bims-moremu 2026-08-09 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–08–09
thirty papers selected by
Anna Vainshtein, Craft Science Inc.

Proteome dynamics reveal Leiomodin 1 as a key regulator of myogenic differentiation.
Exercise-induced lysosomal adaptations in skeletal muscle.
Activation of the Lactate Receptor GPR81 Ameliorates Senescence Hallmarks and Improves Muscle Function in Cellular and Progeroid Models of Aging.
A single-nucleus chromatin accessibility atlas reveals epigenetic dynamics in aging mouse skeletal muscle.
The dual role of cell death in skeletal muscle homeostasis and disease: Mechanisms and therapeutic targeting.
A bitter melon natural compound ameliorates the myotonic dystrophy type 1 skeletal muscle phenotype in a sex-specific manner.
GPR97-Gα12-mTORC1 signaling drives myotube hypertrophy: identification of 5-hydroxy-7-methoxyflavone as a pathway activator.
Hypertrophic cardiomyopathy-linked Tnnc1 variants are associated with distinct myopathic changes in slow skeletal muscle of mice.
Skeletal muscle H3K18 lactylation inhibits hepatic gluconeogenesis through IL-6 mediated interorgan communication.
Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline.
Lactiplantibacillus plantarum WY2401 promotes myogenesis via riboflavin-mediated modulation of METTL3-dependent mRNA m6A methylation.
FAP-derived CCL2 is required for adequate monocyte/macrophage infiltration to support acute skeletal muscle injury repair.
Metabolomics-guided isolation of myogenic progenitor cells for improved transplantation.
Effects of exercise in a fed or fasted state on mitochondrial dynamics regulators in the skeletal muscle of recreationally active males.
Engineered Muscle Tissue Analysis of Irisin Protection Against Glucocorticoid- and Cancer Cachexia-Induced Muscle Wasting and Cardiotoxicity.
Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle.
Reduced Serum Klotho Levels in Disuse-Induced Skeletal Muscle Atrophy: An Experimental Study Related to Orthopedic Immobilization.
Thermal stimulation promotes myogenic differentiation through enhanced glucose uptake and transient lipid droplet accumulation in C2C12 cells.
The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.
BAMBI acts as a molecular switch to determine cell fate of C2C12 myoblasts.
HDAC6 inhibition alleviates dexamethasone-induced skeletal muscle atrophy and enhances UCP3-associated redox homeostasis.
Rethinking Muscle Wasting in Critical Illness: A Systematic Review and Meta-Analysis of Myofiber Size and Protein Turnover.
More muscle, less belly fat: mutations to a gene are linked to wide-ranging benefits.
Maternal Exercise Rescues Embryonic Osteogenesis Impaired due to POLG Mutation Through a Potential Apelin-ATF4 Axis.
IL-17-driven transcriptional programs in muscle fibroblasts are not required for pathogenesis in murine anti-histidyl-tRNA synthetase (Jo-1) myositis.
A pipeline for quantifying cell damage in whole-slide fluorescence images of skeletal muscle.
The Effects of Oral Contraceptives on Muscle Hypertrophy.
A peripheral perspective on brain health: vascular and skeletal muscle contributions.
Timing matters: Exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy.
Heterogeneous human muscle fibroadipogenic progenitors include a DLK1+ subpopulation that prevents fatty infiltration after injury.

Elife. 2026 Aug 04. pii: RP104331. [Epub ahead of print]14

Proteome dynamics reveal Leiomodin 1 as a key regulator of myogenic differentiation.

Ellen Späth, Svenja C Schüler, Ivonne Heinze, Therese Dau, Alberto Minetti, Maleen Hofmann, Katja Hönzke, Julia von Maltzahn, Alessandro Ori.

  During myogenic differentiation, the cellular architecture and proteome of muscle stem cells and myoblasts undergo extensive remodeling. These processes are partially understood and display alterations in disease and aging, resulting in impaired regeneration. Here, we used mass spectrometry to quantify the temporal dynamics of over 6000 proteins during myogenic differentiation. We identified the actin nucleator leiomodin 1 (LMOD1) among a restricted subset of cytoskeletal proteins increasing in abundance during early myogenic differentiation. LMOD1 is expressed by muscle stem cells in vivo and displays increased abundance during skeletal muscle regeneration in mice, particularly during early stages, suggesting its importance in myotube formation. Notably, LMOD1 knockdown in primary myoblasts and during regeneration severely affects differentiation, while its overexpression accelerates and improves myotube initiation. This suggests LMOD1 is a critical component regulating myogenic differentiation. Mechanistically, we show that LMOD1 physically and functionally interacts with the deacetylase sirtuin1 (SIRT1), a regulator of myogenic differentiation. We demonstrate that LMOD1 influences SIRT1 localization and the expression of its target genes. Consistently, depletion or pharmacological inhibition of SIRT1 partially rescues the differentiation impairment observed after LMOD1 knockdown. Our work identifies LMOD1 as a new regulator that might be targeted to improve muscle regeneration in aging and disease.

Keywords:  cytoskeleton; mouse; muscle stem cell; myogenesis; myogenic differentiation; proteomics; regeneration; regenerative medicine; stem cells

DOI:  https://doi.org/10.7554/eLife.104331
Sports Med Health Sci. 2026 Sep;8(5): 487-494

Exercise-induced lysosomal adaptations in skeletal muscle.

Anastasiya Kuznyetsova, David A Hood.

  The adoption of a regular exercise program has immense benefits for whole body health, and for improving the quality of skeletal muscle. This is important as muscle is involved in metabolism, locomotion, and force production, making it a large contributor to the quality of life. The coordinated behavior of several intracellular organelles is responsible for the maintenance of skeletal muscle health, and these organelles are adaptable in response to both acute and chronic exercise. While the adaptations of mitochondria to exercise are well-established, potential alterations in muscle lysosomes are less appreciated. Lysosomes degrade and recycle debris during the terminal step of various forms of autophagy, such as mitophagy, the pathway involved in the removal of dysfunctional mitochondria. This lysosomal activity is important for the maintenance of cellular protein and organelle homeostasis. Recent work has shown that lysosome biogenesis begins with every acute bout of exercise, driven by the nuclear translocation of regulatory transcription factors such as TFEB and TFE3, which mediate the transcription of autophagy and lysosomal genes. These transcription factors also play a role in other pathways such as chaperone-mediated autophagy (CMA) and the regeneration of existing lysosomes through the autophagic-lysosome reformation (ALR) pathway. When performed repeatedly, acute bouts of exercise elicit a longer-term adaptive response, leading to the formation of active lysosomes, which increase lysosomal degradative capacity in skeletal muscle. This review addresses the current knowledge surrounding the effects of acute and chronic exercise on lysosomal adaptations in skeletal muscle, highlighting a novel pathway of muscle plasticity.

Keywords:  Autophagic lysosome reformation; Chaperone-mediated autophagy (CMA); Exercise training; Macroautophagy; Mitophagy; Skeletal muscle; TFEB; Transcriptional regulation

DOI:  https://doi.org/10.1016/j.smhs.2026.06.001
Aging Cell. 2026 Aug;25(8): e70647

Activation of the Lactate Receptor GPR81 Ameliorates Senescence Hallmarks and Improves Muscle Function in Cellular and Progeroid Models of Aging.

Pihu Mehrotra, Sai Harsha Bhamidipati, Pedro Lei, John Toftegaard, Debanik Choudhury, Maryam Elsayed, Yali Zhang, Jianmin Wang, Shweta Chitkara, G Ekin Atilla-Gokcumen, Song Liu, Stelios T Andreadis.

  Skeletal muscle aging is associated with increased lipid accumulation, or myosteatosis, leading to lipotoxicity and loss of muscle function. Here, we report that loss of the lactate receptor GPR81 in cellular and progeroid models of muscle aging is associated with impaired lipid oxidation and enhanced lipid accumulation. Knockdown of GPR81 in young healthy myoblasts led to an increase in senescence hallmarks such as DNA damage, accumulation of reactive oxygen species (ROS), impaired mitochondrial activity, and autophagy. Conversely, treatment of senescent myoblasts with GPR81 agonists enhanced lipid oxidation, leading to a decrease in lipid accumulation, ultimately resulting in decreased DNA damage, ROS accumulation, and enhanced ability to form myotubes. In agreement with our in vitro findings, we observed significant improvement in muscle regeneration and overall health of progeric mice that were treated with GPR81 agonists. Our findings suggest that GPR81 plays a key role in skeletal muscle lipid metabolism, and agonists of GPR81 might play a promising role in reversing age-associated lipid accumulation and loss of muscle function.

