bims-moremu 2026-07-12 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–07–12
34 papers selected by
Anna Vainshtein, Craft Science Inc.

Pik3ip1 mediates thyroid hormone-dependent regulation of the PI3K/Akt/mTOR axis in muscle atrophy.
The Role of Exercise in Regulating Histone Modifications and Non-coding RNAs in Muscle Aging and Sarcopenia.
The role of Piezo1 in skeletal muscle physiology and pathology: from mechanosensing to precision therapy.
C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.
Systemic regeneration medicines for muscular dystrophy: progress and challenges in pro-regenerative drug development.
USP18 regulates skeletal muscle regeneration independently of its deISGylation activity.
Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice.
UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice.
Comprehensive analysis of miRNA expression, secretion profile, and functional network during myogenesis in response to spaceflight.
Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.
Transient MYC Mimicking the Exercise Response Orchestrates Multifaceted Skeletal Muscle Adaptations.
Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.
RNAi-based motility screen of predicted sarcopenia-associated genes during aging in C. elegans.
Skeletal muscle biomass as an underappreciated fate of glucose.
2H2O labeling methods for bulk and single muscle protein synthesis measures, and measures of integrated muscle protein synthesis and breakdown rates: A pilot study.
"Should I stay or should I go?" How do our muscles respond to spaceflight stressors long after we return to Earth?
Going beyond total skeletal muscle area at L3 (tSMA) to accurately assess pancreatic cancer cachexia.
Adipocyte-Derived Exosomal Circ_0000002 Affects the Myoblast Growth and Muscle Regeneration.
Exercise remodels the skeletal muscle immune microenvironment to ameliorate type 2 diabetes mellitus-induced muscle atrophy: From immunometabolism to organ crosstalk.
Mechanosensing at the endoplasmic reticulum by IRE1.
Exercise Resistance in Obese Male NZO Mice Manifests as Local Muscle Remodelling Without Glycaemic Improvements.
Brain-muscle axis regulation of neuroinflammation and sarcopenia in Parkinson's disease: the bridging role of lactylation.
Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.
Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.
Dual Th1 and tissue-repair Treg cells accumulate in skeletal muscle preserving tissue integrity during infection.
Sarcolipin-SERCA uncoupling as a plausible heat source for sustaining fever.
The role of central regulators in lipid hydroperoxide-mediated muscle atrophy. Exploring mechanisms beyond ferroptosis.
Isolation of human satellite cells using CD29/CDH15 and a nanoparticle-based live Pax7 mRNA detection system, and their expansion with extracellular matrix and its derivatives.
Bridging the gap: Multi-omic Insights into Exercise Responses in Post-Menopausal Women.
Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair.
Biomarkers of Sarcopenia: Current Status and Future Perspectives.
BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.
Mapping sarcopenia's causal proteome reveals a leptin-driven inflammatory-mitochondrial axis for early prediction.
Bridging assessment, biomarkers, and interventions: progress in muscle health research.

Mol Metab. 2026 Jul 06. pii: S2212-8778(26)00097-9. [Epub ahead of print] 102413

Pik3ip1 mediates thyroid hormone-dependent regulation of the PI3K/Akt/mTOR axis in muscle atrophy.

Annarita Nappi, Serena Sagliocchi, Federica Restolfer, Caterina Miro, Lucia Acampora, Giovanna Giuseppina Altobelli, Monica Dentice, Annunziata Gaetana Cicatiello.

  Skeletal muscle atrophy is driven by an imbalance between anabolic and catabolic signaling pathways, often involving suppression of the PI3K/Akt/mTOR axis. Thyroid Hormones (THs) are key endocrine regulators of skeletal muscle metabolism and adaptation, exerting context-dependent effects that promote either muscle atrophy or hypertrophy. Here, we identify Phosphoinositide-3-kinase interacting protein 1, Pik3ip1, as a critical regulator of TH-dependent muscle homeostasis. Transcriptomic profiling of skeletal muscle from muscle-specific D2 knockout (mD2KO) and TH Receptor knockout (TRKO) mice revealed a catabolic transcriptional program associated with increased Pik3ip1 expression. Consistently, Pik3ip1 expression negatively correlated with TH signaling in vivo and in vitro. Functional studies in C2C12 myotubes showed that Pik3ip1 overexpression suppresses Akt/mTOR signaling, indicating that its induction is sufficient to impair anabolic pathway activation. In vivo, Pik3ip1 expression was rapidly induced during denervation-induced muscle atrophy and remained persistently elevated in mD2KO and TRKO muscles, characterized by altered TH signaling. Sustained Pik3ip1 expression was associated with impaired activation of the Akt/mTOR pathway and enhanced muscle wasting. Conversely, TH treatment reduced Pik3ip1 levels, restored Akt/mTOR signaling, and promoted anabolic responses. Forced Pik3ip1 expression attenuated TH-induced Akt/mTOR phosphorylation, confirming its role as a mediator of TH-dependent anabolic regulation. Collectively, these findings identify Pik3ip1 as a key negative regulator of PI3K/Akt/mTOR signaling in skeletal muscle and establish the TH-Pik3ip1 axis as an important mechanism controlling muscle mass maintenance during atrophic conditions.

Keywords:  Anabolic signaling; Denervation; Metabolic regulation; Muscle atrophy; PI3K/Akt/mTOR pathway; Skeletal muscle; Thyroid hormone

DOI:  https://doi.org/10.1016/j.molmet.2026.102413
Biochem Genet. 2026 Jul 06.

The Role of Exercise in Regulating Histone Modifications and Non-coding RNAs in Muscle Aging and Sarcopenia.

Junli Wang, Junhua Li.

  Sarcopenia, the progressive loss of skeletal muscle mass and function with age, is a major contributor to frailty and decreased quality of life in older adults. While physical exercise remains the most effective intervention, its molecular mechanisms of action are not fully understood. Emerging evidence highlights the central role of epigenetic regulation-including histone modifications and non-coding RNAs (ncRNAs)-in mediating both the pathogenesis of sarcopenia and the adaptive responses to exercise. This review synthesizes current findings on how aging disrupts the epigenetic landscape of skeletal muscle, fostering anabolic resistance, inflammation, and impaired regeneration. We explore how exercise reverses these effects by modulating histone acetylation, methylation, and the novel mark of lactylation, thereby reactivating key genes involved in muscle maintenance and repair. Additionally, we detail how specific microRNAs and long non-coding RNAs contribute to muscle plasticity, and how their dysregulation underlies age-related functional decline. Importantly, we emphasize the interplay between histone modifiers and ncRNAs, and the translational evidence from human trials supporting exercise as an epigenetic reprogramming agent. Although human evidence is limited compared to animal models, emerging clinical studies in older adults demonstrate that resistance and endurance training modulate histone acetylation/methylation and miRNA profiles, with dose-dependent benefits on muscle function and epigenetic markers (e.g., reduced epigenetic age acceleration via methylation clocks in active elderly). These insights offer promising avenues for therapeutic strategies aimed at extending healthspan and combating sarcopenia in aging populations.

Keywords:  Epigenetics; Exercise; Histone Modifications; Non-Coding RNAs; Sarcopenia

DOI:  https://doi.org/10.1007/s10528-026-11418-x
Biochem Pharmacol. 2026 Jul 05. pii: S0006-2952(26)00558-7. [Epub ahead of print]252 118219

The role of Piezo1 in skeletal muscle physiology and pathology: from mechanosensing to precision therapy.

Fei Xue, Yanan Ji, Jie Wang, Xia Li, Bin Dai, Hualin Sun.

