bims-moremu 2026-08-23 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–08–23
34 papers selected by
Anna Vainshtein, Craft Science Inc.

The hallmarks of skeletal muscle health.
Analytical approaches to account for muscle size when evaluating strength.
The metabokine β-aminoisobutyric acid mediates exercise performance and skeletal muscle adaptation through a PGC1α-BAIBA-PPARδ axis.
Integrative transcriptomic and experimental analyses prioritize TPT1 as a PANoptosis-associated candidate molecular marker in sarcopenia.
Studying the Super-Relaxed (SRX) state in cardiac and skeletal muscle: a protocol-based perspective from fibers to fibrils.
Targeting TGF-β to Attenuate Ischemia-Reperfusion Associated Muscle Fibrosis and Enhance Regeneration: A Preclinical Study.
Four new Duchenne muscular dystrophy mouse models with clinically relevant exon deletions in the human DMD gene.
Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.
When muscles matter in SORD neuropathy.
From NAD+ metabolism to skeletal muscle function: The emerging role of ADP-ribosylation.
Mitochondrial Mechanisms of Resistance Exercise in COPD-Related Skeletal Muscle Dysfunction: A Narrative Review.
Skeletal muscle decorin, apelin and TRIM72 gene expression in relation to insulin sensitivity.
Interpreting skeletal muscle adaptations to excessive training: The importance of defining the physiological state.
Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.
Advanced iPSC-based modelling of LMNA-related congenital muscular dystrophy enables development of genetic therapies for muscle laminopathies.
Comparing the Independent Effects of Weight Loss or Exercise Training on Skeletal Muscle Lipid Localization and Insulin Sensitivity in Humans.
Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.
Autophagic responses to vigorous endurance exercise in men vary by training status but are similar in PBMCs and skeletal muscle: A pilot study.
The Regulation of CCN1 Contributes to Skeletal Muscle Wasting in Chronic Kidney Disease.
Postnatal Pax7-expressing limb cells are multipotent and generate non-myogenic lineages that persist into adulthood.
LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.
Effects of low-dose γ-radiation on skeletal muscle stem cells.
Skeletal Muscle Function in Type 1 Diabetes: A Complementary Outcome for Clinical Care and Research.
Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.
miR-15a-3p promotes excessive autophagy and drives skeletal muscle atrophy in sepsis.
Developmental expression of the skeletal muscle determination gene, MyoD , is regulated by novel enhancer elements that interact with the core enhancer and distal regulatory region.
Integrated SDH, COX histochemistry, and MHC fibre typing in skeletal muscles: Methods and interpretation.
CRISPR/dCas9-mediated tuning of DMPK transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy.
Sciatic denervation differentially remodels skeletal muscle and deep fascia in the lower limb of male mice.
TDP-43 sustains satellite cells to maintain and regenerate skeletal muscle.
Shockwave-Induced Myoblast Exosome-Like Vesicles: Emerging Drivers of Muscle Regeneration.
Loss of LCN2 Function Ameliorates Glucocorticoid-Induced Muscle Atrophy via Remodeling the Extracellular Matrix.
Protocol for manipulating mRNA splicing via vivo-morpholino in early-activating muscle stem cells.
IL-6 signaling orchestrates proteolytic hubs MuRF1 and Atrogin-1 in NSCLC induced sarcopenia.

Nat Metab. 2026 Aug 20.

The hallmarks of skeletal muscle health.

Anna Vainshtein, Bert Blaauw, Katrien De Bock, Pura Munoz-Canoves, Eric N Olson, Coen A C Ottenheijm, Erik A Richter, Jorge L Ruas, Laurent Schaffer, Bruce Spiegelman, Marco Sandri.

Skeletal muscle is a central determinant of organismal health. Preserving muscle quality is therefore critical for preventing disease and sustaining quality of life across the lifespan. Despite its central role, the field lacks a unifying framework that defines the core properties of skeletal muscle health. Here, we propose a conceptual framework for muscle homeostasis built around seven interconnected hallmarks-metabolism and bioenergetics, proteostasis, genomics, excitability, structure, regeneration and cross-talk-that collectively govern muscle integrity, adaptability and resilience. Each hallmark is mechanistically grounded, quantifiable and potentially modifiable. This framework provides a unifying blueprint for the next generation of precision diagnostics and targeted therapies for preserving skeletal muscle health.

DOI: https://doi.org/10.1038/s42255-026-01595-9
Eur J Appl Physiol. 2026 Aug 17.

Analytical approaches to account for muscle size when evaluating strength.

Matthew A Chatlaong, John P Bentley, Kealey J Wohlgemuth, Scott J Dankel, Jeremy P Loenneke, Matthew B Jessee.

  Skeletal muscle strength is multifactorial. Although associated, skeletal muscle size and strength often change disproportionately following resistance training with different loading paradigms. Examining strength relative to muscle size has been used to evaluate the potential contribution of muscle growth or other factors (e.g., neural or intramuscular adaptations) that occur with strength changes. Moreover, as muscle size could explain differing strength between individuals, comparisons of strength per unit of muscle size are sometimes used to account for differences in strength related to size. Several analytical approaches can be used to account for or hold muscle size fixed when evaluating strength. Based on prior work in sports medicine and other fields, we explored the use of ratio normalization and multiple regression techniques. Data from NHANES (1999-2002) and a previous investigation from our group were used in analysis demonstrations. In synthesizing and applying recommendations from previous work, we highlight some nuances and complexities with ratio normalization that may not be readily apparent without testing assumptions.

Keywords:  Hypertrophy; Muscle quality; Normalization; Resistance training; Specific force; Specific tension

DOI:  https://doi.org/10.1007/s00421-026-06376-6
Nat Commun. 2026 Aug 18. pii: 8090. [Epub ahead of print]17(1):

The metabokine β-aminoisobutyric acid mediates exercise performance and skeletal muscle adaptation through a PGC1α-BAIBA-PPARδ axis.

Helene N Daou, Nicole T Watt, Shaimaa A Gad, Amanda Dv MacCannell, Aysha Ali, Chew Cheng, Raquel L Fernando, T Simon Futers, Sumeet A Khetarpal, Harrison Gallagher, Luis D Chinait, Anselmo S Moriscot, Pim Knuiman, Koen Manusama, Marco Mensink, Irvin Teh, Jurgen E Schneider, Richard Cubbon, Guy S Taylor, Daniel J West, David J Beech, T Scott Bowen, Lee D Roberts.

Exercise orchestrates an interorgan communication network, in which skeletal muscle releases signaling molecules known as myokines that contribute to exercise training-induced adaptations. We identified the muscle-derived metabolite beta-aminoisobutyric acid (BAIBA) as a regulator of adipose and hepatic metabolic responses to exercise. Here, we demonstrate that BAIBA regulates muscle metabolism, morphology and function via peroxisome proliferator-activated receptor delta (PPARδ) to determine exercise performance in mice. BAIBA mitigates muscle dysfunction in a mouse model of diabetes. Physiologically, BAIBA exists as D- and L- enantiomers. We identify L-BAIBA as the primary mediator of muscular effects. Knockdown of L-BAIBA's biosynthetic enzyme, 4-aminobutyrate aminotransferase, in mouse hindlimb muscle impairs exercise-induced adaptations and performance gains. L-BAIBA regulates human myotube fibertype and differentiation markers through Mas-related G-protein coupled receptor D. In humans, plasma L-BAIBA correlates with aerobic fitness and increases with endurance exercise training. BAIBA acts through the PGC1α-BAIBA-PPARδ axis to facilitate muscle adaptation and exercise performance.

DOI: https://doi.org/10.1038/s41467-026-76307-8
Front Cell Dev Biol. 2026 ;14 1912393

Integrative transcriptomic and experimental analyses prioritize TPT1 as a PANoptosis-associated candidate molecular marker in sarcopenia.

Shijie Dong, Min Wang, Chen Liang, Peiyu Xu, Ziyi Ye, Jingqing Yao, Zhongquan Tang, Ting Ou, Xiaomin Zhao, Xinyu Dai, Yuntao Li, Guozhong Ji.