Keywords:  aging; lipids; metabolism; mitochondria; sarcopenia; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70647
FEBS J. 2026 Aug 03.

A single-nucleus chromatin accessibility atlas reveals epigenetic dynamics in aging mouse skeletal muscle.

Juan An, Guangyao Lai, Jing Zuo, Jianwen Yuan, Lixin Fu, Bo Zhang, Xiao Zhang, Yuan Lv, Pengcheng Guo, Dajiang Qin, Miguel A Esteban, Yancheng Song, Yiwei Lai.

  Skeletal muscle undergoes a progressive decline in mass and function with aging, a condition that in its extreme form is known as sarcopenia. This is driven by complex cellular and molecular alterations, such as shifts in myonucleus composition, increased fibrosis, and fat or immune cell infiltration. Despite extensive research, effective therapeutic interventions for sarcopenia remain limited. Recent advances in single-cell omics technologies have begun to unravel the cellular and molecular heterogeneity of mouse and human skeletal muscle across the lifespan, identifying age-enriched cell states and dynamic transcriptional changes. However, epigenetic regulation during skeletal muscle aging is less well characterized. To help address this gap, we performed single-nucleus Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) on skeletal muscle from young adult and aged male mice, generating chromatin accessibility profiles from over 43,000 nuclei. Among other findings, our analyses reveal an age-enriched pro-atrophy subpopulation of type IIb myonuclei marked by increased chromatin accessibility at the Ampd3 locus. Furthermore, we delineate the epigenetic mechanisms underlying the transition of healthy type IIb myonuclei into Ampd3+ myonuclei, revealing key chromatin remodeling events that drive this phenotypic shift. Moreover, by integrating with an existing single-nucleus RNA sequencing dataset of the same anatomical origin, we identified thousands of cell-type-specific cis-regulatory elements related to aging programs. Within these elements, we observed a broad depletion of binding motifs for transcription factors with roles in cellular identity and muscle regeneration, concomitant with the gain of stress-responsive transcription factors. Our work helps understand the epigenetic events underlying mammalian skeletal muscle aging.

Keywords:  aging; chromatin accessibility; mouse skeletal muscle; snATAC‐seq

DOI:  https://doi.org/10.1111/febs.70659
Eur J Pharmacol. 2026 Aug 05. pii: S0014-2999(26)00690-4. [Epub ahead of print]1031 179208

The dual role of cell death in skeletal muscle homeostasis and disease: Mechanisms and therapeutic targeting.

Jiahuan Gong, Hongyi Xu, Yuntian Shen, Zihui Gao, Yanan Ji, Xinlei Yao, Jiacheng Sun, Bin Dai, Hualin Sun.

  Skeletal muscle, the largest organ system in the body, plays essential roles in movement, metabolism, and systemic homeostasis. Its dysfunction is implicated in a wide range of conditions, including sarcopenia, cancer cachexia, inflammatory myopathies, and neuromuscular disorders. Diverse forms of regulated cell death-including apoptosis, necroptosis, ferroptosis, pyroptosis, cuproptosis, and autophagy-dependent cell death-contribute to both skeletal muscle homeostasis and pathology through complex and interconnected signaling networks. This review summarizes the molecular mechanisms underlying major cell death pathways and discusses their context-dependent roles in skeletal muscle physiology, including development, adaptation, regeneration, and aging, as well as in disease progression. We further examine emerging therapeutic strategies targeting cell death signaling, including pharmacological agents, exercise and nutritional interventions, and gene- or cell-based approaches, with emphasis on their translational potential and current limitations. Finally, we discuss unresolved challenges in the field, including pathway crosstalk, spatiotemporal heterogeneity, and limited human validation, and highlight future directions for developing more precise therapeutic strategies for skeletal muscle diseases.

Keywords:  Apoptosis; Autophagy; Cell death crosstalk; Ferroptosis; Regulated cell death; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ejphar.2026.179208
Neurotherapeutics. 2026 Aug 03. pii: S1878-7479(26)00148-0. [Epub ahead of print]23(5): e00978

A bitter melon natural compound ameliorates the myotonic dystrophy type 1 skeletal muscle phenotype in a sex-specific manner.

Shatha A Atieh, Chimène Fahmi, Jia Liu, Chunping Tang, Yang Ye, Aymeric Ravel-Chapuis, Bernard J Jasmin.

  Myotonic Dystrophy Type 1 (DM1) is a multisystemic neuromuscular disease characterized by severe skeletal muscle dysfunction. The etiology of DM1 is primarily driven by RNA toxicity resulting from a gain-of-function mutation in DMPK mRNAs. Beyond this hallmark, DM1 is also characterized by the repression of the AMP-activated protein kinase (AMPK) pathway. Previous work has shown that targeting AMPK represents a novel therapeutic avenue for DM1. In this study, we investigated the therapeutic potential of novel AMPK activators derived from Momordica charantia (bitter melon). A screen of 26 bitter melon-derived compounds (BMCs) in C2C12 myotubes identified BMC-25 as a potent AMPK activator. Acute treatment of DM1 (HSALR) mice with BMC-25 induced an expected activation of AMPK in DM1 mice, while chronic treatment restored several DM1 histopathological features, including toxic ribonuclear foci. Interestingly, BMC-25 treatment induced distinct, sex-dependent molecular benefits. In female DM1 mice, BMC-25 treatment corrected the pattern of expression of RNA-binding proteins including CELF1, MBNL1, and Staufen1 in skeletal muscle and achieved a much greater correction of alternative splicing of multiple transcripts relative to their respective controls. In contrast, male DM1 mice exhibited very limited improvements in these parameters. Collectively, our findings indicate that sustained AMPK activation with BMC-25 confers multifaceted benefits to DM1 skeletal muscle by improving core DM1 pathogenic features in a sex-dependent manner. Finally, these results highlight the potential of natural compounds like BMCs as novel, promising and accessible therapeutics for the DM1 muscle pathology.

Keywords:  AMPK; Myotonic dystrophy; Natural compounds; Skeletal muscle; Therapeutics

DOI:  https://doi.org/10.1016/j.neurot.2026.e00978
Arch Biochem Biophys. 2026 Aug 03. pii: S0003-9861(26)00236-5. [Epub ahead of print]785 110964

GPR97-Gα12-mTORC1 signaling drives myotube hypertrophy: identification of 5-hydroxy-7-methoxyflavone as a pathway activator.

Shuhei Fujita, Ayano Kimura, Daisuke Maekawa, Mai Kubota, Tomoya Kitakaze, Naoki Goshima, Naoki Harada, Ryoichi Yamaji.

  Elucidating novel signaling pathways that drive myotube hypertrophy may provide new insights into the mechanisms regulating skeletal muscle growth. We previously reported that 5-hydroxy-7-methoxyflavone (HMF) induces hypertrophy of murine C2C12 myotubes; however, the underlying molecular mechanism remains unclear. Here, loss- and gain-of-function analyses revealed that GPR97 positively regulates myotube size. Furthermore, knockdown and rescue experiments demonstrated that GPR97 is required for HMF-induced myotube hypertrophy. HMF activated mTORC1 signaling in myotubes, and intramuscular administration of HMF also activated mTORC1 signaling in mouse skeletal muscle in vivo. Gpr97 knockdown abolished HMF-induced mTORC1 signaling and protein synthesis. Furthermore, depletion of Gna12 and expression of dominant-negative Gα12 abolished HMF-induced myotube hypertrophy. Gna12 depletion also suppressed HMF-induced mTORC1 signaling and protein synthesis. Beclomethasone dipropionate, a reported GPR97 ligand, suppressed HMF-induced hypertrophy and mTORC1 signaling, while further enhancing HMF-induced serum response factor (SRF)-dependent transcription. Although dominant-negative RhoA inhibited HMF-induced SRF-dependent transcriptional activity, it did not affect myotube hypertrophy. These findings indicate that GPR97-Gα12-mTORC1 signaling promotes hypertrophy independent of the Gα12-RhoA-SRF pathway. GPR97 was predominantly expressed on the myotube surface as a C-terminal fragment generated by N-terminal fragment (NTF) cleavage, and HMF reduced its surface expression. HMF induced hypertrophy in myotubes expressing an NTF cleavage-resistant GPR97 mutant, but not in those expressing an NTF-deleted mutant. These results indicate that NTF cleavage is dispensable and suggest that NTF contributes to GPR97-mediated hypertrophic signaling. These findings identify a novel GPR97-Gα12-mTORC1 signaling axis that mediates HMF-induced myotube hypertrophy.

