subunit implicated in epilepsy and other disorders of inhibitory synapses, highlighting a potential link between skeletal muscle signaling and neuropsychiatric disease. These findings position benzothiazole derivatives as candidate modulators of GABAergic signaling with translational potential for conditions involving dysfunctional inhibitory synapses.

DOI: https://doi.org/10.64898/2026.05.30.728982
Cell Death Dis. 2026 Jun 10.

Deficiency of G9a boosts muscle regeneration through IL13/Musclin-mediated crosstalk between macrophage and myofiber.

Ying Jin, Kaiyang Zhou, Siyu Hao, Hu Yue, Haoyu Wang, Zhiyuan Liu, Yihao Zhou, Yunhao Xie, Xinran Liu, Hong Chen, Yuxia Liu, Anlin Peng, Yangkai Li, Kun Huang, Ling Zheng.

Muscle regenerative capacity declines with aging and disease, which leads to muscle loss and reduced lifespan. Muscle regenerative failure is related to a disrupted network orchestrated by multiple muscle-harbored cell types; whether and how the interplay between macrophages and myofibers contributes to this process is largely unknown. Herein, we report upregulation of histone methyltransferase G9a in both aged human muscle and mouse muscle after injury. Deletion of G9a in either myeloid cells or myofibers accelerates muscle regeneration. Mechanistically, G9a down-regulates macrophage-derived interleukin 13 (IL13) and suppresses myofiber-derived myokine musclin, respectively, to inhibit myogenesis and macrophage phenotype transition during muscle regeneration. Either IL13 or musclin, per se, accelerated muscle regeneration, and their combined administration showed synergistic effects with therapeutic potentials for muscle degeneration disorders. Collectively, we highlight a crosstalk between macrophages and myofibers through IL13-Stat6 signaling and musclin, both regulated by G9a, which steers a pro-recovery microenvironment after muscle injury, with therapeutic potentials for muscle degeneration disorders.

DOI: https://doi.org/10.1038/s41419-026-08944-2
Cell Death Dis. 2026 Jun 12. pii: 567. [Epub ahead of print]17(1):

Inflammation reprograms fibro-adipogenic progenitors to sustain immunopathogenic niches in myositis.

Christopher Nelke, Julian Sanchez-Dal Cin, Charles-Antoine Dallevet, Jin-Soo Park, Jacqueline C Kinold, Christina B Schroeter, Felix Kleefeld, Anne-Katrin Güttsches, Paula Quint, Sara Walli, Derya Cengiz, Vera Dobelmann, Corinna Preusse, Alexander Mensch, Anne Schänzer, Markus Leo, Tim Hagenacker, Benedikt Schoser, Jörg H W Distler, Akiyoshi Uezumi, Werner Stenzel, Sven G Meuth, Olivier Benveniste, Yves Allenbach, Tobias Ruck.

Idiopathic inflammatory myopathies (IIMs) are autoimmune disorders defined by persistent muscle inflammation, fibrosis, and frequent resistance to current therapies. However, the mechanisms perpetuating disease activity despite immunosuppressive treatment remain elusive. Here, we describe a novel role for tissue-resident stromal cells, specifically fibro-adipogenic progenitors (FAPs), in sustaining skeletal muscle inflammation. Utilizing single-nucleus and spatial transcriptomics in 24 IIM patients and six non-diseased controls, we describe how FAPs adapt to their tissue context, favoring T-cell-centric programs in T-cell environments and myeloid programs in macrophage environments. At the spatial level, FAPs form inflammatory niches by co-localizing with muscle stem cells and activated macrophages, positioning them to participate in cell-to-cell communication with both immune and muscle cells. Trajectory and ligand-receptor analyses suggest a dual-input mechanism whereby infiltrating immune cells (via TGF-β) and myofibers (via epidermal growth factor (EGF)) converge on the AP-1 transcription factor to drive FAP differentiation toward a pro-inflammatory and pro-fibrotic phenotype. Mechanistically, exposure of primary human FAPs to TGF-β and EGF induces a primed state by altering the accessibility to AP-1 regulatory elements. Together, our findings reveal a previously unrecognized role of tissue-resident stromal cells in IIM, highlighting microenvironmental cross-talk centered on FAPs as a promising and actionable therapeutic target.

DOI: https://doi.org/10.1038/s41419-026-08966-w
Sci Rep. 2026 Jun 08.

Microneedle patch-based delivery of Pyr-Apelin-13 reverses functional and structural deficits in age-related sarcopenia.

Chrysoula Kokotidou, Konstantinos Tzortzakis, Jake Lombardo, Hojatollah Rezaei Nejad.