   Background: Sarcopenia lacks sensitive molecular markers for early detection, and its relationship with integrated inflammatory cell-death programs remains unclear. PANoptosis integrates apoptotic, pyroptotic, and necroptotic signaling and therefore provides a plausible framework for investigating inflammatory-stress remodeling in aging skeletal muscle.
Methods: We integrated four bulk-transcriptomic datasets from the Gene Expression Omnibus into a training cohort (66 controls; 37 sarcopenia) and used GSE111016 as an external validation cohort (20 controls; 20 sarcopenia). We intersected differentially expressed genes with a curated PANoptosis-associated gene set and then performed enrichment analysis; least absolute shrinkage and selection operator (LASSO), random forest and extreme gradient boosting (XGBoost) feature selection; nomogram and receiver operating characteristic (ROC) analyses; CIBERSORT immune-cell deconvolution; and single-nucleus RNA sequencing (snRNA-seq) reanalysis. We assessed tumor protein, translationally controlled 1 (TPT1) expression in D-galactose-treated mouse and C2C12 models.
Results: Among 608 differentially expressed genes, 47 overlapped with the curated PANoptosis-associated gene set. These genes were enriched in apoptotic signaling; cytokine, nuclear factor kappa B (NF-κB), tumor necrosis factor (TNF), and nucleotide-binding oligomerization domain (NOD)-like receptor pathways; regulated necrosis; extracellular-matrix remodeling; and impaired oxidative phosphorylation. Three machine-learning algorithms converged on neurotrophic receptor tyrosine kinase 1 (NTRK1), TPT1, and TNF receptor-associated protein 1 (TRAP1). TPT1 showed the strongest single-gene discrimination, with areas under the ROC curve of 0.819 (95% confidence interval [CI], 0.737-0.900) in the training cohort and 0.753 (95% CI, 0.598-0.907) in the external cohort. Immune-cell deconvolution linked the candidate genes to estimated mast-cell, plasma-cell, cluster of differentiation 8-positive (CD8+) T-cell, and macrophage proportions. Single-nucleus analysis of 97,154 nuclei from 17 donors showed broad TPT1 expression across myonuclear, satellite-cell, stromal, endothelial, and immune compartments, with lower expression in older muscle. Network and gene set variation analyses associated lower TPT1 expression with inflammatory, oxidative-stress, cell-death, and stress-adaptive pathways. In D-galactose-treated mice and C2C12 myotubes, muscle-wasting or senescence-like changes coincided with lower TPT1 protein abundance.
Conclusion: This study prioritizes TPT1 as a candidate molecular marker associated with the bulk-transcriptomic sarcopenia phenotype. The aging-muscle and D-galactose analyses provide biological context but do not establish sarcopenia specificity or causality. Prospective clinical validation and functional perturbation studies are required.

Keywords:  PANoptosis; TPT1; candidate molecular marker; machine learning; sarcopenia; single-nucleus RNA sequencing; skeletal-muscle aging

DOI:  https://doi.org/10.3389/fcell.2026.1912393
Biophys Rev. 2026 Jun;18(3): 601-611

Studying the Super-Relaxed (SRX) state in cardiac and skeletal muscle: a protocol-based perspective from fibers to fibrils.

Nariman Naber, Clyde Wilson, Cristobal Dos Remedios, Filip Braet, Amy Li.

  The super-relaxed state (SRX) of myosin plays a key role in maintaining muscle efficiency and regulating metabolic rate. In this state, myosin heads exhibit significantly reduced ATPase activity, resulting in lower energy consumption when muscles are at rest. SRX is in dynamic equilibrium with the more disordered relaxed state (DRX), allowing shifts between these states to profoundly influence muscle function and energy expenditure. This deeper understanding of SRX, and its ability to be modulated has important implications for treating cardiac and skeletal muscle disorders where contractile function is impaired. Here, we present a detailed experimental protocol for studying SRX in cardiomyocytes and skeletal muscle fibers developed by Roger Cooke for different species, and adapted for our understanding of SRX biophysics. The protocol encompasses muscle dissection, data analysis, key reagents, auxiliary lab tools, notes, and tips that help with reproducibility and troubleshooting challenges. We hope this contribution will serve as a resource and inspiration for the next generation of scientists to explore muscle function and apply their findings toward improving human health.

Keywords:  Actomyosin; Cardiac myosin; Fluorescence microscopy; Mant-ATP; Muscle fibers; SRX; Skeletal myosin

DOI:  https://doi.org/10.1007/s12551-025-01382-y
FASEB J. 2026 Aug 31. 40(16): e72197

Targeting TGF-β to Attenuate Ischemia-Reperfusion Associated Muscle Fibrosis and Enhance Regeneration: A Preclinical Study.

Hongru Ma, Zhenjia Zhong, Heng Zheng, Yutong Dai, Kaiyang Wang, Benlong Shi, Xu Sun, Zhen Liu, Yong Qiu, Zezhang Zhu, Fengfeng Li.

  Ischemia-reperfusion (IR) injury induces a pro-inflammatory cascade that disrupts inflammation resolution and exacerbates skeletal muscle fibrosis, leading to impaired regeneration through fibrosis and compromised myofiber regeneration. This study aimed to: (1) Demonstrate IR-induced dysregulation of muscle regeneration following acute injury; (2) Elucidating how TGF-β1 signaling within the FAP-associated inflammatory niche mediates fibrosis and impairs myofiber repair; and (3) Evaluating anti-TGF-β neutralization as a mechanism-based strategy to preserve regenerative capacity. Male C57BL6 mice (8 weeks) received CTX injections into the tibialis anterior (TA) to induce skeletal muscle injury. Transient clamping of femoral artery and vein was induced at 3 days post-injury to induce IR. Mice were stratified into CTX group and CTX-IR group depending on the induction of IR injury. TGF-β neutralizing antibody (TGF-β NAb) was administered in vivo to evaluate therapeutic potential. HE and Sirius red staining was used to assess cross-sectional area (CSA) of myofibers and percentage of fibrotic tissue. Western blotting was used to assess the expression of Collagen I, Collagen III and TGF-β. Flow cytometry was used to assess the number of fibro-adipogenic progenitors (FAPs). Collagen I and CD90 were assessed using immunostaining of TA cryosections and FAPs isolated from muscle tissues. The result shows that CTX-IR mice showed smaller myofiber cross-sectional area and more fibrotic tissue than CTX mice. Western blots revealed higher levels of Collagen I, Collagen III and TGF-β1 in CTX-IR samples. TGF-β1 stimulated the expression of collagen I in FAPs. TGF-β NAb application ameliorated the fibrosis of skeletal muscle and improved myofiber regeneration after IR. In conclusion, IR impairs muscle regeneration through TGF-β-associated FAP activation and collagen deposition. Inhibition of TGF-β attenuates fibrosis and increases the CSA of myofibers, demonstrating it as a potential target for promoting structural recovery and regenerative architecture in co-existing muscle injuries during orthopedic trauma.

Keywords:  fibrosis; ischemia–reperfusion; regeneration; skeletal muscle injury

DOI:  https://doi.org/10.1096/fj.202601893R
Dis Model Mech. 2026 Aug 21. pii: dmm.052875. [Epub ahead of print]

Four new Duchenne muscular dystrophy mouse models with clinically relevant exon deletions in the human DMD gene.

Maaike van Putten, Margot Linssen, Christa Tanganyika de Winter, Conny M Brouwers, Jill W C Claassens, Nisha Verwey, Max Walsh, Tiberiu Loredan Stan, Annemieke Aartsma-Rus, Peter Hohenstein.