Keywords:  5-Hydroxy-7-methoxyflavone; G protein-coupled receptor 97; Gα12; RhoA; mTORC1; myotube hypertrophy

DOI:  https://doi.org/10.1016/j.abb.2026.110964
J Muscle Res Cell Motil. 2026 Aug 03. pii: 18. [Epub ahead of print]47(3):

Hypertrophic cardiomyopathy-linked Tnnc1 variants are associated with distinct myopathic changes in slow skeletal muscle of mice.

Sonu Patel, Gabriel Leite da Silva Santos, Jaelynn Florence, Aida Rahimi Kahmini, Yun Shi, Michelle Rodriguez Garcia, Bradley S Gordon, P Bryant Chase, Christopher Solís, Orlando Laitano, J Renato Pinto, Michelle S Parvatiyar.

  Inherited hypertrophic cardiomyopathy (HCM) is considered a disease of the cardiac sarcomere and caused by pathogenic variants present in genes that encode sarcomeric proteins. The human TNNC1 gene is a designated HCM-susceptibility gene encoding the troponin C (TnC) protein, which is expressed in both cardiac and type I slow skeletal muscles and abbreviated as cTnC and ssTnC respectively. HCM patients have been reported to exhibit skeletal muscle weakness and reduced exercise tolerance. Patients bearing TNNC1 cardiac pathogenic variants also express it in type I fibers of their slow skeletal muscles. We hypothesized that the presence of TNNC1 HCM variants in type I fibers may decrease force generating capabilities and alter fatigue resistance of slow skeletal muscles. To address this, we examined the impact of HCM Tnnc1 variants in the soleus muscles of two HCM knock-in mouse models A8V+/-, A8V-/-, and C84Y+/- and their respective wild type (WT) controls. At high stimulation frequencies, we found that A8V-/- soleus muscles had lower tetanic force production than WT, however no differences in fatigue when comparing fatigue indices for either of the variants. The muscles were evaluated by comparing % specific force (N/cm2)-variant and both A8V-/- and C84+/- had increased responsiveness at low stimulation frequencies. Fiber type analysis uncovered an increase in abundance of type I fibers in A8V-/- soleus, however no other differences were observed in fiber-type percentage of either mouse model. Comparison of the cross-sectional areas (CSA) of type I fibers in soleus muscles revealed lower average values for A8V+/+ and A8V-/-, however an increase in C84Y+/- relative to controls. Examination of the CSA of type IIa fibers uncovered decreased values for both A8V+/- and A8V-/- with no changes in C84Y+/- soleus. Histological evaluation of A8V+/- and A8V-/- soleus muscles revealed central nucleation and the detection of embryonic myosin heavy chain by immunofluorescence suggested the presence of mild regeneration. In contrast, no histopathological changes were detected in the C84Y+/- soleus muscle. Serum myokines were also measured to assess systemic impacts of the pathogenic variants and alterations in the physical activity of the mice but no significant changes were found. Taken together our results suggest that the HCM A8V variant alters force production in soleus muscle that may be attributed to fiber atrophy and heightened pathophysiology.

Keywords:  Atrophy; Cardiomyopathy mutants; Force production; Myokines; Myopathy; Skeletal muscle

DOI:  https://doi.org/10.1007/s10974-026-09736-z
Sci Adv. 2026 Aug 07. 12(32): eaed5600

Skeletal muscle H3K18 lactylation inhibits hepatic gluconeogenesis through IL-6 mediated interorgan communication.

Yu Wang, Feijie Wang, Yujie Sun, Yao Gu, Lamei Xue, Mingcong Fan, Haifeng Qian, Yucheng Wang, Hao Ying, Jun Du, Liang Chen, Li Wang, Yan Li.

The mechanisms underlying the dynamic interplay between skeletal muscle and systemic glucose homeostasis in type 2 diabetes remain elusive. Increased lactate level has long been noticed in diabetes, however, whether the elevated lactate is a cause or consequence of impaired glucose metabolism is unclear. Here, we found that elevated circulating lactate levels originated from skeletal muscle with high expression of lactate dehydrogenase A (Ldha), and both metrics correlated strongly with hyperglycemia in both hyperglycemic mouse models and human subjects. Paradoxically, ablation of Ldha in skeletal muscle (LDHA mKO) disrupted whole-body glucose homeostasis, primarily via augmented hepatic gluconeogenesis. Mechanistically, lactate deficiency in muscle epigenetically activated NF-κB signaling through H3K18 lactylation (H3K18la)-mediated transcriptional control of IκBα, which then promoted the transcription of IL-6, thereby reshaping hepatic gluconeogenesis. Lastly, we showed that loss of Ldha in skeletal muscle enhanced hepatic gluconeogenesis and aggravated hyperglycemia in high-fat high-sucrose diet-fed mice. Collectively, our study provides evidence that in glucose intoxication contexts, skeletal muscle-derived lactate acts as the signal to provide negative feedback for hepatic gluconeogenesis, which induces skeletal muscle H3K18la acting as a negative regulator of IL-6 to sustain suppression of hepatic gluconeogenesis, while dysregulation of this network contributes to unrestrained gluconeogenesis in diabetes.

DOI: https://doi.org/10.1126/sciadv.aed5600
Front Immunol. 2026 ;17 1867909

Sarcopenia and sepsis fuel a self-perpetuating cycle of immunometabolism decline.

Elisa Gouvea Gutman, Renan Muniz-Santos, Adilson Moreira da Silva, Giovanna Lucieri Alonso Costa, Carolina Medina Coeli da Cunha, Bianca Portugal Tavares de Moraes, Cassiano Felippe Gonçalves de Albuquerque.

  Sepsis and sarcopenia are intertwined clinical challenges characterized by profound immunometabolic dysregulation. Traditionally viewed as a passive reservoir, skeletal muscle is now recognized as an active immunometabolic rheostat that dynamically influences systemic inflammation and homeostasis. This review synthesizes recent advances that redefine our understanding of muscle in critical illness, moving beyond simplistic views of catabolism to encompass complex adaptive strategies. This review summarizes recent advances and discusses septic autocannibalism, a process in which muscle proteolysis, driven by a metabolic defense priority, provides key substrates, glutamine for immune function and alanine for hepatic gluconeogenesis. Initially adaptive, sustained activation of this response leads to severe muscle wasting and long-term functional impairment. We analyze the bidirectional relationship between these conditions, focusing on shared risk factors such as immunosenescence and obesity. Key molecular pathways, including the IL-6/JAK/STAT and NF-κB axes, are examined, with particular emphasis on how the temporal release of myokines (e.g., IL-6, IL-15, IGF-1) dictates their shift from adaptive signals to chronic catabolic drivers. Furthermore, we discuss how energy reprogramming, characterized by aerobic glycolysis and mitochondrial failure, disrupts muscle homeostasis. We highlight physical activity as a potent modulator of immunometabolic health through the release of anti-inflammatory myokines and enhanced mitochondrial biogenesis. To propel the field forward, we propose experimental avenues: single-cell spatial transcriptomics to map cellular crosstalk, mitochondrial transplantation to restore energetic capacity, and the identification of "muscle resilience" biomarkers for early intervention. This review underscores the urgent need for integrated immunometabolic approaches to improve outcomes in critically ill patients.

