bims-moremu 2026-01-18 papers

bims-moremu

Biomed News

on Molecular regulators of muscle mass

Issue of 2026–01–18
35 papers selected by
Anna Vainshtein, Craft Science Inc.

Protocol to assess myogenic effects of 3T3-L1 and primary murine fibro-adipogenic progenitors on C2C12 myoblast differentiation.
Exercise, Exerkines, and Sarcopenia.
Is Ferroptosis the Mechanistic Bridge Connecting Iron Dysregulation to Muscle Wasting and Functional Decline in Aging?
Differential expression of miRNAs in slow- and fast-muscle fibers isolated from GFP-Myh7 mice.
Intermittent AP-1 activation in muscles contributes to exercise-induced health benefits.
TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.
Integrated cross-species translation and biophysical multi-scale modeling links molecular signatures and locomotory phenotypes in spaceflight-induced sarcopenia.
Genomic and Epigenomic Landscapes of Sarcopenia: From Molecular Etiology to Precision Interventions.
The Impact of Hyperparathyroidism on Skeletal Muscle Pathophysiology and Physical Function.
Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy.
The Important Role of Fatty Infiltration of Skeletal Muscle in Aging: Skeletal Muscle Function, Pathological Mechanisms and Intervention.
CHAMP1 is an essential regulator for human myoblast fusion and muscle development.
Ablation of Tumor-Derived IGFBP-3 Attenuates Cancer-Associated Skeletal Muscle Wasting in Murine Pancreatic Cancer.
Endurance Exercise Induces Distinct Skeletal and Cardiac Mitochondrial Adaptations in Racehorses.
Impacts of exercise, renin-angiotensin system modulation or both on skeletal muscle circadian gene expression.
Transcriptomic characterization of the aberrant alternative splicing in skeletal muscles of sarcopenia patients.
USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy.
Muscle meets Lysosomes: emerging strategies in muscular dystrophy.
Sepsis-associated skeletal muscle wasting is ameliorated by pharmacological inhibition of the STAT3 signaling pathway in mice.
Irisin and the muscle-brain axis: Mechanisms and translational potential.
Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.
Regenerative Index reveals declining muscle regeneration in paediatric patients with Duchenne muscular dystrophy.
HMGB2-RAD21 Axis Promotes Fibro/Adipogenic Progenitor Proliferation and Regulates Fat Infiltration.
Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.
MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.
Genotype-Dependent Morpho-Mechanical Profiling of Patient-Derived Human Myotubes on Nanogrooved Substrates.
Skeletal muscle transcriptional dysregulation of genes involved in senescence is associated with prognosis in severe heart failure.
Emerging therapeutic strategies in muscular dystrophy: an updated review on pathogenesis and treatment advances.
Systems Genomics Reveals Age- and Sex-Dependent Metabolic Dysregulation from Glo1 Reduction in Mice.
Sex differences in cachexia outcomes and branched-chain amino acid metabolism following chemotherapy in aged mice.
Single-cell transcriptional mapping of Mustn1 exhibits consistent mural cell localization across musculoskeletal tissues.
WDR62 is required for proper proliferation and early differentiation of skeletal myoblasts.
Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.
Multi-omics and molecular testing: A new insight into the genetic mechanisms of sarcopenia and arthritis.
Multiple modes of AFM reveal distinct mechanical properties for dystrophin and utrophin not manifest by small fragments.

STAR Protoc. 2026 Jan 09. pii: S2666-1667(25)00738-5. [Epub ahead of print]7(1): 104332

Protocol to assess myogenic effects of 3T3-L1 and primary murine fibro-adipogenic progenitors on C2C12 myoblast differentiation.

Alessandra M Norris, Ambili B Appu, Daniel Kopinke.

  Fibro-adipogenic progenitors (FAPs) are key regulators of skeletal muscle regeneration and influence myogenic differentiation. Here, we present a protocol for the isolation of primary FAPs from injured murine skeletal muscle and the co-culture of C2C12 myoblasts with either 3T3-L1 or primary FAPs. We describe steps for muscle injury, harvest, and digestion followed by FAP isolation. We then detail procedures for co-culture and for assessing myogenic differentiation using immunofluorescence imaging, enabling direct comparison of stromal influences on myoblast differentiation. For complete details on the use and execution of this protocol, please refer to Norris et al.1.