  Mutation specific therapeutic approaches, like exon skipping or gene-editing, hold promise for the treatment of Duchenne muscular dystrophy (DMD). Translatability of preclinical studies investigating these approaches could greatly be improved through the use of humanized mouse models, as these allow preclinical testing of human specific sequences. We developed four novel humanized DMD mouse models with either a deletion of exon 44, 45, 51 or 53 in the human DMD gene, in a mouse dystrophin negative background (mdx mouse; exon 23 nonsense mutation). Our optimized prescreening pipeline allowed us to do so very efficiently with the CRISPR-Cas9 technology. We confirmed either complete lack of dystrophin, or expression of trace levels, which led to development of muscle pathology consisting of muscle fiber de-, and regeneration, inflammation and fibrosis in young adult mice. Intramuscular treatment with vivo-morpholinos targeting a flanking exon induced exon skipping in the DMD strains, which restored the disrupted open reading frame and subsequently dystrophin expression. This validates these models as valuable tools for preclinical studies investigating human sequence specific therapeutic approaches for DMD.

Keywords:  Antisense oligonucleaotide; Duchenne muscular dystrophy; Exon skipping; Genome editing; Mouse model

DOI:  https://doi.org/10.1242/dmm.052875
Mol Ther. 2026 Aug 19. pii: S1525-0016(26)00709-4. [Epub ahead of print]

Antisense oligonucleotides against Il6ra ameliorate cancer cachexia in mice.

Yuanyuan Wang, Qingtao Sun, Wenqiang Zheng, Lijie Han, Qian Zhang, Adrian R Krainer, Bo Li.

Mounting evidence indicates that interleukin-6 (IL-6) plays an essential role in the development of cancer cachexia. Particularly, recent work showed that IL-6 drives cancer cachexia through neurons in the area postrema of the brainstem. However, there are currently no approved drugs for treating cancer cachexia. Here we developed a splice-switching antisense oligonucleotide (ASO)-based therapy for treating cancer cachexia by reducing IL-6 receptor (IL-6R) expression in the brain. In two mouse models of cancer cachexia, a single dose of ASOs, administered by intracerebroventricular injection after cancer onset, reduces IL-6R levels in the brainstem and ameliorates cachectic symptoms. It also extends survival in one of the models. In parallel, the ASO treatment reduces cancer-associated transcriptomic activation of inflammatory pathways in both the brainstem and skeletal muscle. We also developed ASOs that suppress human IL-6R expression, paving the road for clinical studies. Our study thus provides a new approach for treating cancer cachexia.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.028
J Neuropathol Exp Neurol. 2026 Aug 19. pii: nlag057. [Epub ahead of print]

When muscles matter in SORD neuropathy.

Heike Kölbel, Andreas Hentschel, Corinna Preuße, May Tiet, Maike F Dohrn, David Muhmann, Jelle van den Ameele, Lei Chen, Ulrike Schara-Schmidt, Joachim Weis, Rita Horvath, Alexander Mensch, Andreas Roos.

  Biallelic pathogenic variants in SORD (Sorbitoldehydrongenase gene), encoding sorbitol dehydrogenase, are a common cause of autosomal recessive axonal Charcot-Marie-Tooth disease type 2 (CMT2). Recent evidence suggests direct involvement of skeletal muscle in addition to peripheral nerve degeneration. We investigated muscle biopsies from 4 genetically confirmed CMT-SORD patients using an integrative approach. Histological evaluation revealed features of chronic denervation with grouped fiber atrophy, fiber-type grouping and central nuclei, ie, non-specific neurogenic muscle atrophy. Ultrastructural studies demonstrated mitochondrial abnormalities and expansion of the sarcoplasmic reticulum (SR). Proteomic profiling identified 220 significantly dysregulated proteins in CMT-SORD muscle, including alterations in mitochondrial complex I components, redox enzymes, and metabolic regulators distinct from changes observed in other rare recessive CMTs. Quantitative PCR validated increased levels of NNMT, POSTN, TACO1, as well as complement and immunomodulatory factors, suggesting mitochondrial stress, compensatory metabolic activation and tissue remodeling. Despite mitochondrial vulnerability, serum studies indicated that GDF-15 and FGF-21 did not appear to be suitable biomarkers for CMT-SORD. These findings demonstrate that SORD deficiency induces molecular and structural changes in skeletal muscle that extend beyond denervation, implicating impaired sorbitol metabolism, oxidative stress, and mitochondrial dysfunction as intrinsic myopathic features of SORD-related CMT2. They indicate the need for therapeutic strategies targeting both neuronal and muscular compartments.

Keywords:  SORD neuropathy; denervation-induced atrophy; mitochondrial stress; polyol pathway; skeletal muscle metabolism

DOI:  https://doi.org/10.1093/jnen/nlag057
Cell Rep. 2026 Aug 17. pii: S2211-1247(26)00944-7. [Epub ahead of print]45(8): 117866

From NAD+ metabolism to skeletal muscle function: The emerging role of ADP-ribosylation.

Caio Y Yonamine, Ever Espino-Gonzalez, Sheila P Aguilar Lozano, Jonas T Treebak.

  Nicotinamide adenine dinucleotide (NAD+) is a metabolic coenzyme and substrate for enzymes catalyzing post-translational modifications such as ADP-ribosylation. This reversible modification, mediated by ADP-ribosyltransferases and hydrolases, regulates cellular processes. Although studied in cancer and DNA repair, its roles in skeletal muscle remain less defined. Emerging evidence shows ADP-ribosylation modifies structural proteins like actin and desmin, affecting filament organization, contractility, and calcium signaling. It contributes to muscle regeneration by regulating satellite cell activation and differentiation, with ARTC1 implicated in myogenesis. Additionally, ADP-ribosylation intersects with insulin signaling, glycolysis, and mitochondrial function, linking it to systemic metabolism and exercise performance. Roles in extracellular matrix interactions suggest involvement in force transmission and remodeling. Advances in proteomics enable identification of ADP-ribosylation targets, offering insight into functional impact. This review aims to compile studies on ADP-ribosylation in skeletal muscle to enhance our comprehension of these mechanisms, potentially revealing new therapeutic opportunities for metabolic and skeletal muscle diseases.

Keywords:  ADP-ribosylation; CP: metabolism; CP: molecular biology; extracellular matrix; insulin action; mitochondrial function; muscle regeneration; skeletal muscle

DOI:  https://doi.org/10.1016/j.celrep.2026.117866
Int J Chron Obstruct Pulmon Dis. 2026 ;21 610640

Mitochondrial Mechanisms of Resistance Exercise in COPD-Related Skeletal Muscle Dysfunction: A Narrative Review.

Yifan Lv, Qian Gao, Xiaoyu Han, Weibing Wu.

  Chronic obstructive pulmonary disease (COPD) is a heterogeneous pulmonary disorder characterized by airway or alveolar abnormalities. Beyond pulmonary impairment, COPD frequently leads to skeletal muscle dysfunction, manifesting as muscle atrophy, myofibrillar type switching, and reduced muscle strength and endurance, which severely impair exercise capacity and quality of life. Mitochondrial dysfunction, including reduced mitochondrial density, altered respiratory function, and increased oxidative stress, is recognized as a key contributor to skeletal muscle impairment in COPD. Resistance exercise (RE), an effective exercise therapy, has been shown to improve lower-limb muscle function and quality in COPD patients, and it appears feasible even for those with severe airflow obstruction and significant dyspnea. Mechanistically, RE may enhance mitochondrial respiratory capacity and promote mitochondrial biogenesis, and might also counteract mitochondrial dysfunction induced by secondhand smoke. In this narrative review, we analyze the effects of RE on skeletal muscle dysfunction in COPD and summarize the underlying mitochondrial mechanisms.

Keywords:  chronic obstructive lung disease; mitochondrion; resistance training; skeletal muscles

DOI:  https://doi.org/10.2147/COPD.S610640
Exp Clin Endocrinol Diabetes. 2026 Aug 20.

Skeletal muscle decorin, apelin and TRIM72 gene expression in relation to insulin sensitivity.

Dominika Szutko, Marek Straczkowski.