  Skeletal muscle development, homeostasis, and repair rely on mechanical signals. Piezo1, a mechanosensitive cation channel, translates membrane lipid cues into intracellular responses. This review summarizes Piezo1's roles in skeletal muscle physiology and pathology. Physiologically, Piezo1 mediates calcium influx to regulate myogenesis, satellite cell quiescence/activation, myofibrillar protein synthesis/metabolism, and microvascular homeostasis. Pathologically, Piezo1 exhibits a dual nature: its downregulation drives disuse atrophy via the Piezo1/KLF15/IL-6 axis, while aberrant activation in Duchenne muscular dystrophy exacerbates myofiber damage and impairs regeneration. Piezo1 also amplifies post-injury inflammation and modulates intramuscular fat infiltration. We further discuss regulatory networks involving YAP/TAZ, TRP channels, the cytoskeleton, and membrane lipids, highlighting future challenges such as cell-type specificity, signal diversity, subcellular localization, and functional balance. Targeting Piezo1 holds therapeutic promise: agonists (e.g., Yoda1) counter atrophy and promote regeneration; inhibitors (e.g., GsMTx4) alleviate dystrophic damage; and low-intensity pulsed ultrasound enables non‑invasive spatiotemporal control. Thus, based on current evidence, Piezo1 is an important mechanotransducer in muscle biology and a novel target for precision therapies against atrophy, dystrophy, and sports injuries.

Keywords:  Mechanotransduction; Muscle atrophy; Muscle regeneration; Piezo1; Skeletal muscle; Therapeutic strategy

DOI:  https://doi.org/10.1016/j.bcp.2026.118219
Mol Ther. 2026 Jul 09. pii: S1525-0016(26)00567-8. [Epub ahead of print]

C9orf72-associated poly-GR in skeletal muscle leads to neuromuscular junction deficits and muscle atrophy.

Xinyi Tan, Shuangshuang Sun, Yuqing Yan, Wei Li, Ning Ding, Lin Xu, Liying He, Yuhao Zhang, Wenbing Chen, Yongjun Zheng, Lei Li.

Hexanucleotide repeat expansions in C9orf72 produce dipeptide repeat (DPR) proteins that are widely expressed, including the nervous system and skeletal muscle. Among these DPRs, arginine-containing proteins, poly-GR and poly-PR are toxic in the nervous system, but whether DPRs in skeletal muscle contribute to ALS pathogenesis is unclear. Here, we show that muscle-restricted expression of poly-GR drives motor deficits in mice, including muscle atrophy and neuromuscular junction (NMJ) deficits. Poly-GR in muscle interacted with the NMJ key organizer MuSK and promoted MuSK degradation, disrupting postsynaptic structure and impairing neuromuscular transmission. Importantly, a MuSK agonist antibody (X-17) stabilized NMJs and rescued neuromuscular transmission. Moreover, poly-GR in muscle activated the integrated stress response (ISR), elevating eIF2α phosphorylation and broadly suppressing protein translation. ISR inhibition with ISRIB restored translation and MuSK protein levels, and ameliorated both muscle atrophy and NMJ deficits. These findings demonstrate that skeletal muscle actively contributes to C9orf72-ALS pathology. Targeting muscle with ISRIB offers a therapeutic strategy to preserve motor function in C9orf72-ALS.

DOI: https://doi.org/10.1016/j.ymthe.2026.07.002
Cell Regen. 2026 Jul 06. pii: 21. [Epub ahead of print]15(1):

Systemic regeneration medicines for muscular dystrophy: progress and challenges in pro-regenerative drug development.

So-Ichiro Fukada, Atsushi Kubo, Motoi Kanagawa, Yoshitsugu Aoki.

  Regenerative medicine has the potential to restore lost organ and tissue functions, and research on cell transplantation is steadily advancing toward clinical application. However, significant challenges remain in developing cell therapies for skeletal muscle, largely because the human body contains more than 600 individual muscles, making it impractical to treat all affected muscles through local transplantation alone. One strategy to overcome this limitation is to enhance the intrinsic regenerative capacity of muscle through various modalities; in this review, we define these approaches as pro-regenerative drugs. Histone deacetylase (HDAC) inhibitors provide a compelling example, demonstrating that stimulation of endogenous muscle regeneration can confer therapeutic benefits in the genetic disease Duchenne muscular dystrophy (DMD). This raises a fundamental question: why do pro-regenerative drugs provide durable benefits without Dystrophin restoration? This review summarizes the current status and importance of pro-regenerative drug development and discusses why sustained therapeutic effects can be achieved despite the lack of gene complementation. It also highlights key pathways that promote muscle regeneration as potential targets for future therapies.

Keywords:  Muscle satellite cells (MuSC); Muscular dystrophy; Pro-regenerative drug

DOI:  https://doi.org/10.1186/s13619-026-00296-8
Biochim Biophys Acta Mol Basis Dis. 2026 Jul 10. pii: S0925-4439(26)00224-3. [Epub ahead of print] 168361

USP18 regulates skeletal muscle regeneration independently of its deISGylation activity.

T Nijssen, R A O'Shaughnessy, C S Olie, K Potočnik, E Aronica, V Raz.

   OBJECTIVES: USP18 is a multifunctional protein that attenuates type I interferon (IFN-I) signalling and regulates ISG15-mediated ISGylation. Although USP18 has been suggested to suppress myogenic differentiation in vitro, its role in muscle regeneration and inflammatory muscle disease remains unclear. This study aimed to define the spatial localization and functional contribution of USP18 and ISG15 in inflamed and regenerating muscle.
METHODS: USP18 function in myogenesis was examined using inducible knockout and catalytic-inactive mutant muscle cell models. Spatial expression of USP18 and ISG15 was analyzed by quantitative imaging in mouse models of muscular dystrophy, cardiotoxin-induced injury, and healthy muscle, with validation in dermatomyositis patient biopsies.
RESULTS: USP18 depletion enhanced myogenesis and mitochondrial activity in vitro. Importantly, a catalytic-inactive USP18 mutant regulated myogenesis comparably to the wild-type protein, demonstrating that USP18 acts independently of its deISGylation activity. In vivo, USP18 and ISG15 expression diverged in low-inflammatory regions but colocalized in highly inflamed regenerative areas, highlighting context-dependent regulation. Regenerating myofibres exhibited high USP18 expression in the absence of ISG15, whereas fibrotic regions displayed persistent ISG15 with reduced USP18 levels. In vitro, USP18 increased MYOG expression during early differentiation while suppressing mature myosin heavy chain expression, indicating that USP18 promotes early myogenic commitment but limits myofibre maturation.
CONCLUSION: USP18 acts as a context-dependent regulator of muscle regeneration independent of its deISGylation function. These findings identify USP18 as a dual modulator of myogenesis and highlight its potential as a therapeutic target in inflammatory muscle disease.

Keywords:  Histopathology; ISG15; Muscle wasting; USP18

DOI:  https://doi.org/10.1016/j.bbadis.2026.168361
Nat Commun. 2026 Jul 10.

Exercise-associated microbial metabolites prevent skeletal muscle atrophy in adult female mice.

Benjamin I Burke, Taylor R Valentino, Ahmed Ismaeel, Salim S El-Amouri, Jensen Goh, Logan N Scott, Bonnie J Walton, Jai K Joshi, Cecily R Wood, Abigail Burrows-Franco, John B May, Lance A Johnson, Michael D Flythe, Yuan Wen, John J McCarthy.

We previously reported that skeletal muscle adaptation to regular exercise requires a healthy gut microbiome, contributing to growing evidence that some exercise benefits are mediated by microbiome-derived metabolites. Here, to identify such exercise-associated microbial metabolites, we transfer cecal contents from exercise-trained female donor mice into exercise-naïve female recipient mice undergoing unilateral hindlimb immobilization. Recipients of cecal material from exercise-trained donors exhibit less muscle atrophy compared with those receiving transfers from sedentary donors. Untargeted metabolomics reveal metabolites enriched in cecal content, serum, and muscle of recipients from exercise-trained donors, consistent with microbial origin. Oral administration of two such metabolites (pipecolic acid and succinate) attenuates muscle atrophy and preserves muscle function in exercise-naïve mice, potentially by enhancing cellular energy status and translational capacity. These findings further define the gut microbiome-skeletal muscle axis and provide evidence that exercise-associated microbial metabolites serve as a novel class of exercise mimetics for treating conditions responsive to physical activity.