Keywords:  immunometabolism; muscle-immune crosstalk; myokines; sarcopenia; sepsis; skeletal muscle

DOI:  https://doi.org/10.3389/fimmu.2026.1867909
J Adv Res. 2026 Aug 07. pii: S2090-1232(26)00624-7. [Epub ahead of print]

Lactiplantibacillus plantarum WY2401 promotes myogenesis via riboflavin-mediated modulation of METTL3-dependent mRNA m6A methylation.

Jiaqi Liu, Tongyudan Yang, Fangfang Lou, Wei Chen, Zimeng Xin, Shun Chen, Ruiti Ren, Xinxia Wang.

   INTRODUCTION: Lactiplantibacillus plantarum (L. plantarum) is a well-characterized probiotic with a long history of safe application, exhibiting prominent potential in improving skeletal muscle function. As the most prevalent and plentiful mRNA modification in eukaryotes, extensive research has highlighted the non-negligible role of N6-methyladenosine (m6A) in regulating various aspects of skeletal muscle biology. However, the underlying mechanisms through which L. plantarum-derived signals regulate host myogenic programs, as well as whether m6A modification is involved in this process, remain unclear.
OBJECTIVE: To explore the microbe-host regulatory axis through which L. plantarum promotes skeletal muscle regeneration and whether m6A modification is involved in this process.
METHODS: The cardiotoxin-induced muscle injury mouse model was constructed to investigate the impact of L. plantarum WY2401 on skeletal muscle regeneration. Untargeted metabolomics analysis was used to screen out L. plantarum WY2401-derived key metabolite. The changes in m6A modification were determined using dot blot and MeRIP-qPCR.
RESULTS: We identified L. plantarum WY2401 as a pro-myogenic probiotic that promotes skeletal muscle regeneration. Specifically, L. plantarum WY2401 strongly alters circulating metabolomic profiles, particularly elevating the production of microbiota-derived riboflavin. Upregulated riboflavin is transported to skeletal muscle through the bloodstream, where it modulates the expression of the m6A methyltransferase METTL3 in a stage-dependent manner during myogenesis. This modulation promotes myoblast proliferation by enhancing the stability of Cdk2 and Ccnd1 mRNAs through the METTL3-m6A-YTHDF1 pathway. It also facilitates myoblast differentiation by increasing Mef2a mRNA stability through the METTL3-m6A-YTHDF2 pathway.
CONCLUSION: Our findings reveal a novel microbe-host regulatory axis through which L. plantarum WY2401 promotes skeletal muscle regeneration via stage-specific epigenetic modulation of myogenesis. This work highlights the potential of L. plantarum as a functional probiotic supplement for improving skeletal muscle development and provides new insights into probiotic-mediated regulation of muscle regeneration.

Keywords:  Lactiplantibacillus plantarum WY2401; Myogenesis; Riboflavin; mRNA m(6)A

DOI:  https://doi.org/10.1016/j.jare.2026.08.015
iScience. 2026 Aug 21. 29(8): 116933

FAP-derived CCL2 is required for adequate monocyte/macrophage infiltration to support acute skeletal muscle injury repair.

Xingyu Wang, Yinhang Wang, Ruoxi Yuan, Gregory R Smith, Frederique Ruf-Zamojski, Sachiko T Homma, Stuart C Sealfon, Lan Zhou.

  Repair of acutely injured skeletal muscle relies on an adequate inflammatory response predominated by monocyte/macrophage infiltration. The process requires injured muscles to produce C-C chemokine ligand 2 (CCL2). The present study identified fibro/adipogenic progenitors (FAPs) as the primary source of CCL2 in acutely injured muscle, where the pro-inflammatory subcluster of FAPs expanded rapidly and expressed the highest level of CCL2. FAP-specific deletion of Ccl2 largely abolished CCL2 production by acutely injured muscle, reducing monocyte/macrophage infiltration and impairing muscle regeneration. In vitro, the CCL2 expression by both mouse and human FAPs was induced by danger signal-containing muscle homogenates through Toll-like receptor signaling. The CCL2 expression by mouse FAPs was also induced by infiltrating neutrophils, partly through their secretion of pro-inflammatory cytokines. Our findings suggest an important immune sentinel role for FAPs, as they sense muscle damage, produce CCL2 to recruit inflammatory monocytes, and promote injury repair.

Keywords:  CCL2; FAPs; acute muscle injury; monocytes and macrophages; muscle regeneration

DOI:  https://doi.org/10.1016/j.isci.2026.116933
Am J Physiol Cell Physiol. 2026 Aug 06.

Metabolomics-guided isolation of myogenic progenitor cells for improved transplantation.

Lauren K McKay, Christopher G Vann, James R Bain, Shihuan Kuang, Christopher B Newgard, James P White, David E Lee.

  Skeletal muscle maintains considerable capacity for regeneration following injury, but successful regeneration is limited in instances of volumetric muscle loss, advanced aging or muscular dystrophies. Considerable research has been done on muscle stem cell (MuSC) transplantation; however, proliferative exhaustion and donor cell dose requirements have slowed progress. Due to the paramount role of cellular metabolism in regenerative function of stem cells, the clinical potential for MuSC therapy may be improved by minimizing the isolation-induced metabolic perturbations experienced by MuSCs. This study uses a model of simulated cell sorting combined with untargeted, small molecule metabolomic profiling to outline sorting-induced metabolic perturbations in C2C12 myoblasts. We expand upon this by performing a time course of metabolomic profiling on myoblasts recovering from either fluorescence activated cell sorting (FACS) or magnetic-bead activated cell sorting (MACS)-based isolation procedures to determine the method and recovery timing for optimal redox and energetic status. Using this metabolism-informed method, we then performed primary MuSC transplantation studies in mice to demonstrate the generalizability from the in vitro system to in vivo MuSC transplantation during regeneration from BaCl2-induced injury. Our findings demonstrate metabolically favorable strategies to isolate MuSC for analysis of the quiescent-to-activated metabolic transition or enhance transplantation efficacy.

Keywords:  Muscle Stem Cells; metabolism; metabolomics; myoblast; regeneration

DOI:  https://doi.org/10.1152/ajpcell.00337.2026
Exp Physiol. 2026 Aug 06.

Effects of exercise in a fed or fasted state on mitochondrial dynamics regulators in the skeletal muscle of recreationally active males.

Elya J Ritenis, Christos G Stathis, Matthew B Cooke, Stephen Keenan, Andrew Philp, Donny M Camera.

  Exercise and nutritional modulation favourably alter mitochondrial quantity and quality in skeletal muscle. Mitochondrial dynamics, the coordination of fission and fusion events, are poised to mediate key aspects of organelle adaptation that arise from exercise. However, the molecular basis by which exercise affects mitochondrial dynamics remains poorly understood. The objective of this work was to further elucidate the signalling response of mitochondrial dynamics regulators to exercise and explore the synergistic potential to combine exercise and nutritional modulation. In a randomized crossover design, eight healthy, recreationally active men (age 25.8 ± 5.3 years, BMI 24.4 ± 1.2 kg/m2, V̇O2peak 39.2 ± 5.7 ml/kg/min) performed a 1-h bout of workload-matched aerobic exercise on a cycle ergometer at 50-70% of Wmax, either in a fasted or a fed (i.e., following a carbohydrate rich breakfast) state. Gas exchange was measured throughout, and blood samples were collected intermittently. Vastus lateralis muscle biopsies were collected pre-, post- and 3 h post-exercise. Western blotting was performed on cytosolic and mitochondrial fractions. Fasted exercise was accompanied by increased cytosolic acetyl-CoA carboxylase Ser79 phosphorylation (P ≤ 0.001), an effect not observed in the fed group (P > 0.05). The subcellular location of mitochondrial fission effector dynamin-related protein 1 (DRP1) was unchanged (P > 0.05) following exercise. However, group differences (i.e., Fed vs. Fasted) in DRP1 subcellular localization and phosphorylation at residues Ser616 and Ser637 were observed post-exercise. Substrate availability may potentially influence the mitochondrial dynamics signalling response in skeletal muscle to acute aerobic exercise.