INTRODUCTION: Skeletal muscle is an essential tissue for insulin-stimulated glucose uptake. Myokines are proteins, peptides, and other metabolites that are released by muscles and exhibit metabolic functions. Decorin, apelin and TRIM72 are myokines with connection to insulin action. The aim of this paper was to study the expression of these selected myokines in skeletal muscle in relation to insulin sensitivity in individuals without overt metabolic disturbances.
METHODS: Thirty healthy young male volunteers with normal glucose tolerance, 14 normal-weight, 8 with overweight and 8 with obesity, were included in the study population. The vastus lateralis muscle biopsies were performed. Insulin sensitivity (IS) was tested with hyperinsulinemic-euglycemic clamp. Muscle tissue mRNA expresion was assessed via quantitative PCR.
RESULTS: Group consisting of individuals with obesity had lower insulin sensitivity compared to those with normal weight and overweight. Apelin expression was significantly higher in the obese group compared to the normal-weight and overweight groups. All myokines' expressions correlated with insulin sensitivity, decorin - positively, apelin and TRIM72 - negatively. Only apelin was correlated positively with BMI. Apelin was correlated with insulin sensitivity independently of BMI, decorin was also correlated with insulin sensitivity independently of BMI.
CONCLUSION: Apelin, decorin and TRIM72 are correlated with insulin sensitivity and decorin and apelin have BMI-independent associations. This suggests that these molecules can be linked to metabolic health.

DOI: https://doi.org/10.1055/a-2937-4910
J Physiol. 2026 Aug 17.

Interpreting skeletal muscle adaptations to excessive training: The importance of defining the physiological state.

Matheus da Silveira Costa, Gabriel Albanese Kafouri, Henrique Izaias Marcelo.



Keywords:  endurance athletes; insulin resistance; mitochondria; overtraining; proteomics

DOI:  https://doi.org/10.1113/JP291955
Aging Cell. 2026 Sep;25(9): e70678

Aged Mitochondrial DNA Is Associated With Aberrant Acute Exercise-Induced Redox Responses in Human Skeletal Muscle.

Bradley A Ruple, Nicholas A Carlini, Jason S Kofoed, Helya Rostamkhani, Brady E Hanson, Jesse C Craig, Shelby C Osburn, Allison M Manuel, Paul A Stewart, Jonathan Wanagat, Ryan M Broxterman, Joel D Trinity.

  Redox imbalances and mitochondrial dysfunction are key contributors to age-related declines in skeletal muscle and may contribute to impaired exercise responsiveness. Here, we investigated the influence of aging on skeletal muscle redox at rest and in response to acute exercise, examining how mitochondrial quality and quantity relate to skeletal muscle redox status. Skeletal muscle biopsies were obtained from 12 young (22 ± 4 years) and 10 older adults (66 ± 7 years) before and immediately after 60-min of high-intensity knee-extension exercise. We assessed mitochondrial respiration, mitochondrial DNA (mtDNA) copy number and deletion mutation frequency at baseline, while skeletal muscle redox proteomics was performed on pre- and post-exercise biopsies in a subset of participants. Mitochondrial respiration was preserved with age (max respiration, p = 0.123). However, the older adults had a lower mtDNA copy number (p = 0.046) and higher mtDNA deletion frequency (p = 0.001), with widespread remodeling of the skeletal muscle redox proteome, including altered thiol occupancy of proteins involved in metabolism, immune function, and extracellular matrix organization. In response to exercise, young skeletal muscle exhibited predominantly reversible peptide reductions, whereas preferential oxidation of mitochondrial antioxidant proteins, including PRDX3, occurred in older muscle. Both mtDNA deletion frequency and mitochondrial respiration were strongly associated with exercise-induced redox modifications in mitochondrial proteins. These findings suggest that aging alters both the regulation and resolution of exercise-induced redox signaling, with mitochondrial genomic instability and respiration shaping redox responsiveness.

Keywords:  aging; exercise; mitochondrial DNA; oxidative stress; redox proteomics

DOI:  https://doi.org/10.1111/acel.70678
Mol Ther. 2026 Aug 19. pii: S1525-0016(26)00707-0. [Epub ahead of print]

Advanced iPSC-based modelling of LMNA-related congenital muscular dystrophy enables development of genetic therapies for muscle laminopathies.

Daniel Moore, Heather Steele-Stallard, Luca Pinton, Valentina Maria Lionello, Lucia Rossi, Artadokht Aghaeipour, Vanessa Todorow, Salma Jalal, Cherry Tsz Yan Wong, Angela Clara-Hwang, SungWoo Choi, Gisèle Bonne, Peter S Zammit, Francesco Saverio Tedesco.

LMNArelated congenital muscular dystrophy (L-CMD) is one of the most severe laminopathies, which are incurable diseases primarily caused by pathogenic LMNA variants. LMNA encodes Lamin A/C: key components of the nuclear lamina, which provides structural stability to the nucleus, whilst regulating chromatin organisation and gene expression. L-CMD research is hindered by lack of humanised, tissue-specific models that accurately recapitulate disease phenotypes. We previously reported nuclear shape abnormalities and Lamin mislocalisation in LMNA-mutant induced pluripotent stem cell (iPSC)-derived skeletal muscle cells. Here, we expand the selection of L-CMD iPSCs, validate disease-associated readouts using a transgene-free differentiation protocol and assess gene editing strategies using 2D and 3D cultures. Results showed no overt defects in developmental myogenesis but recapitulated pathological nuclear shape abnormalities in monolayer cultures and engineered muscles, nuclear envelope protein mislocalisation and transcriptomic alterations across multiple pathogenic LMNA variants. We then used our platform to assess outcomes of LMNA gene editing. CRISPR-based exon-removal generated sRNA and protein Lamin A/C species, without normalisation of nuclear morphology or transcriptomic profile. Conversely, precise editing of the same variant corrected nuclear morphometrics, alongside normalisation of the pro-inflammatory transcriptomic signature, providing an advanced, humanised platform for translational research and precision medicine in laminopathies.

DOI: https://doi.org/10.1016/j.ymthe.2026.08.026
Diabetes. 2026 Aug 18. pii: db260239. [Epub ahead of print]

Comparing the Independent Effects of Weight Loss or Exercise Training on Skeletal Muscle Lipid Localization and Insulin Sensitivity in Humans.

Simona Zarini, Karin Zemski Berry, Amanda Garfield, Emily Macias, Purevsuren Jambal, Sophia Bowen, Melanie G Cree, Janet K Snell-Bergeon, Chris Johnson, P Darrell Neufer, Ian Tamburini, Marcus Seldin, Bryan C Bergman.

ARTICLE HIGHLIGHTS: Subcellular accumulation of lipids is linked to insulin resistance, but changes in localization from weight loss or exercise training have not been thoroughly explored. We evaluated the independent effects of two insulin-sensitizing interventions, weight loss and exercise training, on lipid subcellular distribution in fractionated skeletal muscle, muscle mitochondrial function, and gene expression. Exercise training increased cytosolic storage of diacylglycerols and sphingolipids, and weight loss increased cytosolic sphingosine and decreased mitochondrial/endoplasmic reticulum triacylglycerol and diacylglycerol accumulation. Exercise training prevented the negative effects of mitochondrial lipids on mitochondrial function. Changes in specific subcellular lipid storage help explain muscle insulin sensitization following lifestyle interventions.

DOI: https://doi.org/10.2337/db26-0239
JCI Insight. 2026 Aug 20. pii: e203167. [Epub ahead of print]

Histopathology and spatial transcriptomics jointly map myofiber-specific pathological programs in mTORC1-driven myopathy.

Jer-En Hsu, Qingyang Zhao, Weiqiu Cheng, Hyun Min Kang, Susan V Brooks, Myungjin Kim, Jun Hee Lee.