DOI: https://doi.org/10.1038/s41467-026-74852-w
Dis Model Mech. 2026 Jul 06. pii: dmm.052935. [Epub ahead of print]

UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice.

Michelle Curley, Flavia A Graca, Anna Stephan, Wei Wang, Vishwajeeth R Pagala, Yong-Dong Wang, Anthony A High, Fabio Demontis.

  UBA1 is the primary ubiquitin-activating enzyme that initiates ubiquitination, which regulates protein function and turnover. While UBA1 loss is cell lethal, silent mutations that reduce UBA1 mRNA levels cause spinal muscular atrophy X-linked 2 (SMAX2), a disorder marked by skeletal muscle weakness and wasting. However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle. Here, we examined Drosophila and mice with muscle-targeted UBA1 knockdown and found that this intervention reduces protein ubiquitination, muscle function, and lifespan. Integrated transcriptomic and proteomic analyses indicate that a limited set of proteins is modulated post-transcriptionally by UBA1RNAi, suggesting that these UBA1-sensitive proteins may rely on optimal UBA1 levels for degradation (UBA1RNAi-upregulated proteins) and stability (UBA1RNAi-downregulated proteins). Therefore, despite its general function in ubiquitination, UBA1 knockdown alters the levels of relatively few critical proteins, which may contribute to muscle weakness and SMAX2 pathogenesis. Moreover, although SMAX2-linked UBA1 mutations occur ubiquitously, experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2.

Keywords:  Muscle function; Proteostasis; SMAX2; Skeletal muscle; UBA1; Ubiquitination

DOI:  https://doi.org/10.1242/dmm.052935
NPJ Microgravity. 2026 Jul 11.

Comprehensive analysis of miRNA expression, secretion profile, and functional network during myogenesis in response to spaceflight.

Wenqing Kong, Mei Ma, Zhuoyang Li, Linjun Wang, Ruisen Ma, Siyi Shen, Xiaojun Yan, Ping Fan, Zhoumin Niu, Jingjing Chen, Tianyuan Qiu, Nuo Shi, Yuting Wu, Tao Zhang, Yuying Li, Hao Ying.

MicroRNAs (miRNAs) are key regulators of skeletal muscle development and homeostasis. As secretory factors, previous studies have identified and validated a space flight-associated circulating microRNA (miRNA) signature in response to space flight. However, the muscle-derived miRNAs are not clear. Here, we comprehensively analyzed the variations of miRNA during mouse myoblast myogenesis in response to space flight, including expression and secretion. We validated some miRNA expression by qRT-PCR analysis in the limb muscle of a disuse-induced atrophy mouse model, mimicking the unloading following microgravity. Functional assays using miRNA mimics further supported the regulatory roles of some miRNAs in target gene expression, as well as in myoblast proliferation and differentiation. These results suggest that deregulation of these miRNAs may play a functional role in muscle atrophy, and they could be candidate biomarkers of muscle atrophy-associated muscular disease. Importantly, our analysis also suggests that spaceflight may regulate miRNA secretion and retention by modulating RNA-binding proteins (RBPs). Secreted miRNAs originating from skeletal muscle cells have been implicated in various diseases affecting the nervous and skeletal systems. Collectively, these findings highlight the potential role of skeletal muscle-derived miRNAs in systemic adaptation to spaceflight.

DOI: https://doi.org/10.1038/s41526-026-00632-x
J Cachexia Sarcopenia Muscle. 2026 Aug;17(4): e70335

Divergent AKT Signalling Mechanisms Regulate GLUT4 Translocation and Glucose Uptake in Skeletal Muscle and Adipose Tissue.

Natasha Jaiswal, Matthew Gavin, Louise Lantier, Olivia Yu Yu Ong, David H Wasserman, Paul M Titchenell.

   BACKGROUND: The serine/threonine kinase AKT is a key regulator of glucose and energy metabolism. Prevailing dogma suggests that AKT is an obligate intermediate for glucose uptake in all metabolic tissues and that impaired AKT signalling is a major molecular driver of insulin resistance in obesity. However, whether AKT is universally required for insulin-stimulated glucose uptake across tissues in vivo has remained unresolved.
METHOD: Several mouse models of adipose-specific AKT2 deletion (F-AKT2KO) and skeletal muscle-specific AKT1, AKT2 and combined AKT1/AKT2 knockout mice (M-AKT1KO, M-AKT2KO and M-AKTDKO) were generated. Skeletal muscle and adipose tissues were analysed following in vivo administration of insulin (2 U/kg), using Western blotting, phosphoproteomics, PI(3,4,5)P3 ELISA and mitochondrial respiration assays. Glucose metabolism was assessed using [3H]-2-deoxyglucose uptake, hyperinsulinemic-euglycemic clamps, glucose and insulin tolerance tests. Global phosphoproteomics was performed in insulin-stimulated skeletal muscle lacking AKT isoforms.
RESULTS: Loss of AKT2 in adipose tissue impaired insulin signalling, including reduced pAS160Thr649, and markedly decreased insulin-stimulated glucose uptake (~2-3 fold reduction in F-AKT2KO vs F-Control, p < 0.001, n = 7-11), resulting in systemic insulin resistance. In contrast, M-AKTDKO mice exhibited a robust increase in insulin-stimulated glucose uptake (~3-4 fold increase) despite complete loss of AKT signalling, including pAS160Thr649. Phosphoproteomic analysis of M-AKTDKO (n = 3-4) identified ~7088 phosphosites, with 795 uniquely upregulated in insulin-stimulated M-AKTDKO muscle (fold change > 2, p < 0.05), enriched in PI3K and AMPK pathways. Consistently, ~8-fold (p < 0.05) increase in PIP3 levels was observed in M-AKTDKO muscle in response to insulin. Additionally, AKT deficiency was associated with reduced complex I-dependent mitochondrial respiration (~37% decrease in state 3 respiration), consistent with altered energetic status and AMPK activation. Genetic epistasis experiments demonstrated that both AKT and AMPK activity are required for insulin-stimulated glucose uptake, systemic glucose homeostasis and whole body insulin sensitivity.
CONCLUSION: These findings challenge the long-standing assumption that AKT is universally required for insulin-stimulated glucose uptake in vivo. The study demonstrates that while AKT is essential in adipose tissue, it is dispensable for insulin-stimulated glucose uptake in skeletal muscle. AKT exerts negative feedback on PI3K signalling in both tissues; however, only skeletal muscle engages AMPK in the abscence of AKT to preserve glucose uptake. These findings redefine tissue-specific insulin signalling mechanisms and identify AMPK as a critical downstream target of PI3K that coordinates with AKT to regulate glucose uptake.

Keywords:  AKT signalling; AMPK signalling; GLUT4 translocation; PI3K‐PIP3 pathway; insulin signalling

DOI:  https://doi.org/10.1002/jcsm.70335
bioRxiv. 2026 Jun 30. pii: 2026.06.29.735332. [Epub ahead of print]

Transient MYC Mimicking the Exercise Response Orchestrates Multifaceted Skeletal Muscle Adaptations.

Ronald G Jones, Pieter J Koopmans, Nathan Serrano, Ana Regina Cabrera, Francielly Morena, Toby L Chambers, Ruth Walters, Agnieszka K Borowik, Michael E Taylor, Ross P Wohlgemuth, Jazmine A Eccles Miller, Abigail L Zirbel, Lea C Range, Sebastian Edman, Ferdinand von Walden, Christopher S Fry, Joanna L Fiddler, Benjamin F Miller, Ahmed Ismaeel, Yuan Wen, Kevin A Murach.