Keywords:  exercise; mitochondrial dynamics; skeletal muscle

DOI:  https://doi.org/10.1113/EP093336
Biochip J. 2026 ;20(3): 562-578

Engineered Muscle Tissue Analysis of Irisin Protection Against Glucocorticoid- and Cancer Cachexia-Induced Muscle Wasting and Cardiotoxicity.

Young Hoon Son, Christina Y Sheng, Ji-Eun Jeong, Yuri Choi, Hyocheol Jung, Jihee Won, Audrey Atinsky, Junbeom Park, Jin Chul Kim, Keel Yong Lee, Young Il Park, Sung-Jin Park.

  Muscle atrophy, a condition characterized by an imbalance between protein synthesis and degradation, leads to skeletal muscle wasting, exacerbating disease progression and increasing mortality rates. Exercise has been shown to counteract muscle wasting, with myokines-exercise-induced secretome proteins, and among them, irisin is known to mediate systemic benefits such as improved metabolism, reduction of oxidative stress, and promotion of tissue repair in skeletal muscle, thereby mediating beneficial effects of exercise against atrophy. Despite its promising therapeutic potential, the precise functions and signaling pathways of irisin in muscle and other organs remain insufficiently explored owing to the complexity and heterogeneity of in vivo environments. In this study, we present engineered skeletal muscle tissue models as biomimetic platforms to study irisin-mediated therapeutic interventions. Using this platform, we validated the ability of irisin to mitigate dexamethasone (DEX)-induced muscle atrophy by restoring myogenic markers, enhancing AKT-mediated protein synthesis, suppressing ubiquitin-proteasome-driven degradation, and preserving contractile function under catabolic stress. (e.g., irisin pretreatment increased tetanic stress in DEX-treated tissues by ~ 43% vs. DEX alone, n = 7-9 per group, p < 0.05). Furthermore, irisin effectively counteracted cancer cachexia-induced muscle wasting by improving myogenic gene expression, reducing atrophy markers, and enhancing muscle contractility (baseline stress restored by ~ 77%, n = 6-9 per group, p < 0.05). Extending these findings to cardiac tissues, we demonstrated irisin's protective effects against DEX-induced cardiotoxicity using a human induced pluripotent stem cell-derived cardiomyocyte (hiPSC-CM) model (irisin significantly improved contractile amplitude and reduced cell death indices in DEX-treated hiPSC-CMs, p < 0.05). This study underscores the utility of engineered muscle platforms for investigating irisin's therapeutic mechanisms. The demonstrated protective effects of irisin highlight its potential as a translatable therapeutic agent for muscle wasting and cardiac dysfunction. These platforms provide valuable insights into the systemic benefits of exercise-induced myokines and pave the way for developing exercise-mimetic therapies targeting muscle and cardiac disorders.
Supplementary Information: The online version contains supplementary material available at 10.1007/s13206-026-00268-9.

Keywords:  Exercise; Irisin; Microphysiological system; Muscle atrophy; Myokine; Myotube

DOI:  https://doi.org/10.1007/s13206-026-00268-9
Geroscience. 2026 Aug 07.

Aging is associated with altered estrogen receptor expression and alters redox protein balance in human female skeletal muscle.

Andrea Tamariz-Ellemann, Line Boel Nørregaard, Mikkel Oxfeldt, Line Barner Dalgaard, Susana Novella, Mette Hansen, Ylva Hellsten, Lasse Gliemann.

  It has been hypothesized that age‑related declines in skeletal muscle and vascular function in females may be partly estrogen‑dependent. This study investigated skeletal muscle protein expression of estrogen receptor α (ERα), estrogen receptor β (ERβ), and G protein-coupled estrogen receptor 1 (GPER1), and their association with proteins involved in redox regulation and vascular function, in relation to age, menopausal status, and lifelong physical activity. Skeletal muscle biopsies were obtained from 107 healthy females aged 19-70 years, including 26 postmenopausal females who were lifelong exercise trained. Protein expression of ERα, ERβ, GPER1, and downstream redox‑ and vascular‑related proteins was quantified. Age‑ and menopause‑related differences, associations between protein targets, and effects of lifelong exercise were examined. ERα protein expression was lower in older females with a 48% lower expression in the ≥ 55 years age group compared with the < 30-year group. GPER1 protein expression was 22% lower across all older age groups compared with the < 30-year group. ERβ expression was reduced in mid‑life (45-59 years) but not in the oldest age group. Both ERα and ERβ were positively correlated with endothelial nitric oxide synthase (eNOS) expression, whereas GPER1 showed no association with eNOS. ERβ expression was associated with pro‑oxidative NOX2 expression. Aging in females is associated with a lower ERα and GPER1 protein expression in skeletal muscle. Furthermore, lower ER expression by aging is associated with a lower eNOS expression, indicating associations with proteins involved in nitric oxide-related redox regulation in skeletal muscle in aged females.

Keywords:  Estrogen receptors; Females vascular aging; Menopause; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1007/s11357-026-02432-3
Acta Orthop Belg. 2026 Aug 05. 92(2):

Reduced Serum Klotho Levels in Disuse-Induced Skeletal Muscle Atrophy: An Experimental Study Related to Orthopedic Immobilization.

S Key, Ö Esmez, A Agar, O S Tanyeri, G Arkali, S Çeribaşi, A Yüce.

Klotho is an anti-aging protein involved in phosphate homeostasis, oxidative stress regulation, and tissue regeneration. Although circulating Klotho levels decline with chronological aging, its response to acute disuse- induced skeletal muscle alterations remains unclear. In this experimental study, sixteen male Wistar rats (3 months old) were randomly assigned to a control group (n = 8) or an intermittent hindlimb unloading group (3 h/day for 15 consecutive days) (n = 8). Skeletal muscle morphology was evaluated in the extensor digitorum longus (EDL) and soleus muscles using hematoxylin-eosin staining, and muscle fiber cross-sectional area (CSA) was quantified with ImageJ software. Interstitial connective tissue changes were qualitatively assessed using Masson's trichrome staining, and serum Klotho concentrations were measured using enzyme-linked immunosorbent assay (ELISA). Intermittent unloading induced histological features consistent with early disuse-associated muscle remodeling in both EDL and soleus muscles, accompanied by a modest reduction in muscle fiber CSA compared with controls. Serum Klotho levels were significantly lower in the unloading group (7.44 ± 0.54 vs 8.21 ± 0.81, p = 0.045), and a moderate positive correlation was observed between circulating Klotho concentrations and mean muscle fiber CSA (r = 0.58, p = 0.02). Mild interstitial connective tissue expansion was qualitatively noted in the soleus muscle following unloading. These findings suggest that short-term intermittent hindlimb unloading in young adult rats is associated with reduced circulating Klotho levels and mild skeletal muscle remodeling. Serum Klotho may represent a candidate biomarker of early disuse-associated muscle alterations; however, further studies are required to confirm its clinical applicability. These results may have potential implications for orthopedic conditions characterized by immobilization, including fracture treatment, casting, and postoperative rehabilitation.

DOI: https://doi.org/10.52628/92.2.15471
In Vitro Cell Dev Biol Anim. 2026 Aug 05.

Thermal stimulation promotes myogenic differentiation through enhanced glucose uptake and transient lipid droplet accumulation in C2C12 cells.

Rumana Mahzabin, Satoko Hayashi, Md Rezwanul Habib, Yukako Tokutake, Shinichi Yonekura.

  Mild thermal stimulation enhances skeletal muscle differentiation; however, its underlying metabolic basis remains unclear. Here, we demonstrate that thermal stimulation promotes myogenic differentiation through enhanced glucose uptake and transient lipid droplet (LD) accumulation in C2C12 myoblasts. Thermal stimulation at 39 °C induced a transient increase in LD formation during early differentiation. Early transient LD accumulation, particularly on days 1 and 2, was positively correlated with the day 5 fusion index, suggesting that early LD formation is associated with subsequent myogenic differentiation. Suppression of LD formation by Plin2 knockdown impaired myotube formation, indicating that LD formation is functionally required for myogenic differentiation. Thermal stimulation enhanced glucose uptake, accompanied by increased Slc2a4 and Ppargc1a expression and increased GLUT4 fluorescence intensity. Moreover, higher glucose availability further supported LD formation and myogenic differentiation even under serum-free conditions. Notably, mitochondrial mass, ATP content, and oxidative capacity remained largely unchanged, suggesting that enhanced glucose uptake is associated with LD accumulation without a corresponding increase in mitochondrial oxidative capacity. These findings identify transient LD formation as a key metabolic event driving myogenic differentiation under thermal stimulation.