  Skeletal muscle is composed of heterogeneous myofiber types and non-myocyte populations. Myopathies occur in many diseases, but mechanisms driving these pathologies remain largely unknown, partly because conventional approaches cannot link histopathological features to molecular states at single-fiber resolution. To address this challenge, we brought histopathology and spatial transcriptomics together by applying high-resolution Seq-Scope technology to a mouse model of mTORC1 hyperactivation. Cross-sections from extensor digitorum longus (EDL) and soleus (SOL), two muscles with distinct fiber-type compositions, were profiled to determine how transcriptome changes are linked to histopathological outcomes. mTORC1 hyperactivation elicited distinct, fiber-type-dependent pathological programs. Type I and IIa fibers were largely resistant to mTORC1-induced pathology, exhibiting relatively limited morphological alterations. In contrast, type IIx fibers diverged into opposing fates: in SOL, they underwent abnormal enlargement associated with sustained growth signaling, cytoskeletal remodeling, and impaired proteostasis; in EDL, they developed basophilia associated with increased RNA content and lipid, oxidative, and nucleotide metabolism-related signatures. Within EDL, type IIb fibers displayed heterogeneity with discrete transcriptional states. Non-myocytic populations, including macrophages and fibroblasts, accumulated preferentially in SOL, forming a fibrotic microenvironment associated with inflammation, remodeling, and hypertrophy. These findings provide a link between histopathological phenotypes and molecular states at single-fiber resolution.

Keywords:  Autophagy; Cell biology; Muscle biology; Skeletal muscle; Transcriptomics

DOI:  https://doi.org/10.1172/jci.insight.203167
Physiol Rep. 2026 Aug;14(16): e71064

Autophagic responses to vigorous endurance exercise in men vary by training status but are similar in PBMCs and skeletal muscle: A pilot study.

Jonathan W Specht, Jeremy B Ducharme, Alyssa R Bailly, Michael R Deyhle.

  Vigorous exercise triggers signaling cascades that activate autophagy markers like the degradation of sequestosome 1 (p62) and accumulation of Light Chain 3 II (LC3II). Limited human data exist on autophagic responses across different local and systemic tissues and how training status affects these relationships. This study investigates the vigorous exercise-induced changes in p62 and LC3II expression in peripheral blood mononuclear cells (PBMCs) and skeletal muscle between endurance-trained and untrained men. Twelve men (endurance-trained n = 7, untrained n = 5) completed 60 min of cycling at their second ventilatory threshold. Skeletal muscle biopsy samples and PBMCs were collected pre- and 3-h post-exercise and analyzed for p62 and LC3II protein expression. We found significant interaction effects of time and training status for p62 (p < 0.001) and LC3II (p = 0.002). In untrained men, p62 decreased in PBMCs (FC = 0.50 ± 0.14; p < 0.001) and skeletal muscle (FC = 0.57 ± 0.21; p < 0.001), while LC3II increased in both tissues (FC = 1.74 ± 0.79; p = 0.019 for PBMCs; FC = 1.69 ± 0.47; p = 0.033 for skeletal muscle). No changes were observed in endurance-trained men (all p > 0.05). These results suggest that a bout of vigorous endurance exercise increased autophagy-related markers in both skeletal muscle and PBMCs in the untrained men only, suggesting a diminished autophagic response in the trained men.

Keywords:  LC3II; autophagy; exercise; p62; trained; untrained

DOI:  https://doi.org/10.14814/phy2.71064
Am J Nephrol. 2026 Aug 21. 1-24

The Regulation of CCN1 Contributes to Skeletal Muscle Wasting in Chronic Kidney Disease.

Yidan Zuo, Ruyi Chen, Diyan Xu, Wenli Zhang, Shengnan Luo, Feifei Hu, Zhen Su.

BACKGROUND: Sarcopenia is a prevalent complication of chronic kidney disease (CKD), yet reliable biomarkers remain limited. CCN1, a matricellular protein involved in cellular senescence, has been implicated in muscle wasting, but its role in CKD-associated muscle strength decline is incompletely understood.
METHODS: Serum CCN1 levels were measured by ELISA in 40 stage 3-5 CKD patients and 27 age-matched controls and correlated with handgrip strength (HGS). A 5/6 nephrectomy (NX) mouse model was established to evaluate muscle strength and senescence markers. C2C12 myotubes were treated with recombinant CCN1 or Wnt3a, with or without integrin β1 inhibitor or DKK-1. Senescence-associated β-galactosidase staining, qPCR, Western blot, co immunoprecipitation, and immunofluorescence were performed to explore mechanisms.
RESULTS: GEO database analysis and our clinical data showed significantly elevated serum CCN1 levels in CKD patients versus controls. A trend toward a negative association was observed between serum CCN1 levels and HGS. In NX mice, reduced grip strength was associated with increased skeletal muscle CCN1 expression, upregulation of p53/p21/p16, and elevated Fbx32/Trim63. Co immunoprecipitation revealed physical interaction between CCN1 and integrin α6/β1. Blockade of integrin β1 attenuated CCN1 induced myotube senescence. Wnt3a dose dependently upregulated CCN1 and senescence markers, while DKK-1 partially reversed these effects. Serum from CKD mice with muscle wasting directly induced senescence in C2C12 myotubes, an effect also mitigated by DKK-1.
CONCLUSIONS: CCN1 promotes muscle senescence through integrin α6/β1 signaling, with Wnt3a as an upstream regulator. CCN1 may serve as a potential biomarker for CKD related muscle wasting, and targeting the Wnt3a CCN1 integrin axis could represent a novel therapeutic strategy.

DOI: https://doi.org/10.1159/000553578
Dev Cell. 2026 Aug 21. pii: S1534-5807(26)00288-1. [Epub ahead of print]

Postnatal Pax7-expressing limb cells are multipotent and generate non-myogenic lineages that persist into adulthood.

Stamatia Gioftsidi, Takuto Hayashi, Sidy Fall, Sabrina Jagot, Matthieu Dos Santos, Fabien Le Grand, Frederic Relaix, Philippos Mourikis.

  Organs comprise diverse cell types originating from shared or distinct lineages. During embryogenesis, mesodermal Pax7+ progenitors give rise to skeletal muscle as well as non-muscle lineages like dermis and adipocytes. Here, we asked whether Pax7+ cells retain multipotency during early postnatal limb muscle growth. Lineage tracing in neonatal mice revealed unexpected early postnatal plasticity, yielding multiple non-myogenic lineages, including a previously unrecognized subpopulation of fibro-adipogenic progenitors, termed Pax7FAPs. Using mouse models, we demonstrated that Notch signaling primes neonatal Pax7+ cells toward a fibrogenic molecular identity, biasing their trajectory away from myogenesis. Long-term tracing confirmed that neonatally generated Pax7FAPs persist into adulthood. Furthermore, adult muscle injury triggered de novo generation of Pax7FAPs, which exhibited higher proliferative capacity than resident stromal cells. This postnatal Pax7+ multipotency reveals an additional cellular contribution to muscle development and regeneration.

Keywords:  FAPs; Notch signaling; lineage tracing; multipotency; muscle; plasticity; postnatal development; progenitors; stem cells

DOI:  https://doi.org/10.1016/j.devcel.2026.07.019
Ann N Y Acad Sci. 2026 Aug;1562(1): e70364

LKB1 Dysregulation in Duchenne Muscular Dystrophy Models: Disease Specificity and Epigenetic Control by HDAC Inhibitors.

Brigida Boccanegra, Lisamaura Tulimiero, Raffaella Quarta, Elena Conte, Simonetta Andrea Licandro, Alessandra Decio, Roberta Lenti, Alberto Ladisa, Giorgia Dinoi, Gaia Carbone, Letizia Claudione, Giulia Maria Camerino, Sabata Pierno, Paola Mantuano, Ornella Cappellari, Gianluca Fossati, Christian Steinkühler, Annamaria De Luca.