Despite decades of study, MYC's physiological role in adult tissues remains obscured by the models used to investigate it. Most work relies almost exclusively on chronic or constitutive MYC induction that recapitulates the sustained activity found in tumorigenesis and expectedly produces pathological outcomes. What has gone largely untested is how MYC operates when induced in a controlled and physiologically relevant manner, as it is during adaptive processes such as exercise. Using a recombination-independent strategy in adult skeletal muscle, transient MYC bursts drive coordinated hypertrophic-metabolic reprogramming followed by a shift in myosin fiber type, recapitulating adaptations characteristic of concurrent endurance and resistance training. A single pleiotropic transcription factor governing several aspects of muscle health reframes perspectives on a gene understood almost entirely in the context of pathology. We uncover a previously unrecognized muscle-specific role for MYC in controlling muscle cell composition and present a multi-timepoint multi-omic resource for interrogating MYC: data.myoanalytics.com/study/myc_transient/gene.

DOI: https://doi.org/10.64898/2026.06.29.735332
J Clin Invest. 2026 Jul 09. pii: e190646. [Epub ahead of print]

Neuromuscular junction failure in sarcopenia is linked to NaV1.4 loss and reversed by ClC-1 inhibition.

W David Arnold, Jeanette Jeppesen Morgen, Pernille Bogetofte Thomasen, Martin Broch-Lips, Leatha A Clark, Thomas Groennebaek, Martin Skov, Jeppe Blichfeldt Winther, Abdullah F Ramadan, Philippa A Rust, Jessica H Myers, Fereshteh B Darvishi, Anna R Dashtmian, Lauren A Fish, Deepti Chugh, Jane Bold, Jorge A Quiroz, John Hutchison, Hiroshi Nishimune, Ross A Jones, Xueyong Wang, Justin R Fallon, Thomas H Gillingwater, Mark M Rich, Thomas Holm Pedersen, Brian C Clark.

  Sarcopenia is the age-related loss of muscle strength and size that leads to mobility limitations and loss of independence in older adults. The underlying cellular mechanisms remain unclear, and treatments are limited. As the critical interface between the nervous system and muscle, the neuromuscular junction (NMJ) is essential for muscle activation and force production. Here, we demonstrate that weak older individuals exhibit NMJ transmission failure that correlates with muscle weakness severity. Preclinical experiments showed similar NMJ transmission failure in aged rodents that was associated with localized loss of muscle fiber excitability at the NMJ. This excitability defect, distinct from potential synaptic cholinergic transmission abnormalities, represents a novel disease mechanism of sarcopenia. Across species, immunohistochemistry identified a localized reduction in the voltage-gated sodium channel specific for skeletal muscle (NaV1.4) at the post-synaptic NMJ membrane. Acute NaV1.4 inhibition with μ-conotoxin GIIIB in adult rats reproduced findings of NMJ transmission failure observed in aged rodents and humans. Finally, ClC-1 chloride ion channel inhibition enhanced muscle excitability and improved NMJ transmission and muscle function in old rodents. Together, these findings demonstrate that NMJ transmission deficits are a key, reversible driver of sarcopenia and reveal a novel therapeutic target for addressing muscle weakness in aging.

Keywords:  Aging; Excitation contraction coupling; Neuroscience; Sodium channels; Synapses

DOI:  https://doi.org/10.1172/JCI190646
MicroPubl Biol. 2026 ;2026

RNAi-based motility screen of predicted sarcopenia-associated genes during aging in C. elegans.

Iurii Orlov, Merlin Naud, Walha Taras, Ilke Sen.

Sarcopenia, the age-related decline in skeletal muscle mass, function, and strength, is driven by mechanisms that are incompletely understood. We analyzed a large meta-analysis of human skeletal muscle transcriptomic datasets to identify candidate regulators of sarcopenia. Orthologs of these candidate genes in Caenorhabditis elegans were targeted by RNA interference, and age-dependent motility was assessed by thrashing assay on days 1, 4, 7, and 11 of adulthood. Of 243 genes tested, silencing of 143 did not significantly alter motility at any time point. These results provide a reference dataset for future studies of muscle aging and sarcopenia.

DOI: https://doi.org/10.17912/micropub.biology.002167
Am J Physiol Cell Physiol. 2026 Jul 06.

Skeletal muscle biomass as an underappreciated fate of glucose.

Henning Wackerhage, Moritz Eggelbusch, Juha J Hulmi, Sakari Mäntyselkä.

  Glucose is traditionally viewed as a substrate for ATP production and glycogen storage in skeletal muscle. Here, we review evidence that glucose also serves as a building block for biomass synthesis in proliferating muscle satellite (stem) cells and hypertrophying skeletal muscle fibers, drawing parallels to anabolic metabolic reprogramming in cancer cells. In cancer and other growing cells, increased glucose uptake, aerobic glycolysis (Warburg effect), and the TCA cycle provide substrates for anabolic pathways that generate macromolecules required for growth and proliferation. Radiotracer studies in mammalian cancer and muscle cells demonstrate that approximately 8-15% of the cell dry mass originates from glucose. Mechanistic insights, obtained predominantly from cell culture models, indicate that glucose-derived glycolytic and TCA cycle intermediates provide substrates for serine synthesis and the pentose phosphate pathway, glycine and one-carbon metabolism, non-essential amino acid synthesis, nucleotide and lipid synthesis as well as for epigenetic methylation and acetylation. We further review evidence that human resistance training, hypertrophy through muscle-specific expression of Akt1 in mice, loss or inhibition of myostatin/activin signaling, and other hypertrophy-inducing interventions improve glucose homeostasis under conditions of obesity, insulin resistance, and type 2 diabetes. We discuss the possibility that glucose incorporation into biomass contributes to this effect.

Keywords:  Glucose; Warburg effect; cancer; diabetes mellitus; serine biosynthesis; skeletal muscle; skeletal muscle hypertrophy

DOI:  https://doi.org/10.1152/ajpcell.00295.2026
Physiol Rep. 2026 Jul;14(13): e71013

2H2O labeling methods for bulk and single muscle protein synthesis measures, and measures of integrated muscle protein synthesis and breakdown rates: A pilot study.

Grith Højfeldt, Bjørk Wulff Helge, Gerrit van Hall, Peter Schjerling, Michael Kjær, Abigail L Mackey, Jatin G Burniston, Jakob Agergaard.

  This methodological pilot study explored the feasibility of an integrated tracer approach for simultaneous measurement of human skeletal muscle protein synthesis and breakdown during prolonged deuterium oxide (2H2O) labeling. Four healthy men completed a five-week protocol combining daily oral 2H2O intake with selected stable isotope amino acid tracers to assess bulk fractional synthesis rates, fractional breakdown rates, and single-protein turnover. The study specifically addressed the methodological question of whether bulk or individual protein synthesis measurements remain consistent over a prolonged 2H2O labeling period. We suggest that measurements of mixed-protein fractions in muscle might be vulnerable to error due to the rise-to-plateau kinetics associated with longer-duration labeling. Mean mixed-protein synthesis rates could be underestimated when labeling exceeds approximately 4 weeks. Increasing precursor enrichment mitigated this effect but highlights the need for controlled enrichment strategies in long-term studies. In contrast, dynamic proteome profiling (DPP) provided more robust single-protein turnover estimates across the full period because the different isotopic plateaus of individual peptides could be modeled. The study also tested the feasibility of combining 2H2O labeling with 15N-alanine-based breakdown measurements and evaluated potential interference from multiple tracers on DPP outputs. Together, these findings outline practical considerations, limitations, and feasibility of an integrated multi-tracer framework for studying human muscle protein turnover over extended periods.

Keywords:  D2O; dynamic proteome profiling; muscle protein breakdown; muscle protein synthesis

DOI:  https://doi.org/10.14814/phy2.71013
Am J Physiol Regul Integr Comp Physiol. 2026 Jul 09.

"Should I stay or should I go?" How do our muscles respond to spaceflight stressors long after we return to Earth?