Keywords:  Thermal stimulation. Myogenic differentiation. Lipid droplets. Glucose uptake. GLUT4

DOI:  https://doi.org/10.1007/s11626-026-01232-5
Biochim Biophys Acta Rev Cancer. 2026 Aug 03. pii: S0304-419X(26)00148-4. [Epub ahead of print] 189676

The ER stress-autophagy axis in cancer-induced muscle wasting: Unveiling the IRE1α/XBP1 pathway as a therapeutic target.

Guanran Ding, Wang Yang, Yixin Zhao, Xiangliang Liu, Jiuwei Cui.

  Cancer cachexia is a multifactorial syndrome of progressive skeletal muscle wasting and functional decline that affects 50-80% of patients with advanced malignancies, frequently overlaps with sarcopenia, and contributes to 22-30% of cancer-related deaths. Effective therapies remain lacking, in part because the driving mechanisms are incompletely understood. Systemic inflammation-particularly interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α)-has long been considered central to muscle wasting, yet cytokine-targeted trials have shown limited efficacy, prompting investigation of additional pathways. Among these, endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) have emerged as candidates, and this review focuses specifically on the IRE1α/XBP1 branch. The rationale rests on three observations from recent preclinical studies: XBP1s activity is increased in cachectic muscle; XBP1s occupies regulatory regions of autophagy-lysosome and ubiquitin-proteasome genes, a direct transcriptional link to protein degradation that distinguishes it from the translation-attenuating PERK and folding-oriented ATF6 branches; and genetic or pharmacological suppression of IRE1α/XBP1 attenuates wasting in these models. We examine how tumor-derived signals activate IRE1α/XBP1 to upregulate both the autophagy-lysosome pathway (ALP) and ubiquitin-proteasome system (UPS); its crosstalk with inflammatory (JAK-STAT3, NF-κB) and metabolic (mitochondrial dysfunction, fatty acid metabolism) networks; the evidence across cancer models and clinical contexts; and the therapeutic potential of IRE1α inhibitors, XBP1-directed strategies, and nutritional approaches including arginine. We frame the ER stress-autophagy axis as a mechanistically plausible, potentially tractable therapeutic target that requires further cross-model and clinical validation.

Keywords:  Arginine; Autophagy; Cancer cachexia; Endoplasmic reticulum stress; IRE1α; Muscle wasting; Therapeutic target; Ubiquitin-proteasome system; XBP1

DOI:  https://doi.org/10.1016/j.bbcan.2026.189676
J Mol Endocrinol. 2026 Aug 06. pii: JME-25-0169. [Epub ahead of print]

BAMBI acts as a molecular switch to determine cell fate of C2C12 myoblasts.

Xiangping Yao, Liwei Xie.

  Myogenesis is a tightly regulated process by a cascade of well-coordinated events and pathways. Other than the known myogenic regulator factor (MRF) family including Myf5, MyoD, Myogenin and MRF4, our previous study identified BAMBI is involved in muscle regeneration and siRNA-mediated BAMBI knockdown impairs C2C12 myoblast differentiation. However, the potential role of BAMBI in determining cell linage and fate specification in C2C12 myoblast remains unexplored. In this study, we analyzed the RNA-seq data and discovered that BAMBI expression was dynamically regulated during proliferation and differentiation period of C2C12 myoblasts. By establishing cell line with the loss of function and gain of function of BAMBI in C2C12 myoblasts, we demonstrated that BAMBI deletion totally abrogated myogenic differentiation of C2C12 myoblast cells. In addition, loss of BAMBI converts C2C12 myoblasts to brown adipocytes through downregulation MyoD and upregulation of Prdm16. Conversely, BAMBI overexpression strikingly enhanced myogenic differentiation of C2C12 myoblasts by upregulating MyoD expression. Taken together, our results establish that BAMBI is a vital myogenic factor involved in myoblasts differentiation and as a key regulator governing the balance between myogenic and adipogenic lineage in C2C12 myoblast cells.

Keywords:  Adipogenesis; BAMBI; C2C12; Myogenesis

DOI:  https://doi.org/10.1530/JME-25-0169
Free Radic Biol Med. 2026 Aug 05. pii: S0891-5849(26)00974-3. [Epub ahead of print]

HDAC6 inhibition alleviates dexamethasone-induced skeletal muscle atrophy and enhances UCP3-associated redox homeostasis.

Kai Wang, Chang Li, Yiding Bian, Ziwen Zheng, Mingming Deng, Gang Hou.

   OBJECTIVE: Long-term use of glucocorticoids, such as dexamethasone, often leads to glucocorticoid-induced muscle atrophy (GIMA), a condition associated with mitochondrial oxidative stress and abnormal activation of protein degradation pathways. Histone deacetylase 6 (HDAC6) is involved in cellular stress regulation, but its role in GIMA remains unclear. We investigated the protective effects of HDAC6 inhibition/loss-of-function against dexamethasone-induced muscle atrophy and its potential molecular mechanisms.
METHODS: Using Hdac6 knockout (KO) mice and C2C12 myotube models, combined with the HDAC6-selective inhibitor ACY-1215, we evaluated the phenotype of dexamethasone-induced muscle atrophy. We performed transcriptomic sequencing, Western blotting, immunofluorescence assays, and measured oxidative stress markers including reactive oxygen species (ROS), malondialdehyde (MDA), and the reduced glutathione to oxidized glutathione disulfide ratio (GSH/GSSG). Mitochondria-specific parameters, including mitochondrial superoxide (MitoSOX), mitochondrial membrane potential (MT-1 and JC-1), mitochondrial biogenesis markers (PGC-1α and TFAM), and antioxidant enzymes (SOD2, GPx1, and GPx4), were assessed. To investigate the regulatory mechanism, we assessed Ucp3 mRNA abundance and UCP3 protein stability. We also performed UCP3 knockdown and overexpression experiments in C2C12 myotubes to determine the functional contribution of UCP3 to the protective effects of HDAC6 loss or inhibition.
RESULTS: Hdac6 knockout or HDAC6 inhibition significantly attenuated dexamethasone-induced muscle atrophy, as evidenced by increased grip strength, restored muscle mass, enlarged muscle fiber diameter, and downregulated MuRF1/Atrogin-1 expression in mice. RNA-seq analysis identified DEX-responsive changes in redox-related pathways in Hdac6-deficient skeletal muscle, with Ucp3 among the DEX-responsive genes. Mechanistically, HDAC6 knockdown increased Ucp3 mRNA abundance without detectably altering UCP3 protein stability. This was accompanied by reduced mitochondrial superoxide, restored mitochondrial membrane potential, and increased expression of mitochondrial biogenesis markers and antioxidant enzymes. Importantly, UCP3 overexpression in C2C12 myotubes, without HDAC6 manipulation, was sufficient to attenuate dexamethasone-induced myotube atrophy. Functional rescue experiments showed that UCP3 knockdown reversed the antioxidant and anti-atrophic effects of HDAC6 knockdown. ACY-1215 attenuated dexamethasone-induced muscle atrophy in both mice and C2C12 myotubes. In C2C12 myotubes, UCP3 knockdown abolished the antioxidant and anti-atrophic effects of ACY-1215, demonstrating UCP3 dependence in the in vitro model.
CONCLUSION: This study identifies UCP3-associated redox homeostasis as an important downstream mechanism linking HDAC6 inhibition to protection against dexamethasone-induced muscle atrophy. In C2C12 myotubes, UCP3 was required for the protective effects of HDAC6 knockdown and ACY-1215, whereas UCP3 overexpression was sufficient to attenuate dexamethasone-induced myotube atrophy. ACY-1215 also alleviated dexamethasone-induced muscle atrophy in mice, although the UCP3 dependence of this in vivo effect remains to be determined.