  Efficient skeletal muscle contraction requires tight mechano-metabolic coupling, a process regulated by AMP-activated protein kinase (AMPK). Duchenne muscular dystrophy (DMD) is characterized by aberrant AMPK activation and disrupted metabolic signaling. This study investigates the expression and regulation of the LKB1-STRADα-MO25 heterotrimeric complex, the primary upstream activator of AMPK, in DMD models. We analyzed muscles from dystrophic mice (BL10 mdx and D2 mdx) and patient-derived cells and found significant downregulation of the LKB1 complex across all disease stages in the DMD models, a defect not observed in an amyotrophic lateral sclerosis model. Treatment with the broad-spectrum HDAC inhibitor vorinostat effectively restored LKB1 expression at both transcript and protein levels in D2 mdx mice. This restoration was mechanistically linked to downregulation of miR-451, miR-195, and miR-17, which function as post-transcriptional repressors of LKB1. Conversely, the selective HDAC1/2 inhibitor Rodin-A increased Lkb1 mRNA but failed to rescue protein levels or alter miRNA expression. Our data identify the axis LKB1-STRADα-MO25 as a critical regulatory node that is disrupted in DMD, but remains responsive to epigenetic modulation. These findings suggest that restoring LKB1 activity via HDAC inhibition or miRNA targeting may represent a therapeutic avenue to address dystrophic muscle dysfunction.

Keywords:  AMPK; Duchenne muscular dystrophy; animal models; epigenetic; histone deacetylases inhibitors; liver kinase B1; microRNAs

DOI:  https://doi.org/10.1111/nyas.70364
Int J Radiat Biol. 2026 Aug 19. 1-10

Effects of low-dose γ-radiation on skeletal muscle stem cells.

Soji Sebastian, Oluwaseun Olowonyo, Jais Kavumkal, Matthew Flegal, Tommy Alain, Dmitry Klokov.

  Introduction: Exposure to low dose ionizing radiation (LDIR) has been associated with aging related health effects. The aging related decline in the regenerative capacity of muscle stem cells in elderly individuals, as well as other myopathy conditions, represents a major health issue. Effects of LDIR exposures, such as those from routine medical CT scans on functional status of muscle stem cells, are not known.Methods: We investigated how a single acute 60Co γ-irradiation (10 and 100 mGy) affected myogenesis into mature muscle fibers in cultures of mouse C2C12 myoblasts and biopsy-derived human skeletal muscle stem cells.Results: We observed a substantial decrease in differentiation capacity in unirradiated control cells with age and time in culture; the loss of differentiation potential was partially restored in cultures exposed to LDIR at early passage. In C2C12 cells, LDIR exposure also resulted in lower frequencies of cells with anaphase bridges and micronuclei throughout the aging in vitro experiment, suggesting a suppressed genomic instability state. In human cells, mutational burden readouts assessed by the TruSight Oncology 500 NGS-based assay revealed no changes in LDIR-exposed cells vs. non-irradiated controls.Conclusion: Our results propose that exposure to single acute dose of LDIR lead to a partial reversal of an aging-related decline of the myogenic function in muscle myoblasts. In human cells, this effect was concurrent with the lack of accumulation of a mutational burden, while in mouse cells the results suggest improved genome integrity.

Keywords:  Low doses; aging; gamma-radiation; muscle stem cells; mutation; myoblasts

DOI:  https://doi.org/10.1080/09553002.2026.2699713
Diabetes Metab Res Rev. 2026 Sep;42(6): e70218

Skeletal Muscle Function in Type 1 Diabetes: A Complementary Outcome for Clinical Care and Research.

Antonio García-Hermoso, Jacinto Muñoz-Pardeza, Ignacio Hormazábal-Aguayo, Yasmin Ezzatvar.

DOI: https://doi.org/10.1002/dmrr.70218
IUBMB Life. 2026 Aug;78(8): e70127

Exercise as a Programmable Regulator of Mitophagy Sensitivity in Aging Muscle and Age-Related Disease.

Peng Ran, Lifang Yang.

  Aging is increasingly recognized as a systems-level process marked by progressive deterioration of mitochondrial performance in tissues with high energetic demand, placing skeletal muscle at the center of systemic metabolic and functional decline. Beyond its mechanical role, skeletal muscle acts as a regulatory hub for energy homeostasis, redox balance, and inter-organ signaling, functions that depend critically on effective mitochondrial quality control. Emerging evidence indicates that age-related mitochondrial dysfunction arises not only from impaired biogenesis but also from dysregulated mitophagy, the selective autophagic removal of damaged mitochondria. Mitophagy is now understood as a dynamic, context-sensitive process integrating metabolic state, mechanical loading, and cellular stress, rather than a binary response to severe mitochondrial damage. Exercise represents a uniquely potent, non-pharmacological modulator of this process. By transiently perturbing cellular energy balance, calcium flux, and redox signaling, physical activity activates coordinated mitophagic and biogenic programs that promote mitochondrial renewal without precipitating energetic collapse. In contrast to chronic pathological stressors, exercise induces pulsatile, recoverable mitochondrial challenges that recalibrate quality-control thresholds. Importantly, mitophagic responses to exercise are heterogeneous and nonlinear. Exercise modality, intensity, frequency, and temporal organization generate distinct mitochondrial signals, producing fiber-type-specific and age-dependent adaptations. In aging muscle, elevated activation thresholds, delayed clearance kinetics, and lysosomal constraints frequently blunt adaptive mitophagy, indicating remodeling rather than a simple suppression of quality-control logic. This review integrates molecular, physiological, and translational evidence to redefine exercise as a precision regulator of mitophagy in aging skeletal muscle. This review proposes that tailored exercise strategies targeting mitophagy may provide a scalable, non-pharmacological approach to preserve mitochondrial quality and functional resilience during aging.

Keywords:  aging; exercise; healthspan; mitochondrial quality control; mitophagy; skeletal muscle

DOI:  https://doi.org/10.1002/iub.70127
Shock. 2026 Aug 18.

miR-15a-3p promotes excessive autophagy and drives skeletal muscle atrophy in sepsis.

Ling-Ling Zhou, Shu-Li Zhang, Wei-Qing Xiao, Xiao-Yong Zhang, Xiao-Yan Zhu, Peng-Xiang Wang, Yu-Jian Liu.

  Approximately 50% of sepsis patients develop acute skeletal muscle atrophy and dysfunction. Autophagy plays an important role in skeletal muscle atrophy and dysfunction, and skeletal muscle autophagy is known to be regulated by multiple miRNAs. In this study, we found that miR-15a-3p was significantly upregulated in published Gene Expression Omnibus (GEO) datasets of septic patients and septic mouse skeletal muscle. Correlation analysis revealed that miR-15a-3p was associated with autophagy activation in septic patients and septic mouse skeletal muscle. Inhibition of miR-15a-3p attenuated excessive autophagy and ameliorated skeletal muscle atrophy in septic mice and differentiated C2C12 myotubes. Overexpression of miR-15a-3p increased autophagy and skeletal muscle atrophy in mice and differentiated C2C12 myotubes. Furthermore, we identified peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC1α) as a direct target of miR-15a-3p. Our findings elucidate the molecular mechanisms underlying miR-15a-3p in sepsis-induced autophagy and skeletal muscle injury, highlighting its potential as a therapeutic target.

Keywords:  PGC1α; autophagy; microRNA-15a-3p; sepsis; skeletal muscle atrophy

DOI:  https://doi.org/10.1097/SHK.0000000000002924
bioRxiv. 2026 Jul 30. pii: 2026.07.29.741533. [Epub ahead of print]

Developmental expression of the skeletal muscle determination gene, MyoD , is regulated by novel enhancer elements that interact with the core enhancer and distal regulatory region.

Heather K Jamieson, James R Camp, Katherine Fleck, Cory J Jubinville, Erica Korolev, Jennifer C J Chen, Leighton J Core, Jelena Erceg, Masakazu Yamamoto, David J Goldhamer.