Thaysa Ghiarone, Kleiton A S Silva.



Keywords:  Hindlimb unloading; Skeletal muscle; Spaceflight; ionizing radiation; mitochondrial dysfunction

DOI:  https://doi.org/10.1152/ajpregu.00225.2026
J Gastrointest Oncol. 2026 Jun 30. 17(3): 191

Going beyond total skeletal muscle area at L3 (tSMA) to accurately assess pancreatic cancer cachexia.

Rishi Surana, Kimberly J Perez.



Keywords:  Pancreatic cancer; cachexia; edema; sarcopenia

DOI:  https://doi.org/10.21037/jgo-2026-0221
FASEB J. 2026 Jul 15. 40(13): e72102

Adipocyte-Derived Exosomal Circ_0000002 Affects the Myoblast Growth and Muscle Regeneration.

Lin Liang, Weipeng Zhang, Shilong Yu, Haoran Chen, Jianchen Yan, Jianrong Huo, Junxing Zhao.

  Skeletal muscle development is strongly influenced by crosstalk between adipose tissue and muscle, yet the underlying molecular mechanisms in Ovis aries remain insufficiently defined. This study investigated the regulatory effects of adipocyte-derived exosomes on sheep primary myoblasts. Co-culture with adipocytes significantly enhanced myoblast proliferation, as indicated by increased cyclin-dependent kinase 4 (CDK4), proliferating cell nuclear antigen (PCNA), and Cyclin D1 expression, while simultaneously suppressing differentiation via reduced myogenin (MYOG), myogenic differentiation 1 (MYOD), and myosin heavy chain (MYHC) levels. Exosomes isolated from mature adipocytes (30-150 nm), expressing TSG101, CD63, and CD9, were effectively internalized by myoblasts and reproduced these effects. RNA sequencing identified circ_0000002 as one of the most abundant circular RNAs (circRNAs) in adipocyte-derived exosomes. Functional assays demonstrated that circ_0000002 promoted myoblast proliferation and inhibited differentiation. Mechanistically, circ_0000002 acted as a competing endogenous RNA (ceRNA) by sponging miR-27a, thereby relieving miR-27a-mediated repression of myostatin (MSTN). Dual-luciferase reporter assays confirmed direct interactions between circ_0000002 and miR-27a and between miR-27a and the MSTN 3' untranslated region (3´UTR). Co-transfection experiments further validated that the ceRNA-like mechanism of circ_0000002/miR-27a/MSTN regulates myoblast differentiation. In a cardiotoxin (CTX)-induced tibialis anterior injury mouse model, intramuscular administration of adipocyte-derived exosomes impaired muscle regeneration and increased MSTN expression, supporting the in vivo relevance of this pathway. Collectively, our findings reveal that exosomal circ_0000002 regulates sheep myoblast differentiation via miR-27a/MSTN ceRNA pathway. This work provides the first evidence that an adipocyte-derived exosomal circRNA mediates fat-muscle communication and highlights a potential target for improving muscle growth in sheep.

Keywords:  adipocyte‐derived exosomes; circ_0000002; fat–muscle crosstalk; miR‐27a/MSTN pathway; regeneration; sheep myoblast differentiation

DOI:  https://doi.org/10.1096/fj.202602375R
Rev Endocr Metab Disord. 2026 Jul 04.

Exercise remodels the skeletal muscle immune microenvironment to ameliorate type 2 diabetes mellitus-induced muscle atrophy: From immunometabolism to organ crosstalk.

Fu Pengyu, Xu Huiyun, Gong Lijing.

  Type 2 diabetes mellitus (T2DM) complicated by muscle atrophy (diabetic sarcopenia) significantly increases mortality risk, with immunometabolic imbalance-driven disruption of the skeletal muscle microenvironment as a core mechanism. This review focuses on the immune cell-myocyte crosstalk network to elucidate the pathological mechanisms of T2DM-induced muscle atrophy, the local remodeling effects of exercise, and systemic organ crosstalk. In the T2DM state, M1/M2 imbalance and metabolic reprogramming of macrophages, dysregulated mast cell activation and histamine signaling, NLRP3 inflammasome-mediated pyroptosis, T-cell immunosenescence, and chemokine storms collectively disrupt muscle homeostasis. Exercise reverses these abnormalities by downregulating TRIB3/AKT to promote M2 polarization, restoring mast cell function, inhibiting the NLRP3/caspase-1/GSDMD pyroptosis pathway, increasing Treg infiltration, and downregulating the chemokine network, thereby shifting the local microenvironment from a "pro-inflammatory/destructive" to a "reparative/regenerative" state. Furthermore, exercise exerts systemic regulation through multiple organ axes, including adipose tissue (adipokines and inflammation), gut microbiota, liver (SIRT1/FGF21 signaling), and the brain (hypothalamic-pituitary-adrenal axis and myokines such as BDNF and CTSB for bidirectional neuroimmune regulation). In summary, exercise directly remodels the local immune crosstalk network in skeletal muscle and synergistically improves T2DM-associated muscle atrophy through multi-organ interactions, providing a theoretical basis for precise exercise interventions.

Keywords:  NLRP3 inflammasome; Type 2 diabetes mellitus; exercise; gut–muscle axis; immune–myocyte crosstalk; muscle atrophy

DOI:  https://doi.org/10.1007/s11154-026-10069-y
Res Sq. 2026 Jul 01. pii: rs.3.rs-10144286. [Epub ahead of print]

Mechanosensing at the endoplasmic reticulum by IRE1.

Hesso Farhan, Michaela Mayr, Luiz Garcia-Souza, Murphy McDermott, Utku Horzum, Yannick Frey, Margot Haun, Stephan Geley, Chao Jiang, Mattias Luber, Anush Bakunts, Camilla Pirolo, Alesia Yakimchyk, Klaus Liedl, Wylie Stroberg, Timo Betz, Liam Holt.

Sensing and integration of mechanical forces in eukaryotic cells have largely been attributed to the plasma membrane and the nucleus. Here, we identify the endoplasmic reticulum (ER) as an autonomous mechanosensitive organelle and uncover IRE1 as an ER-resident mechanosensor. We show that applying mechanical forces to ER membranes increases lateral tension, which is sensed by the transmembrane domain of IRE1. Mechano-activation of IRE1 was unrelated to its canonical role in the unfolded protein response and occurred independently of nuclear mechanosensing. Instead, mechanically activated IRE1 triggered JNK signaling and increased global protein synthesis independently of XBP1 splicing. In engineered skeletal muscle tissue, both electrical stimulation and passive stretch similarly activated IRE1, increased translation, and contributed to training-induced increases in contractile force. Collectively, our results uncover a non-canonical role for IRE1 as an ER-based mechanosensor that couples mechanical forces to the regulation of protein translation.

DOI: https://doi.org/10.21203/rs.3.rs-10144286/v1
Diabetes Obes Metab. 2026 Jul 06.

Exercise Resistance in Obese Male NZO Mice Manifests as Local Muscle Remodelling Without Glycaemic Improvements.

Christian Springer, Sebastian Sill, Christian Binsch, Taylor Schoen, Laura Toska, Matthias Lienhard, Ralf Herwig, Stefan Börno, Bernd Timmermann, Diran Herebian, D Margriet Ouwens, Delsi Altenhofen, Angelika Horrighs, Birgit Knebel, Regina Ensenauer, Dominik Pesta, Michael Roden, Alexandra Chadt, Hadi Al-Hasani.