Keywords:  HDAC6; UCP3; dexamethasone; muscle atrophy; oxidative stress

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.07.047
Crit Care Med. 2026 Aug 07.

Rethinking Muscle Wasting in Critical Illness: A Systematic Review and Meta-Analysis of Myofiber Size and Protein Turnover.

Felipe González-Seguel, Cayla M Robinson, Camilo Caceres-Parra, Cecilia Villablanca, Catalina Olave, Felipe Muñoz-Muñoz, Owen Gustafson, Madeline Cavallaro, Zoe Calulo Rivera, Selina M Parry, Yuan Wen, Benjamin F Miller, Kirby P Mayer, Esther E Dupont-Versteegden.

   OBJECTIVES: To identify biological findings underlying skeletal muscle dysfunction in adults with critical illness and meta-analyze myofiber cross-sectional area and protein turnover variables.
DATA SOURCES: Six databases were electronically searched from inception to January 2025.
STUDY SELECTION: We included original studies reporting biological findings obtained from skeletal muscle biopsies of adults with critical illness.
DATA EXTRACTION: Bibliometrics, characteristics of the patients/controls, and biological findings were extracted in duplicate. Descriptive statistics of biological findings were performed. Random-effects meta-analyses investigated mean differences (MDs) in myofiber cross-sectional area and protein turnover compared with controls.
DATA SYNTHESIS: From 22,035 titles screened, 75 studies (n = 2,023 patients; n = 642 controls) published between 1988 and 2024 were included, with 48 unique patient datasets. Biopsies were mainly collected from vastus lateralis (64 [85%] studies) during the first ICU week (50% of studies) and post-ICU (9%). Biological findings included predominant type II myofiber atrophy with necrosis and structural degeneration, mitochondrial dysfunction, inflammatory/fibrotic changes, and upregulated ubiquitin-proteasome/autophagy pathways. Data from six studies (n = 100 patients; 193 controls) indicated that cross-sectional area was 22% lower in patients with critical illness before (MD, -689 µm2; 95% CI, -1265 to -113 µm2; p = 0.02) and after (MD, -775 µm2; 95% CI, -1512 to -37 µm2; p = 0.04) ICU discharge. Across seven studies (n = 126 patients; 61 controls) protein synthesis was not significantly different in patients with critical illness compared with controls (MD, 0.007%/hr; 95% CI, -0.010 to 0.027; p = 0.36). Protein degradation pathway markers were significantly higher (standardized MD ranging, 0.5-1.7) in data from 11 studies (n = 439 patients; 163 controls).
CONCLUSIONS: Muscle wasting during critical illness reflects multifaceted biological disturbances. While myofiber size is significantly lower in patients with critical illness, pooled analyses show no significant differences in muscle protein synthesis compared with non-ICU controls, whereas protein degradation markers are consistently higher.

Keywords:  critical illness; intensive care unit-acquired weakness; muscle atrophy; muscle biopsy; muscle weakness; proteostasis

DOI:  https://doi.org/10.1097/CCM.0000000000007288
Nature. 2026 Aug 05.

More muscle, less belly fat: mutations to a gene are linked to wide-ranging benefits.

Lynne Peeples.



Keywords:  Cardiovascular biology; Genetics; Metabolism; Obesity

DOI:  https://doi.org/10.1038/d41586-026-02438-z
Adv Sci (Weinh). 2026 Aug 07. e77029

Maternal Exercise Rescues Embryonic Osteogenesis Impaired due to POLG Mutation Through a Potential Apelin-ATF4 Axis.

Song Ah Chae, Ryan C Riddle, Zhihua Jiang, Chaeyoung Shin, Min Du, Jun Seok Son.

  For proper locomotion, bone and muscle development must be tightly coordinated. Skeletal muscle secretes myokines that affect tissues, including bone. We previously showed that maternal exercise (ME) enhances fetal muscle development through apelin signaling. However, whether mitochondrial dysfunction impairs fetal skeletal development and whether ME mitigates these defects remain unclear. Heterozygous POLG mutant (Polgmut/+) mice were used to examine the effects of ME and apelin signaling on fetal osteogenesis. Pregnant Polgmut/+ females underwent treadmill exercise, and apelin receptor knockdown (ApjKD) mice and maternal apelin supplementation were used to evaluate apelin signaling. POLG mutation impaired fetal osteogenesis and disrupted skeletal morphology. RNA-seq revealed downregulation of pathways related to cytoskeletal organization and mitochondrial function. ME was associated with upregulation of osteogenesis and development. ME increased apelin abundance in maternal-fetal circulation and tissues, including fetal muscle and bone. Importantly, apelin administration increased fetal osteogenesis in POLG mutation, whereas ApjKD reduced osteogenic signaling in fetal bone and myogenic gene expression in fetal muscle. Apelin also enhanced mitochondrial respiration in fetal bone-derived osteogenic cells. Mechanistically, ME-induced apelin signaling was associated with increased mitochondrial biogenesis and enhanced ATF4-RUNX2 regulatory signaling. Collectively, these findings suggest that ME-induced apelin signaling contributes to fetal skeletal development under mitochondrial dysfunction.

Keywords:  bone; exercise; fetus; pregnancy; skeletal muscle

DOI:  https://doi.org/10.1002/advs.77029
J Immunol. 2026 Aug 04. pii: vkag225. [Epub ahead of print]215(8):

IL-17-driven transcriptional programs in muscle fibroblasts are not required for pathogenesis in murine anti-histidyl-tRNA synthetase (Jo-1) myositis.

Decheng Li, Daniel P Reay, Yang Li, Shachi P Vyas, Kenta Yamamoto, Dana P Ascherman, Sarah L Gaffen.

  Idiopathic inflammatory myopathy (IIM) is a systemic autoimmune disease targeting muscle and extramuscular organs, but the molecular mechanisms driving IIM pathogenesis remain largely undefined. Muscle fibroblasts are central to orchestrating inflammation in myositis. Here, we investigated muscle fibroblast dynamics using a single-cell RNA sequencing approach in an established murine model of anti-histidyl-tRNA synthetase (HRS, also known as Jo-1)-induced myositis. In fibroblasts, there was a robust activation of an IL-17 gene signature during disease. Among the induced genes was Nfkbiz, which encodes IκBζ, a noncanonical NF-κB transcriptional coactivator known to be key for pathologic IL-17 signaling in a variety of autoimmune settings. In muscle fibroblasts, IκBζ was potently activated by IL-17 in vitro and was essential for IL-17 signaling responsiveness. Surprisingly, however, the IL-17-IκBζ signaling axis was dispensable for the histopathological phenotype in HRS-induced myositis. Thus, despite a prominent IL-17 transcriptional signature, IL-17 and IκBζ are not required for autoantibody production or tissue inflammation in this model system.

Keywords:  IL-17; IκBζ; Th17; cytokine signaling; idiopathic inflammatory myopathy

DOI:  https://doi.org/10.1093/jimmun/vkag225
Methods. 2026 Aug 06. pii: S1046-2023(26)00170-2. [Epub ahead of print]

A pipeline for quantifying cell damage in whole-slide fluorescence images of skeletal muscle.

Marisa Sargent, Alastair W Wark, Arjan Buis.

  Quantitative fluorescence imaging of formalin-fixed paraffin-embedded (FFPE) tissue is often limited by intensity heterogeneity, endogenous autofluorescence, and fixation-induced artifacts. Together, these factors reduce analytic accuracy and reproducibility. In murine skeletal muscle, dyes such as Procion Yellow (ProY) are used to identify membrane-compromised cells following injury; however, overlapping autofluorescence and uneven staining hinder reliable quantification. Existing segmentation workflows, including ImageJ-based approaches, are sensitive to these variations, and standard preprocessing methods often fail to adequately normalise fluorescence intensity across whole-slide images. Here, we present a workflow for quantitative analysis of ProY-stained FFPE skeletal muscle. The pipeline combines spectral characterisation of the dye and autofluorescence, optimised whole-slide fluorescence image acquisition, ratiometric intensity normalisation, automated segmentation using Cellpose, adaptive thresholding, and particle analysis. This approach improves segmentation robustness and consistency in highly autofluorescent FFPE tissue sections while reducing user-dependent variability. As proof-of-principle, validation in mechanically injured murine skeletal muscle demonstrated that the workflow could distinguish between different levels of tissue injury. This workflow provides a quantitative approach for fluorescence-based imaging in preclinical studies, with potential for future integration into more standardised clinical histopathology workflows. Although optimised for ProY-labelled skeletal muscle, the pipeline could be adapted to other dyes and tissue types affected by autofluorescence.