MyoD plays a central role in determining the skeletal muscle lineage in vertebrate embryos. The core enhancer (CE) and distal regulatory region (DRR) are the only known MyoD enhancers, and together, they recapitulate all major aspects of MyoD expression in the embryo. However, knocking out each enhancer individually has only modest effects on MyoD expression. Here, we show that embryos lacking both enhancers maintain muscle-specific MyoD expression, indicating the existence of unknown MyoD regulatory elements. Precision run-on sequencing together with available ChIP-seq and DNase I hypersensitivity datasets identified three new candidate enhancer regions within 96 kb of MyoD 5' flanking sequences. Transgenic analysis revealed that DNA elements at -36 and -60 kb are active in all muscle-forming regions, each recapitulating aspects of endogenous MyoD expression. Enhancer activities in muscle regulatory factor-deficient mice suggest that they are components of the auto- and cross-regulatory circuitry that maintains MyoD expression. Analysis of Hi-C data showed that the entire -96 kb region constitutes a loop domain, within which multiple interactions between elements and with the MyoD gene were detected. A larger loop domain delimited by CTCF sites was also identified from -96 kb to +220 kb relative to the MyoD transcriptional start site. These data indicate that the newly identified enhancers are key components of a cis regulatory network that controls the activation and maintenance of MyoD expression in the embryo.
One sentence summary: Cis regulation of MyoD transcription during development.

DOI: https://doi.org/10.64898/2026.07.29.741533
Methods Enzymol. 2026 ;pii: S0076-6879(26)00174-6. [Epub ahead of print]733 223-251

Integrated SDH, COX histochemistry, and MHC fibre typing in skeletal muscles: Methods and interpretation.

Aastha Munjal, Ridhi Singh, Ashwini Bhelave, Shwetha Sekar, Ninitha Asirvatham-Jeyaraj, Nagalingam R Sundaresan.

  Skeletal muscle plays a vital role in metabolic homeostasis, accounting for the majority of glucose uptake, lipid oxidation, and adaptive thermogenesis. Its plasticity enables rapid, controlled remodelling in response to exercise, nutrients, hormonal changes, ageing, and disease. This metabolic plasticity is due to fibre-type heterogeneity. Each muscle fibre has distinct contractile and bioenergetic properties. Sirtuins are known critical regulators of skeletal muscle mitochondrial content and oxidative metabolism. Sirtuins, are NAD+-dependent acetylases and deacetylases that regulate mitochondrial biogenesis, redox balance, and cellular response to stress. Thus, studying the role of sirtuins in muscle physiology requires assays that can identify metabolic and contractile phenotypes. In this chapter, we provide a comprehensive histochemistry protocol for succinate dehydrogenase (SDH) and cytochrome c oxidase (COX) to assess mitochondrial oxidative capacity, and Myosin Heavy Chain (MHC) immunohistochemistry to assess fibre-type classification. Additionally, we have discussed detailed guidance for troubleshooting the critical steps of the protocol, including cryoinjury, tissue sectioning, staining optimisation, and imaging.

Keywords:  COX; MHC immunohistochemistry; Metabolism; Mitochondria; Muscle fibre typing; SDH; Sirtuins; Skeletal muscles

DOI:  https://doi.org/10.1016/bs.mie.2026.05.046
Hum Mol Genet. 2026 Aug 10. pii: ddag079. [Epub ahead of print]35(17):

CRISPR/dCas9-mediated tuning of DMPK transcription reveals a quantitative relationship between toxic repeat RNA expression and MBNL1 activity in myotonic dystrophy.

Lise Ripken, Thomas D Hoekman, Marieke Willemse, Maeve L Troost, Angelique N Kenyon, Walther J A A van den Broek, Derick G Wansink.

  Myotonic dystrophy type 1 (DM1) is caused by (CUG)n-expanded DMPK transcripts that sequester the splicing factor MBNL1 in the nucleus, resulting in widespread splicing abnormalities. Although significant progress has been made in understanding DM1 pathogenesis, the contribution of DMPK transcript levels to disease severity, and the variability of these levels across cell types, tissues, and patients, remains poorly understood. To investigate this in a quantitative manner, we developed isogenic human immortalized myoblast models with inducible modulation of DMPK RNA levels using CRISPR activation (CRISPRa) and interference (CRISPRi) guided by synthetic sgRNAs. CRISPRa elevated DMPK RNA levels by more than three-fold, intensifying MBNL1-dependent splicing defects. In contrast, CRISPRi reduced DMPK RNA expression by approximately 80%, partially rescuing splicing abnormalities. These changes were validated by visualizing (CUG)n foci using RNA FISH. Lowering DMPK transcript levels increased the availability of free nucleoplasmic MBNL1, whereas upregulation further depleted MBNL1, reinforcing the central role of MBNL1 sequestration in repeat RNA toxicity. Our findings demonstrate that expanded DMPK transcript levels modulate free MBNL1 concentration and alternative splicing in a dose-dependent manner, underscoring the central role of repeat RNA expression in DM1 pathogenesis. These models provide a powerful platform for dissecting variability in DMPK expression and for defining the therapeutic thresholds required for effective DMPK knockdown, thereby offering critical insights for the design and evaluation of DMPK and MBNL1-directed therapeutic strategies.

Keywords:  CRISPR/dCas9; DMPK; MBNL1; transcription modulation; triplet repeat

DOI:  https://doi.org/10.1093/hmg/ddag079
Physiol Rep. 2026 Aug;14(16): e71063

Sciatic denervation differentially remodels skeletal muscle and deep fascia in the lower limb of male mice.

Shun Otsuka, Yuki Tamaki, Kanae Umemoto, Naoyuki Hatayama, Munekazu Naito.

  The deep fascia surrounds skeletal muscles and contributes to force transmission and mechanical coordination, but its response to denervation remains unclear. This study investigated morphological and transcriptional adaptations of the deep fascia following sciatic nerve denervation in mice. Male C57BL/6J mice (n = 5-6/group) underwent unilateral sciatic nerve denervation or sham surgery. Fourteen days later, tibialis anterior (TA) muscle and overlying deep fascia (anterior crural fascia) were analyzed by histology and quantitative PCR. Denervation induced significant TA muscle atrophy with upregulation of inflammatory (Il6, p = 0.001), profibrotic (Tgfb, p < 0.001), and extracellular matrix (ECM)-related genes (Mmp2, p = 0.006; Col3a1, p = 0.005), and downregulation of regenerative factors (Fgf2, p < 0.001). Deep fascia thickness increased approximately 1.5-fold (p = 0.012) and was accompanied by elevated Il6 (p < 0.001), Tgfb (p = 0.035), Col1a1 (p = 0.006), and Col3a1 (p = 0.003) expression and a higher proportion of collagen type III (p = 0.015). In conclusion, sciatic nerve denervation induces muscle atrophy and deep fascia thickening accompanied by extracellular matrix remodeling. These findings demonstrate coordinated yet tissue-specific remodeling of skeletal muscle and deep fascia following sciatic nerve denervation.

Keywords:  deep fascia; denervation; extracellular matrix; immobilization

DOI:  https://doi.org/10.14814/phy2.71063
Stem Cell Reports. 2026 Aug 20. pii: S2213-6711(26)00261-4. [Epub ahead of print] 103050

TDP-43 sustains satellite cells to maintain and regenerate skeletal muscle.

Theodore E Ewachiw, Tenaya K Vallery, Shloka Dhar, Hayden Clarkson, Tiffany Elston, Haileigh Gay, Bradley B Olwin.

  Skeletal muscle satellite cells (SCs), residing between the myofiber plasma membrane and the surrounding basement membrane, continue to maintain and repair skeletal muscle throughout life. Typically, quiescent SCs can transition into a reversible alert state (GAlert) that primes them for rapid activation to maintain or repair muscle. From GAlert, SCs can either re-enter quiescence or commit to the cell cycle, expand, and differentiate to fuse with existing regenerating myofibers. Exit from quiescence requires extensive post-transcriptional remodeling, including changes in RNA processing and RNA-binding protein activity. We show that TDP-43, an RNA-binding protein, is essential for SC maintenance and muscle repair. Conditional deletion of TDP-43 in SCs caused a consistent and progressive loss of GAlert SCs, even in uninjured muscle, leading to depletion of the SC pool. TDP-43 haploinsufficiency was sufficient to impair SC maintenance, indicating that both alleles are required. Integrative analysis suggests that TDP-43 supports the expression of stress response-associated transcripts during the quiescent-to- GAlert transition and that failure to mount this response contributes to SC apoptosis. Thus, we identified TDP-43 as a critical regulator of survival of SCs as these cells activate, and we establish that TDP-43 is required for the maintenance and repair of skeletal muscle.