   AIMS: Exercise improves glycaemic control, yet some individuals show limited benefit, termed exercise resistance. We investigated tissue-specific adaptations to chronic exercise in a polygenic model of obesity-driven type 2 diabetes (T2D).
MATERIALS AND METHODS: Male New Zealand Obese (NZO) mice were fed a high-fat diet and underwent 6 weeks of interval treadmill training. Physical capacity, body composition, glucose metabolism, skeletal muscle and liver glycogen and triglycerides, mitochondrial function, transcriptomics and systemic metabolites were assessed.
RESULTS: The training regime had a positive impact on several physiological parameters, including increased physical capacity (18%, p < 0.01), skeletal muscle AMPK phosphorylation (25%, p < 0.05), complex I-linked respiration (67%, p < 0.05) and transcriptomic enrichment of muscle contraction pathways in trained versus sedentary NZO mice. However, body weight, fat mass, fasting glycaemia, insulin-stimulated glucose uptake, AKT phosphorylation and GLUT4 abundance remained unaltered. Plasma branched-chain amino acids (BCAAs) and ketone bodies (3.3-fold higher in trained, p < 0.05) increased, hepatic triglycerides rose (25%, p < 0.001) with hepatic glycogen depletion (37%, p < 0.05) and caloric intake was slightly higher.
CONCLUSIONS: Interval training induced muscle-specific remodelling and enhanced physical capacity without improving systemic insulin sensitivity. Persistent adiposity, exacerbated hepatic steatosis and elevated circulating BCAAs may contribute to limited glycaemic improvement, with altered energy balance as a possible confounder. Consequently, the NZO model offers translational insight into tissue-uncoupled exercise resistance observed in human polygenic obesity and T2D heterogeneity.

Keywords:  exercise resistance; interval training; mitochondrial adaptation; obesity; skeletal muscle metabolism

DOI:  https://doi.org/10.1111/dom.71068
Neurol Sci. 2026 Jul 04. pii: 612. [Epub ahead of print]47(8):

Brain-muscle axis regulation of neuroinflammation and sarcopenia in Parkinson's disease: the bridging role of lactylation.

WenXia Sun, Huiwen Huang, Xiyan Lan, An Yin, Qiong Deng, Yanbiao Zhong, MaoYuan Wang.

   BACKGROUND: Sarcopenia is a common and often overlooked nonmotor symptom of Parkinson's disease (PD), significantly increasing the risk of falls and exacerbating the disease burden. Increasing evidence suggests that PD is not merely a neurodegenerative disease confined to the central nervous system (CNS) but also involves significant systemic metabolic disturbances and peripheral tissue dysfunction, indicating a systemic pathological character. In recent years, epigenetic modifications have gradually become an important perspective for understanding the inflammatory progression of PD. Lactate is no longer simply considered the end product of glycolysis, but can regulate gene transcription and protein function through protein lactylation.
OBJECTIVE: This paper systematically proposes that lactylation is a key molecular bridge between neuroinflammation and sarcopenia in PD.
METHODS: We searched literature from the PubMed database from 2010 to 2026, screened qualified English articles, and integrated the latest research advances in neuroimmunology, skeletal muscle biology, and metabolic epigenetics.
RESULTS: In PD, microglia epigenetic modifications and metabolic reprogramming lead to lactate accumulation, which may drive a persistent neuroinflammatory response through lactate modification. Simultaneously, chronic inflammation and metabolic abnormalities can propagate along the brain-muscle axis, promoting skeletal muscle protein metabolic imbalance and accelerating the development of sarcopenia. Based on this, this paper systematically proposes that lactylation is a key molecular bridge between neuroinflammation and sarcopenia in PD. Combining the latest research advances in neuroimmunology, skeletal muscle biology, and metabolic epigenetics, this paper elucidates the potential mechanisms by which abnormal lactate metabolism and lactylation play a role in altered glial cell inflammatory phenotypes and skeletal muscle homeostasis imbalances. Furthermore, in conjunction with exercise intervention studies, this paper explores how lactylation, as a key regulatory molecule, can achieve bidirectional improvement in CNS inflammation and peripheral muscle function, providing a new theoretical basis for systemic intervention strategies for PD.

Keywords:  Lactate; Lactylation; Neuroinflammation; Parkinson’s disease; Sarcopenia

DOI:  https://doi.org/10.1007/s10072-026-09199-7
Nat Commun. 2026 Jul 08.

Elimination of myotonia improves myopathy in a muscleblind-like knockout model of myotonic dystrophy.

Matthew T Sipple, Sakura A Hamazaki, Vanessa Todorow, Lily A Cisco, Katherine M Lupia, Christina S Heil, Peter Meinke, Charles A Thornton, John D Lueck.

A cardinal sign of myotonic dystrophy type 1 (DM1) is myotonia, slow muscle relaxation after voluntary contraction. Myotonia results from mis-regulated splicing of chloride channel 1 (ClC-1), leading to loss of channel function and runs of involuntary action potentials in muscle fibers. Preceding the onset of weakness, myotonia is often the first symptom of DM1, and thus this raises the possibility that muscle hyperexcitability contributes to the subsequent weakness and myopathy. Here, we show that genomic deletion of ClC-1 exon 7a (E7a), a cryptic exon abnormally regulated in DM1, completely rescues of ClC-1 function and yields permanent elimination of myotonia in the muscleblind-like 1 (Mbnl1) knockout mouse model of DM1. The restoration of normal excitability results in normalization of muscle force generation, correction of fiber-type distribution, and improvement of muscle histology. E7a deletion also partially corrects the muscle transcriptome, including changes of differential gene expression and alternative splicing. These results indicate that E7a inclusion is a lynchpin splice event that contributes to myotonic myopathy, and support myotonia reduction as a therapeutic objective in DM1.

DOI: https://doi.org/10.1038/s41467-026-75243-x
DNA Repair (Amst). 2026 Jul 07. pii: S1568-7864(26)00029-7. [Epub ahead of print]165 103950

Tissue-specific CTG•CAG expansion rate and disease severity are modified by DNA repair genes expression levels in myotonic dystrophy type 1 patients.

Melissa Palma-Jiménez, Lisbeth Ramirez-Carvajal, Hailey Olafson, Eric T Wang, Fernando Morales.

  Myotonic dystrophy type 1 (DM1) is a multisystemic autosomal dominant disorder caused by the expansion of an unstable CTG•CAG repeat in the DMPK gene. This study examined whether differential expression of DNA repair genes in three different tissues from the same DM1 patient contributed to tissue-specific somatic instability of the repeat tract. RNA-Seq was used to quantify expression levels of eight DNA repair genes (MSH2, MSH3, MSH6, MLH1, MLH3, PMS2, LIG1, and FAN1). Results indicate that the expression levels varied significantly across tissues, with no inter-tissue correlations, suggesting independent regulation and patient-specific differences. Somatic expansion of the repeat tract in blood and muscle was effectively predicted by a complex ePALxAge interaction, while in muscle it was further influenced by MSH3 and PMS2 gene expression, confirming their role as tissue-specific genetic modifiers in DM1. Although only marginally significant, muscle expression of PMS2 and FAN1 appeared to affect age-at-onset: higher FAN1 expression was associated with reduced somatic expansion and later onset. Our findings also suggest a complex competitive balance between promoters and stabilizers of repeat instability, shaping muscle expansion dynamics and potentially modifying clinical onset. Overall, these results indicate that certain DNA repair genes exert stronger, tissue-dependent effects on somatic instability. We confirm that MSH3, PMS2, and FAN1 act as key modifiers not only of somatic expansion, especially in skeletal muscle, but also of DM1 severity. Although RT-qPCR data might be required to validate some of these results, these genes therefore represent promising therapeutic targets for modulating disease progression.

Keywords:  CTG•CAG repeats; Gene expression; Tissue-specific ratios; trans-modifiers

DOI:  https://doi.org/10.1016/j.dnarep.2026.103950
bioRxiv. 2026 Jul 03. pii: 2026.06.29.734788. [Epub ahead of print]

Dual Th1 and tissue-repair Treg cells accumulate in skeletal muscle preserving tissue integrity during infection.

Cintia L Araujo Furlan, Santiago Boccardo, Camila M S Gimenez, Yamila Gazzoni, Julio Gareca, Constanza Rodriguez, Jorge H Mukdsi, María C Amezcua Vesely, Adriana Gruppi, Carolina L Montes, Bola S Hanna, Eva V Acosta Rodríguez.