Keywords:  FFPE tissue; Fluorescence imaging; Histopathology; Image normalisation; Quantitative image analysis; Skeletal muscle

DOI:  https://doi.org/10.1016/j.ymeth.2026.08.001
Int J Sports Med. 2026 Aug 06.

The Effects of Oral Contraceptives on Muscle Hypertrophy.

Madeline S Phillips, Madhusmita Misra, Sara N Raiser.

Muscle mass is essential for both general health and athletic performance because it supports strength, functional capacity, and physical performance. Hormonal contraceptives are used by a variety of individuals, including athletes and those who exercise. Most contraceptives contain ethinyl estradiol and a progestin, hormones that may impact muscle adaptations and hypertrophy. A limited number of studies, predominantly focused on oral contraceptives, have examined the relationship between hormonal contraceptives and muscle hypertrophy, with mixed findings. This narrative review synthesizes the current literature on how oral contraceptives may affect hypertrophic responses, considering both mechanistic and applied perspectives. The evidence generally suggests that oral contraceptive use does not consistently alter muscle hypertrophy following resistance training, though a small number of studies reported significant negative effects. These findings may be attributable, in part, to the use of more androgenic progestins. However, variability in contraceptive formulation, training protocols, and cohort sizes limits direct comparisons across studies. While mechanistic studies suggest that endogenous and synthetic sex hormones influence pathways involved in skeletal muscle remodeling, clinical studies of oral contraceptive use have not consistently demonstrated clinically meaningful differences in muscle hypertrophy. We recommend well-powered studies comparing progestins with differing androgenic activity, as well as mechanistic studies on muscular growth pathways, to better understand the influence of oral contraceptives on muscle adaptation.

DOI: https://doi.org/10.1055/a-2933-1360
Am J Physiol Heart Circ Physiol. 2026 Aug 07.

A peripheral perspective on brain health: vascular and skeletal muscle contributions.

Joshua L Keller, Kase J Pennartz, Justin D Sprick, Ethan J Hein, Brian A Irving, Christopher G Vann, Evan-Angelo R Butlig, Sima Al-Masri, Amy R Nelson.

  Age- and disease-related declines in brain health contribute to impairments in physical function, yet effective approaches to lessen these declines remain limited. Overall health is governed by a network of interdependent organ systems, such that dysfunction in one system can propagate across others. Although the brain has been viewed as a top-down regulator of vital functions, evidence indicates that cognition is affected by signals from peripheral organs. This interorgan communication likely explains the coexistence of Alzheimer's disease and related dementias with cardiovascular and metabolic disorders characterized by overlapping pathophysiology. Skeletal muscle and the peripheral vasculature are key contributors to this and represent modifiable systems that can alter brain structure and function. Skeletal muscle regulates myokine release through motor neuron function, contractile activity, and metabolic perturbations, thereby influencing neuroplasticity, mitochondrial function, and inflammatory signaling, and may affect measures of peripheral vascular function, like reactive hyperemia. Other properties of the vasculature, including arterial stiffness, directly affect cerebral perfusion and blood-brain barrier permeability. These systems form a muscle-vascular-brain axis that contributes to brain health and impacts the risk of cognitive impairment. Therefore, our aim was to synthesize the current understanding of interactions among skeletal muscle, the peripheral vasculature, and the brain, and their collective role in maintaining cognitive health. We also highlight recent clinical trials and emerging strategies affecting interorgan crosstalk. These conclusions support a model in which lifestyle interventions targeting peripheral systems, such as resistance training, may preserve brain health across all populations, offering scalable approaches applicable across the lifespan.

Keywords:  Alzheimer's Disease and Related Dementias; Cognitive decline; Interorgan communication; Myokines; Neurovascular coupling; Physical activity

DOI:  https://doi.org/10.1152/ajpheart.00462.2026
Mol Ther Nucleic Acids. 2026 Sep 08. 37(3): 103017

Timing matters: Exon skipping therapy is most effective when initiated early in a mouse model of Duchenne muscular dystrophy.

Sofia Stenler, Junyu Huang, Tirsa L E van Westering, Anna M L Coenen-Stass, Yahya Jad, Kaarel Krjutškov, Samir El Andaloussi, Matthew J A Wood, Thomas C Roberts.

  Exon skipping is a leading therapeutic approach for Duchenne muscular dystrophy (DMD), whereby modulation of pre-mRNA splicing is used to restore the dystrophin translation reading frame. Four exon skipping drugs have received FDA accelerated approval, despite limited clinical efficacy. To investigate how treatment timing influences exon skipping outcomes, dystrophin-deficient mdx mice were injected with peptide-conjugated phosphorodiamidate morpholino oligonucleotide (PPMO) exon skipping conjugates beginning at adult (12-week-old) or aged (75-week-old) stages, followed by biochemical and transcriptomic analyses in tibialis anterior muscles. Mean Dmd exon 23 skipping was 79% in adults and 44% in aged PPMO-treated mdx mice, whereas dystrophin protein restoration was 35% and 8%, respectively. Histopathological improvements were evident only in the adult treated mice. PPMO-treatment in adult mdx mice induced a broad transcriptomic shift toward a wild-type signature, whereas treatment in aged mice resulted in negligible gene expression changes, indicating that late intervention fails to reverse disease-associated pathologies despite low-level dystrophin restoration. Increased expression of the dystrophin-repressing microRNA miR-31-5p, which was more strongly upregulated in aged mdx muscle, provides a potential mechanistic explanation. In conclusion, PPMO-mediated exon skipping is substantially more effective when initiated in adult vs. aged dystrophic muscle, supporting early therapeutic intervention in DMD-affected individuals.

Keywords:  DMD; MT: Oligonucleotides: Therapies and Applications; PPMO; dystrophin; exon skipping; treatment timing

DOI:  https://doi.org/10.1016/j.omtn.2026.103017
Sci Transl Med. 2026 Aug 05. 18(861): eaeb7213

Heterogeneous human muscle fibroadipogenic progenitors include a DLK1+ subpopulation that prevents fatty infiltration after injury.

Steven M Garcia, Justin Lau, Agustin Diaz, Miguel Lizarraga, Hannah Chi, Aboubacar Wague, Sankalp Sharma, Gardner Rees, Cristhian Montenegro, Michael R Davies, Xuhui Liu, Brian T Feeley.

Fatty infiltration and fibrosis drive poor outcomes after chronic muscle injury. Here, we characterized fibroadipogenic progenitor cell (FAP) subpopulations from healthy and injured human rotator cuff muscle by single-cell RNA sequencing, full-spectrum flow cytometry, and functional assays and found distinct subpopulations, including a preadipogenic population that expresses delta-like noncanonical notch ligand 1 (DLK1+) and a prefibrogenic population that expresses decay-accelerating factor (CD55+). We used in vitro and flow cytometry experiments to show that human FAP lineages displayed unique surface marker expression across adipogenic and fibrogenic differentiation. In chronic human rotator cuff injury, expression of DLK1 RNA and DLK1 protein was decreased compared with that in healthy muscle. Overexpression of DLK1 in primary human FAPs suppressed differentiation into adipocytes in vitro, whereas DLK1 knockdown increased adipogenesis. In an immunodeficient murine model of glycerol-induced acute muscle injury, xenotransplantation of DLK1-overexpressing human FAPs into the injured murine muscle resulted in reduced fatty infiltration after 14 days by histological assessment, supporting a functional role for DLK1 in restraining adipogenesis. Together, we defined molecularly distinct, clinically relevant human FAP subpopulations, established DLK1 as a regulator of adipogenic potential in vivo, and provided a framework to identify pathogenic FAP states that may be used in the pursuit to prevent maladaptive muscle remodeling.

DOI: https://doi.org/10.1126/scitranslmed.aeb7213