  Sarcopenia, the age-associated loss of skeletal muscle mass and function, currently lacks effective pharmacological interventions. Pyr-Apelin-13, a potent endogenous peptide that stimulates mitochondrial biogenesis and myofiber regeneration, is limited by rapid plasma clearance and the need for frequent injections. We report the first preclinical evaluation of a transdermal Pyr-Apelin-13 microneedle (MN) patch (HeroPatch) in aged mice. The solid-state "drug-in-resin" design achieved near-complete release efficiency (≈100% in vitro; 83-99% in vivo), enabling reproducible multi-milligram delivery with minimal residual loss. Daily MN dosing significantly improved muscle fiber cross-sectional area and grip strength relative to controls, with outcomes comparable to daily intraperitoneal injection. Histological analysis revealed a shift toward larger fiber sizes, consistent with enhanced myofiber remodeling, and mitochondrial DNA content increased concordantly. Weekly dosing produced smaller, non-significant trends, reflecting lower cumulative exposure. These findings demonstrate that HeroPatch enables efficient, reproducible, and non-invasive systemic delivery of Apelin-13, providing a scalable platform for peptide-based therapy of sarcopenia and related muscle-wasting disorders.

Keywords:  Apelin-13; Microneedles; Mitochondria; Muscle function; Sarcopenia; Transdermal

DOI:  https://doi.org/10.1038/s41598-026-43238-9
JCI Insight. 2026 Jun 09. pii: e201810. [Epub ahead of print]

Semaglutide-induced loss of skeletal muscle mass is blunted by co-administration of ketone esters.

Yasser Abuetabh, Mya A Schmidt, Masaaki Naganuma, Ramana Vaka, Mahmoud A El-Ghiaty, Shelly Braun, Ethan A Kwan, Matthieu Cp Zolondek, Darius Sahid, Laibah Khan, Rajat K Shandal, Ashley L Trudeau, Yaning Li, Sufyan O Malik, Qiuyu Sun, Danica K Roth, Daniela Y Morales-Llamas, Jody L Levasseur, Mourad Ferdaoussi, Richard P Fahlman, Jason Rb Dyck.

  While glucagon-like peptide-1 receptor agonists (GLP-1RAs) like semaglutide are effective in treating obesity, up to 45% of the resulting weight loss can be attributed to skeletal muscle loss. Given the critical role of skeletal muscle in health and mobility, this may have long-term adverse consequences. Herein we investigated whether oral ketone ester supplementation could prevent semaglutide-induced muscle loss and explored the underlying molecular mechanisms. Obese, glucose-intolerant mice received vehicle, semaglutide, or semaglutide plus a β-hydroxybutyrate-generating ketone ester for three weeks. Body composition, muscle strength, and endurance were assessed longitudinally. Semaglutide monotherapy reduced lean mass, impaired muscle strength, and suppressed mitochondrial gene expression while elevating atrophy-related genes in skeletal muscle samples. Co-administration with ketone ester preserved skeletal muscle mass and function without compromising fat loss. Mechanistically, ketone ester co-treatment prevented semaglutide-induced changes in mitochondrial and atrophy-related gene expression, suggesting mitochondrial defects and impaired ketone metabolism contribute to GLP-1RA-induced muscle loss. Together, these findings demonstrate that ketone ester supplementation can maintain muscle mass and performance during semaglutide-driven weight loss. These preclinical findings support ketone therapy as a promising strategy to counteract the sarcopenia-promoting effects of GLP-1RAs and warrant clinical evaluation to assess its translational potential.

Keywords:  Metabolism; Muscle biology; Obesity

DOI:  https://doi.org/10.1172/jci.insight.201810
Commun Biol. 2026 Jun 10.

Oxaliplatin triggers adipose and muscle wasting through cancer-independent metabolic and CNS pathways in mouse models.

Junwei Du, Rachel L Mintz, Leland C Sudlow, Rachael L Field, Christine Stander, Jonathan R Brestoff, Gwendalyn J Randolph, Mikhail Y Berezin.

Oxaliplatin, a platinum-based chemotherapeutic, is a first-line treatment for colorectal and other cancers frequently associated with cachexia. The extent to which oxaliplatin induces cachexia independently of cancer and the mechanisms involved remain unclear. Here we show that treatment with a human-equivalent dosage of oxaliplatin leads to cachexia-like symptoms in mice commonly observed in cancer patients, including severe loss of body mass resulting from adipose tissue depletion and wasting of skeletal muscle. The mice experience alterations in whole-body metabolism, including decreased food intake, reduced ambulatory activity, lowered core body temperature, and altered respiratory exchange ratio. Histological analyses demonstrate marked muscle fiber atrophy and increased immune cell infiltration. Transcriptomics analyses performed on subcutaneous adipose tissue, skeletal muscle, and the hypothalamus identify metabolic rewiring as a dominant response associated with chemotherapy-induced cachexia. RNA-seq demonstrates signaling pathways associated with these processes across muscle, adipose, and hypothalamus. Specifically, adipokine genes are dysregulated in white adipose tissue and in the hypothalamus, while genes involved in inflammatory pathways are upregulated in muscle.