Chronic infections require mechanisms that limit tissue damage while preserving pathogen control, yet the contribution of regulatory T (Treg) cells to this balance remains unclear. In this study, we characterized Treg cell responses during a chronic parasitic infection using experimental Trypanosoma cruzi infection as a model of persistent low-level parasitism and chronic tissue inflammation. We found that, although Treg cell numbers decline in the spleen, they accumulate in parasite-affected tissues such as skeletal muscle, where they adopt a combined Th1-associated and tissue-repair program. Systemic Treg cell depletion had limited impact on immune and disease-associated parameters, whereas local depletion in skeletal muscle exacerbated tissue damage and increased parasite burden. Moreover, transient systemic perturbation of Treg cells during the acute phase impaired their long-term accumulation in skeletal muscle, resulting in increased tissue damage and parasite burden during chronic infection. Additionally, accumulation of reparative Treg cells in skeletal muscle was impaired in the absence of ST2. Together, these findings identify a tissue-adapted Treg cell population that integrates inflammatory and reparative programs to preserve skeletal muscle integrity during chronic parasitic infection.
SUMMARY: Chronic parasite infection drives the emergence of tissue-adapted regulatory T cells that integrate Th1-associated and tissue-repair programs. These cells accumulate in skeletal muscle, where they preserve tissue integrity while contributing to microbial control, highlighting the dynamic specialization of Treg cells across disease stages.

DOI: https://doi.org/10.64898/2026.06.29.734788
Front Physiol. 2026 ;17 1865484

Sarcolipin-SERCA uncoupling as a plausible heat source for sustaining fever.

A Humaid, A R Tupling.

  Fever is an evolutionarily conserved host defence that elevates defended core temperature and metabolic rate, yet the dominant thermogenic tissue sustaining febrile heat production in adult mammals remains unresolved. Brown adipose tissue and shivering thermogenesis are emphasized in classical models, but adult BAT is quantitatively limited, and shivering is often intermittent and behaviourally costly. Because skeletal muscle is high-mass and widely distributed, skeletal muscle non-shivering thermogenesis is positioned as a viable contributor to febrile hypermetabolism, particularly during the maintenance phase. Febrile responses persist in UCP1-deficient models, while UCP3 disruption blunts LPS-induced hyperthermia, consistent with a muscle-linked contribution to febrile thermogenesis. Given that UCP3 is generally viewed as a metabolic-support uncoupler rather than a dedicated adaptive heat generator, sarcolipin-mediated SERCA uncoupling emerges as a plausible, scalable alternative. Inflammatory challenges are associated with increased muscle SLN expression without parallel SERCA expansion. These observations motivate integrated calorimetry, electromyography, and tissue-specific perturbation approaches to quantify skeletal muscle heat production during fever and distinguish putative SERCA uncoupling from shivering across translational models.

Keywords:  Ca2+ cycling; febrile thermogenesis; non-shivering thermogenesis; skeletal muscle; thermoregulation

DOI:  https://doi.org/10.3389/fphys.2026.1865484
Clin Sci (Lond). 2026 Aug 12. 140(8): 1617-1633

The role of central regulators in lipid hydroperoxide-mediated muscle atrophy. Exploring mechanisms beyond ferroptosis.

Hiroaki Eshima.

  The oxidation of lipids in biological systems generates lipid hydroperoxides, which are implicated in cellular dysfunction, such as arteriosclerosis and cognitive decline. Although multiple lipid species, including phospholipids, ceramides, triglycerides, and free fatty acids, are susceptible to oxidation, the specific lipid species that drive disease development remain poorly defined. Lipid oxidation is primarily initiated and propagated by reactive oxygen species (ROS). ROS are highly reactive molecules that participate in diverse and complex intracellular signaling pathways. Ferroptosis is a recently identified form of regulated, non-apoptotic cell death characterized by iron-dependent accumulation of lipid peroxides, especially the peroxidation of polyunsaturated fatty acids in cellular membranes, ultimately leading to loss of membrane integrity. Oxidized phospholipids are considered key execution factors in ferroptosis, suggesting an important role for lipid peroxidation in maintaining physiological homeostasis across multiple organs. Our group recently demonstrated that oxidized phospholipids could serve as a source of ROS, thereby promoting muscle atrophy. In the present review, we summarize emerging evidence that membrane lipids, particularly oxidation of phospholipids and polyunsaturated fatty acids, contribute to the generation and propagation of cellular ROS, ultimately facilitating muscle atrophy.

Keywords:  lipid peroxidation; oxidized phospholipids; polyunsaturated fatty acids; reactive oxygen species; skeletal muscle

DOI:  https://doi.org/10.1042/CS20260445
Stem Cell Res Ther. 2026 Jul 07.

Isolation of human satellite cells using CD29/CDH15 and a nanoparticle-based live Pax7 mRNA detection system, and their expansion with extracellular matrix and its derivatives.

Shudong Zhao, Shubhankar Sood, Ruixiang Yu, Luis Arvizu Gutierrez, Takhmina Ayupova, Sara Taiyari, Jonathan Miles, Stephen Hamilton, Massimiliano Cerletti.

  Human skeletal muscle stem cells, also called satellite cells, have great potential for treating neuromuscular diseases and combating muscle aging. However, progress toward clinical use has been limited by the scarcity of donor tissue and the technical challenges of isolating, preserving, and culturing these rare cells. In this study, we introduce a new combination of cell surface markers and a gold nanoparticle-based live Pax7 mRNA detection system, both of which enable efficient isolation of human satellite cells. Additionally, we show that extracellular matrix (ECM) components support the maintenance of human satellite cells and improve their function in vivo. These findings provide integrated methods to enhance the production of human muscle-forming cells for translational and clinical applications.

Keywords:  Cell surface markers; Decellularization; ECM; Human satellite cells; Nanoparticle-based live mRNA detection probes; Skeletal muscle regeneration

DOI:  https://doi.org/10.1186/s13287-026-05134-x
Am J Physiol Endocrinol Metab. 2026 Jul 07.

Bridging the gap: Multi-omic Insights into Exercise Responses in Post-Menopausal Women.

Rushali Kullachanda Aiyanna, Sisi Wang, Robin Grolaux, Elizabeth Reisman, Bernadette Jones-Freeman, Nir Eynon.

  Post-menopausal women represent the fastest-growing demographic at risk of sarcopenia and cardiometabolic disease, yet exercise biology research remains disproportionately derived from male or hormone-replete phenotypes. Menopause constitutes a chronic endocrine perturbation characterized by sustained reductions in estrogen and progesterone and altered androgen balance, superimposed on the acute and chronic perturbations induced by exercise. This hormonal shift modifies substrate metabolism, inflammation, redox balance, and recovery capacity, factors that shape molecular responses to exercise across tissues and time. Here, we synthesize current evidence on exercise responses in post-menopausal females across genomics, epigenomics, transcriptomics, proteomics and metabolomics/lipidomics. Across omics layers, direct data in post-menopausal cohorts remain limited, with frequent under-reporting of menopausal status, hormone therapy exposure, circulating hormone concentrations, medication use, and bio sampling timing relative to exercise and hormone dosing. We outline a menopause-aware framework for exercise-omics that prioritizes endocrine stratification, repeated sampling across exercise and recovery, and integrative multi-omics approaches linking molecular responses to functional outcomes. We also outline minimum reporting standards to improve reproducibility, inclusivity, and translational relevance. Advancing menopause-aware exercise-omics will be essential for developing precision exercise strategies that improve healthspan and functional independence in later life.

Keywords:  Exercise; epigenomics; lipidomics; menopause; metabolomics; proteomics

DOI:  https://doi.org/10.1152/ajpendo.00172.2026
JCI Insight. 2026 Jun 23. pii: e205137. [Epub ahead of print]

Excess muscle plasma membrane leak disrupts extracellular matrix content and shifts macrophage-mediated muscle repair.