Keywords:  RNP; TDP-43; muscle; muscle stem cell; myo-granule; regeneration; satellite cell

DOI:  https://doi.org/10.1016/j.stemcr.2026.103050
FASEB J. 2026 Aug 31. 40(16): e72214

Shockwave-Induced Myoblast Exosome-Like Vesicles: Emerging Drivers of Muscle Regeneration.

Larisa Ryskalin, Federica Fulceri, Lorenzo Germelli, Maria Cristina D'Agostino, Paola Soldani, Eleonora Da Pozzo, Marco Gesi.

  Exosomes, a subset of nanosized extracellular vesicles, are key mediators of intracellular communication that show growing therapeutic potential in skeletal muscle regeneration. By shuttling bioactive cargoes between cells, they modulate recipient cell behavior, influencing proliferation, differentiation, and tissue remodeling. Previous studies demonstrated that different tensile load regimes can modulate both the production and regenerative capacity of myoblast-derived exosomes, positioning mechanically induced vesicle release as a potential driver of morpho-functional adaptations required for myoblast differentiation and myotube formation. Within this framework, shockwave (SW) therapy is gaining increasing attention as a non-invasive mechanical stimulus in regenerative medicine; however, the precise cellular mechanisms linking SW stimulation and tissue repair remain poorly understood. Preclinical evidence shows that extracellular vesicles (EVs) derived from SW-treated cardiomyocytes possess pro-angiogenic and regenerative properties, suggesting that SW-induced paracrine signaling may be conserved across tissues. In this study, we investigated whether in vitro SW treatment affects myogenic exosome release, contributing to SW-mediated muscle regeneration. Tunable Resistive Pore Sensing analysis revealed a significant increase in EV concentration at 6 h post-treatment, with no detectable differences between treated cells and controls at 12 h, indicating a rapid and transient secretory response. Importantly, vesicle size distribution remained unchanged across conditions, suggesting that SW primarily modulates EV production dynamics rather than vesicle morphology. Ultrastructural analyses further confirmed this transient activation, showing vesicular trafficking and exosome-like EV secretion in treated myoblasts. Further mechanistic insights into SW-induced exosome release may uncover novel pathways, contributing to SW regenerative effects supporting its translational application to muscle injuries and disorders.

Keywords:  cell communication; extracorporeal shockwave therapy; muscles; secretory vesicles; skeletal myoblasts; treatment outcome

DOI:  https://doi.org/10.1096/fj.202603103R
Adv Sci (Weinh). 2026 Aug 18. e77189

Loss of LCN2 Function Ameliorates Glucocorticoid-Induced Muscle Atrophy via Remodeling the Extracellular Matrix.

Hongwei Shi, Xiaojing Hao, Yi Yan, Fengyang Li, Yaru Zhang, Zixin Li, Wenjuan Xie, Jiayin Lu, Xiaomao Luo, Yanjun Dong, Haidong Wang, Juan Wang.

  Chronic glucocorticoid (GC) exposure is the leading clinical cause of skeletal muscle atrophy, steroid myopathy, and secondary sarcopenia, triggering irreversible motor function decline, disease progression, and elevated all-cause mortality. The underlying pathological mechanisms remain unclear, and no safe and effective targeted interventions are currently available. This study identifies Lipocalin 2 (LCN2) as a pivotal driver of GC-induced muscle atrophy. Using multi-omics analysis, dexamethasone-induced mouse models, primary myotube models, and gain/loss-of-function assays, we found that LCN2 was the most strikingly upregulated factor in atrophic muscle, and that its transcription was directly activated by glucocorticoid receptor (GR) binding to the conserved glucocorticoid response element (GRE) in its promoter. Muscle-specific LCN2 overexpression disrupts extracellular matrix (ECM) homeostasis and triggers severe muscle atrophy and motor dysfunction, whereas LCN2 silencing markedly alleviates GC-induced ECM injury and atrophy without impairing normal muscle homeostasis. Mechanistically, the interaction of LCN2 with matrix metalloproteinase 9 (MMP9) triggers ECM dysregulation and consequent focal adhesion kinase (FAK) signaling inactivation, which represses the PI3K-Akt-mTOR anabolic cascade and activates FoxO-driven catabolic signaling, thereby leading to dysregulated muscle protein metabolism. This study reveals the core pathogenic role of the LCN2-MMP9-ECM-FAK axis in GC-induced muscle atrophy, providing a promising novel therapeutic target for steroid myopathy.

Keywords:  Lipocalin 2; MMP9; extracellular matrix; glucocorticoid receptor; muscle atrophy

DOI:  https://doi.org/10.1002/advs.77189
STAR Protoc. 2026 Aug 20. pii: S2666-1667(26)00449-1. [Epub ahead of print]7(3): 104796

Protocol for manipulating mRNA splicing via vivo-morpholino in early-activating muscle stem cells.

Kangning Lin, Yishu Yin, Tom H Cheung.

  Muscle stem cells (MuSCs), also called satellite cells (SCs), are essential for skeletal muscle regeneration. SCs undergo rapid splicing changes upon activation, hindering the study of alternative splicing during SC activation. Here, we describe a protocol for manipulating mRNA splicing in early-activating SCs during isolation using vivo-morpholino (Vivo-MO). We also detail steps for isolating vivo-morpholino-treated SCs, validating the splicing alteration by RT-PCR, and evaluating the functional outcome in SC activation using an EdU incorporation assay. For complete details on the use and execution of this protocol, please refer to Lin et al.1.

Keywords:  Cell Biology; Cell isolation; Flow Cytometry; Molecular Biology; Stem Cells

DOI:  https://doi.org/10.1016/j.xpro.2026.104796
Front Immunol. 2026 ;17 1885023

IL-6 signaling orchestrates proteolytic hubs MuRF1 and Atrogin-1 in NSCLC induced sarcopenia.

Gautam Kumar, Shailza Singh.

  Non-small cell lung cancer (NSCLC) is frequently associated with sarcopenia, a debilitating condition of muscle wasting driven by complex tumor-muscle cross-talk. To unravel the regulatory mechanisms underlying this phenotype, we reconstructed a comprehensive signaling network integrating inflammatory, anabolic, catabolic, and proteolytic pathways. The network was translated into a mechanistic mathematical model using ordinary differential equations, enabling dynamic simulations of pathway activity. Flux analysis revealed that only a limited number of reactions dominate system behavior, with cytoplasmic IL-6 export and SMAD2/3-4 mediated induction of MuRF1 and Atrogin-1 emerging as major control points for muscle protein breakdown. Crosstalk analysis identified these proteolytic regulators as central hubs, integrating signals from inflammatory cytokines, oxidative stress, and transcriptional modulators. Principal component analysis further confirmed that sarcopenic progression is governed by a compact regulatory core, with IL-6/STAT3, myostatin/SMAD, and FOXO/NF-κB pathways converging on MuRF1 and Atrogin-1. Experimental validation using immunofluorescence-based confocal microscopy demonstrated increased expression and altered localization of these ubiquitin ligases in C2C12 cells co-cultured with lung cancer lines, corroborating model predictions. Together, these findings provide a systems-level framework that transforms broad observations of inflammation into ranked therapeutic targets and support combined strategies aimed at blocking the IL-6/STAT3-myostatin/SMAD-FOXO1/3-MuRF1/Atrogin-1 axis to mitigate NSCLC-associated sarcopenia.

Keywords:  Atrogin-1; IL-6; MuRF1; NSCLC; sarcopenia; signaling; therapeutics

DOI:  https://doi.org/10.3389/fimmu.2026.1885023