DOI: https://doi.org/10.1038/s42003-026-10441-3
Mol Metab. 2026 Jun 10. pii: S2212-8778(26)00075-X. [Epub ahead of print] 102391

Hepatokines lipocalin 2 and osteopontin drive muscle atrophy in MASH.

Amy R Fumo, Simon I Dreher, Pauline Morigny, Honglei Ji, Raul Terron Exposito, Tuna F Samanci, Tushar More, Lara Ruoff, Joël J Tissink, Carmen Paredes Yubero, Ana Jimena Alfaro, Christine von Törne, Stefanie Hauck, Sophie H A Nusser, Zoltan Czigany, Kenneth A Dyar, Stephan Herzig, Mauricio Berriel Diaz, Anja Zeigerer, Karsten Hiller, Theresa H Wirtz, Cora Weigert, Maria Rohm.

A bidirectional relationship exists between metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive inflammatory form, metabolic dysfunction-associated steatohepatitis (MASH), and sarcopenia, with each worsening the prevalence and prognosis of the other. Hepatokines have recently been shown to affect skeletal muscle metabolism and function, both in the context of MASLD and wasting diseases. We here explored the possibility of targeting hepatokines to counteract MASLD-induced sarcopenia. Integrating mouse and human liver transcriptomics with muscle proteomics from MCD- and GAN-diet induced murine MASH models with sarcopenia, we identified three MASH-induced hepatokines, namely LCN2, LGALS3 and OPN. These hepatokines were elevated in the circulation of mouse MASH models with sarcopenia and in sarcopenic patients with advanced chronic liver disease. C2C12 myotubes treated with liver-secreted proteins as well as recombinant LCN2 and LGALS3 exhibited atrophy. Stable isotope tracing and mitochondrial respiration showed that liver-secreted proteins altered mitochondrial metabolism in C2C12 myotubes, which was recapitulated in primary human myotubes. Human 3D skeletal muscle organoids treated with recombinant proteins exhibited functional impairment. Virus-mediated knockdown of LCN2 in liver of mice with MASH improved muscle function and myotube size, whereas virus-mediated overexpression of LCN2 in the liver aggravated MASH-induced myotube atrophy. Targeting hepatokines may therefore be a feasible future therapeutic strategy against sarcopenia.

DOI: https://doi.org/10.1016/j.molmet.2026.102391
Nat Biomed Eng. 2026 Jun 11.

Skeletal-muscle-targeted non-viral delivery of full-length DMD mRNA for Duchenne muscular dystrophy.

Yu Tian, Yutong Liu, Yuhao Tong, Kristin Huntoon, Liqun Yang, Junfeng Shi, Yifan Ma, Shiyan Dong, Seong Dong Jeong, Andreanne Poppy Estania, You Yi, Kwang Joo Kwak, Yifan Wang, Annette Wu, Jared L Edwards, Xiaotian Wang, Yen-Tzu Chang, Jianhong Cao, Huan Zhang, Man Sun, Adam J Grippin, Zhaogang Yang, Wen-Jing Lu, Ly James Lee, Eman Bahrani, Hongjia Zhang, Long Bai, Patricia K Nguyen, Wen Jiang, Feng Lan, Betty Y S Kim, Andrew S Lee.

Duchenne muscular dystrophy (DMD) is a severe, progressive muscle-wasting disorder caused by mutations in the DMD gene, which encodes dystrophin. Although gene therapy using viral vectors has shown promise for the treatment of DMD, the clinical application of viral gene therapies is limited by vector toxicity, immunogenicity and the inability to package full-length dystrophin. Recent advances in messenger RNA (mRNA) technology offer a non-integrating, transient approach to restoring protein expression. Here we report the systemic delivery of skeletal-muscle-targeted full-length DMD mRNA in a murine model of DMD using allogenically engineered targeting extracellular vesicles (DMD t-EVs). This approach restores the endogenous translation of wild-type dystrophin and substantially improves muscle function. We further demonstrate the safety and biocompatibility of DMD t-EVs in non-human primates, supporting their translational potential. These findings highlight the promise of mRNA-loaded extracellular vesicles as a therapeutic platform for treating genetic disorders involving large, difficult-to-package genes.

DOI: https://doi.org/10.1038/s41551-026-01689-5