GaHyun Lee, Alexander J Fitt, Ashlee M Long, Lauren A Vaught, Dorothy DeBiasse, Alexander R Keeble, Jason M Kwon, Patrick Gt Page, Marie-Therese Daher, Michele Hadhazy, Alexander B Willis, David Ceja Galindo, Maxwell C McCabe, Connor Lantz, Kirk C Hansen, Rachelle H Crosbie, Edward B Thorp, Alexis R Demonbreun, Elizabeth M McNally.

  Plasma membrane repair is critical for tissue integrity, especially for elongated contractile muscle cells. Genetically-mediated defects in plasma membrane resealing produce persistent leak, leading to a disordered extracellular matrix. Loss of the membrane repair protein dysferlin slows sarcolemmal resealing and promotes excess leak. Annexin A6 is also implicated in sarcolemmal repair, forming repair caps at the site of membrane disruption. On its own, deletion of the gene for annexin A6, Anxa6, had little effect on muscle health. In contrast, combined loss of dysferlin and annexin A6 (DysfA6) generated muscle fibers with profoundly defective membrane leak. Strikingly, Anxa6 deletion in the context of loss of dystrophin (mdxA6) did not exacerbate muscle defects. The persistent membrane leak in DysfA6 muscle resulted in marked macrophage infiltration with disordered macrophage polarization. Injured muscle fibers were targets of macrophage efferocytosis. Loss of Anxa6 was associated with increased expression of annexins A1 and A2, both of which were heavily deposited into the extracellular matrix. In vitro, macrophages exposed to annexins A1 and A2 increased Csf1 expression, consistent with a model where excess leak results in annexins A1 and A2 in the extracellular matrix, where this protein composition influences macrophage proliferation and efferocytosis.

Keywords:  Inflammation; Macrophages; Muscle biology

DOI:  https://doi.org/10.1172/jci.insight.205137
Aging Med (Milton). 2026 Jun;9(3): 325-337

Biomarkers of Sarcopenia: Current Status and Future Perspectives.

Bijin Luo, Wenhan Li, Yi Zhang, Mengchen Liu, Kemeng Zhang, Sui Huang, Ping He.

  Sarcopenia is an age-related skeletal muscle disorder characterized by progressive declines in muscle mass, strength, and physical function, which profoundly impair quality of life in older adults. Although current clinical guidelines propose various diagnostic approaches and cutoff values, considerable heterogeneity among criteria and assessment tools continues to pose challenges for the accurate and early diagnosis of sarcopenia. In recent years, an increasing number of studies have identified potential biomarkers associated with sarcopenia, which can be broadly classified into biochemical, imaging-based, and physical performance-related categories. The identification of these biomarkers has improved diagnostic accuracy, provided additional means for monitoring disease progression, and opened new avenues for therapeutic intervention. This narrative review aims to summarize currently established and emerging biomarkers related to sarcopenia, with a particular focus on their biological relevance, clinical applicability, and limitations. Furthermore, potential directions for future research are discussed to facilitate the development of integrated, multimodal biomarker strategies for the early detection, risk stratification, and personalized management of sarcopenia.

Keywords:  biochemistry biomarkers; biomarker; body imaging techniques; diagnosis; physical test; sarcopenia

DOI:  https://doi.org/10.1002/agm2.70088
Am J Physiol Regul Integr Comp Physiol. 2026 Jul 09.

BCAAs, LAT1, and the Metabolic Competition between Tumor and Peripheral Tissues during Cancer Cachexia.

Jessica L Halle, Benjamin F Miller.



Keywords:  BCAA; Cancer Cachexia; Colorectal Cancer; LAT1; Metabolism

DOI:  https://doi.org/10.1152/ajpregu.00219.2026
J Adv Res. 2026 Jul 06. pii: S2090-1232(26)00519-9. [Epub ahead of print]

Mapping sarcopenia's causal proteome reveals a leptin-driven inflammatory-mitochondrial axis for early prediction.

Jing Sun, Mingchen Yan, Jiang Dan, Chen Yang, Fuyu Duan, Jie Luo, Hao Chen, John Zh Zhang, Qizhou Lian.

   INTRODUCTION: Sarcopenia, the age-related loss of muscle mass and function, is a major barrier to healthy aging. However, its molecular origins remain obscure, and current clinical tools lack the sensitivity needed to detect risk before significant decline occurs.
OBJECTIVES: We sought to map the causal proteome of sarcopenia to clarify its pathogenesis and derive a blood-based signature capable of predicting disease onset years in advance.
METHODS: Our approach integrated multi-omics with causal inference. We first screened muscle transcriptomes to guide a proteome-wide Mendelian randomization (MR) analysis, leveraging cis-pQTLs and UK Biobank GWAS data to isolate causal proteins. Concurrently, we analyzed 2,920 plasma proteins in the UK Biobank to pinpoint markers associated with future sarcopenia risk. We then combined these causal and prospective datasets to train a machine learning predictor.
RESULTS: We identified 39 circulating proteins with causal effects on muscle mass or strength, implicating specific growth (HBEGF), inflammatory (TLR2), and metabolic (MDH1) pathways. By integrating these causal drivers with prospective biomarkers, our machine learning model predicted incident sarcopenia up to six years prior to diagnosis (AUC = 0.738). Notably, the model distinguished true sarcopenia from simple muscle weakness. Network analysis placed Leptin (LEP) at the core of this signature, linking systemic metabolic signals to downstream inflammatory effectors.
CONCLUSION: Our findings support a mechanism where chronic, LEP-associated inflammation converges with mitochondrial bioenergetic failure to drive muscle decline. This study provides proof-of-concept for a plasma proteomic tool for early risk stratification and establishes a new framework of high-confidence targets for therapeutic development.

Keywords:  Dual-mechanism; Mendelian randomization; Multi-omics; Pathogenesis; Proteomics; Risk prediction; Sarcopenia

DOI:  https://doi.org/10.1016/j.jare.2026.07.001
Front Rehabil Sci. 2026 ;7 1874273

Bridging assessment, biomarkers, and interventions: progress in muscle health research.

Dustin J Oranchuk, Jason M DeFreitas, André R Nelson, Michael O Harris-Love.

  The concept of 'muscle health' is increasingly recognized as a central determinant of physical function, metabolic regulation, and disease resilience, yet its clinical integration remains fragmented by inconsistent definitions and measurement approaches. This Perspective synthesizes insights from the Research Topic 'Advancing Muscle Health: From Technical and Clinical Research to Practice', which brings together nine contributions spanning assessment technologies, biomarkers, clinical populations, and interventions. Collectively, these works illustrate a field transitioning from isolated advances toward more integrated, clinically meaningful frameworks. Emerging ultrasound-based methods demonstrate how improved reliability and automation may enable scalable muscle assessment, while biomarker studies highlight both the promise and limitations of metabolomic, functional, and surrogate metrics in capturing the systemic nature of muscle health. Evidence from neurological, vascular, and oncological contexts reinforces that muscle is not only an outcome of disease, but a key modifier of disease progression and risk. Across these domains, exercise, particularly resistance-based and multimodal approaches, continues to emerge as a key, yet under-implemented, strategy. Despite this progress, critical gaps remain. The field lacks longitudinal, diverse-cohort data, standardized measurement frameworks, and robust integration of emerging technologies such as multi-omics and artificial intelligence. Moving forward, advancing muscle health will require interdisciplinary, translational approaches that align mechanistic insight with clinical application, enabling precise phenotyping and scalable interventions. Bridging these gaps is essential to move muscle health from a research construct to a core component of routine clinical care and public health strategy.

Keywords:  clinical populations; exercise; functional outcomes; muscle quality; muscle strength; precision medicine; sarcopenia; ultrasound imaging

DOI:  https://doi.org/10.3389/fresc.2026.1874273