Keywords:  Cell Biology; Cell differentiation; Cell isolation; Cell separation/fractionation; Microscopy; Stem cells

DOI:  https://doi.org/10.1016/j.xpro.2025.104332
Diabetes Metab J. 2026 Jan;50(1): 19-29

Exercise, Exerkines, and Sarcopenia.

Hye Soo Chung, Kyung Mook Choi.

  Sarcopenia is a progressive age-related musculoskeletal disorder characterized by loss of skeletal muscle mass, strength, and physical function. Closely associated with aging and physical inactivity, it significantly compromises mobility, independence, and quality of life in older adults. Exercise is widely recognized as an effective non-pharmacological intervention for managing sarcopenia. However, the underlying molecular mechanisms remain incompletely elucidated. Among the emerging mediators, exerkines, physical exercise-induced signaling molecules, are secreted by multiple tissues, including the skeletal muscle, bone, liver, and adipose tissue, and mediate the systemic beneficial impacts of exercise via autocrine, paracrine, and endocrine signaling. These factors play critical roles in interorgan communication, regulation of muscle regeneration, mitochondrial function, inflammation, and metabolic homeostasis. Importantly, the secretion profiles and biological functions of exerkines are modulated by exercise-specific parameters such as mode, intensity, and duration. Understanding the regulatory dynamics of exerkine signaling may offer novel therapeutic avenues, particularly for individuals unable to engage in regular physical activity. This review focuses on the recently identified exerkines relevant to skeletal muscle physiology and their implications in the pathophysiology of sarcopenia. We also provided a comprehensive overview of exerkine responses to various exercise modalities in the prevention and treatment of sarcopenia.

Keywords:  Adipose tissue; Aging; Exercise; Liver; Muscle, skeletal; Sarcopenia

DOI:  https://doi.org/10.4093/dmj.2025.0972
Aging Cell. 2026 Feb;25(2): e70367

Is Ferroptosis the Mechanistic Bridge Connecting Iron Dysregulation to Muscle Wasting and Functional Decline in Aging?

Rola S Zeidan, Simon Reinhard, Anna Picca, Emanuele Marzetti, Christiaan Leeuwenburgh, James F Collins, Stephen D Anton.

  Age-related decline in physical function is a hallmark of aging and a major driver of morbidity, disability, and loss of independence in older adults, yet the molecular processes linking muscle aging to functional deterioration remain incompletely defined. Emerging evidence implicates ferroptosis, defined as iron-dependent, lipid peroxidation-driven cell death, as a compelling but underexplored contributor to age-related muscle wasting and weakness. Although ferroptosis signatures appear in aged muscle across cellular, animal, and human studies, their causal role in functional decline has not been clearly established. Here, we synthesize current evidence to propose a framework in which iron dyshomeostasis, impaired antioxidant defenses, and dysregulated ferritinophagy converge to create a pro-ferroptotic milieu that compromises muscle energetics, structural integrity, and regenerative capacity. We delineate key knowledge gaps, including the absence of ferroptosis-specific biomarkers in human muscle and limited longitudinal data linking ferroptotic stress to mobility outcomes. Finally, we highlight potential therapeutic opportunities targeting iron handling and lipid peroxidation pathways. A better understanding of the contribution of ferroptosis to muscle aging may enable development of mechanistically informed biomarkers and interventions to preserve strength and mobility in older adults.

Keywords:  Ferroptosis; iron; older adults; physical function; skeletal muscle

DOI:  https://doi.org/10.1111/acel.70367
Physiol Genomics. 2026 Jan 14.

Differential expression of miRNAs in slow- and fast-muscle fibers isolated from GFP-Myh7 mice.

Koichi Ojima, Mika Oe, Susumu Muroya.

  MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression in various cell types. Skeletal muscle consists of bundles of muscle fibers, which are classified as either slow-type or fast-type according to their properties. However, the roles of miRNAs in modulating physiological muscle phenotypes remain unclear. Here, we profiled fiber-type-enriched miRNAs to gain insight into differences in gene regulation between the two fiber types. To avoid cross-contamination, we used GFP-Myh7 mice, in which slow-type muscle fibers express green fluorescent protein (GFP), allowing easy discrimination between GFP-positive slow-type fibers and GFP-negative fast-type fibers under fluorescence microscopy. Here, we profiled miRNA expression in two muscle fiber types in GFP-Myh7 mice. Microarray analysis showed that 18 and 12 miRNAs were highly expressed in slow-type and fast-type fibers, respectively, with more than 2-log2 fold-change (log2FC) relative to their counterparts. These distinct miRNA expressions were largely consistent with PCR results. Gene ontology analyses predicted that target genes of these miRNAs were mainly involved in "regulation of transcription" in slow-type muscle fibers, and in "extracellular matrix (ECM)"-related terms in fast-type fibers. Our results suggest that distinct miRNA expression patterns in each fiber type may participate in modulating fiber-type-specific intracellular and extracellular environments.

Keywords:  Skeletal muscle; miRNAs; muscle fiber type; myogenic regulatory factor

DOI:  https://doi.org/10.1152/physiolgenomics.00023.2025
bioRxiv. 2026 Jan 06. pii: 2026.01.05.696542. [Epub ahead of print]

Intermittent AP-1 activation in muscles contributes to exercise-induced health benefits.

Abhinav Choubey, Udhaya Kumar S, Tingting Yang, Jennifer Jager, Sungguan Hong, Manashree Damle, Huiqi Yin, Ruxing Zhao, Chengchuang Song, Ege Sanem Oturmaz, Hui Tong, Jason Puglise, Elisabeth R Barton, Bin Fang, Zhaoyong Hu, Lan Liao, Jianming Xu, Ye Lan, Zheng Sun.

Regular physical exercise extends healthspan, yet the molecular mechanisms that translate intermittent contractile stress into lasting benefit remain incompletely understood. Using global nuclear run-on (GRO-seq) in mouse skeletal muscle after treadmill running, we profiled enhancer RNA (eRNA), a sensitive marker of enhancer activity. Activation protein-1 (AP-1), a family of pioneering factors for senescence, emerged as the top transcription factor with motif enrichment in exercise-activated enhancers. Our screen in the contracting C2C12 myotubes pinpointed cFos/JunD as the primary AP-1 factor responsible for contraction-induced transcriptional changes. Muscle-specific overexpression of A-Fos, a dominant-negative mutant of cFos, disrupted transcriptomic responses to exercise and attenuated exercise-mediated improvement in muscle functions. Interestingly, intermittent but not continuous overexpression of cFos/JunD in mouse muscles mimicked exercise-induced transcriptomic changes, increased mitochondrial volume density, enhanced muscle strength and fatigue resistance, and improved glucose tolerance. These results define a transcriptional regulatory signaling pathway linking exercise intermittency to beneficial adaptations and highlight the necessary recovery cycles in training. The paradoxical anti- and pro-aging roles of AP-1 offer insights into the timing and dynamics of stressors and stress responses in shaping senescence and healthspan.

DOI: https://doi.org/10.64898/2026.01.05.696542
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00023-7. [Epub ahead of print]

TRPV1 activation by active heat acclimation drives skeletal muscle mitochondrial turnover.

Yixiao Xu, Yishun Gong, Jiafa Zhong, Binghong Gao.

   OBJECTIVE: Active heat acclimation is widely used by athletes or workers exposed to heat, yet its impact on skeletal muscle mitochondrial function and the underlying molecular regulators remain incompletely understood. This study aimed to investigate how active heat acclimation improves skeletal muscle mitochondrial function, with a specific focus on transient receptor potential vanilloid 1 (TRPV1) as an important mediator.
METHODS: A 4-week intervention was conducted in trained runners (exercise in heat vs. thermoneutral conditions) and in mice exposed to heat, exercise, TRPV1 activation (nonivamide), or TRPV1 inhibition (AMG9810). Aerobic performance, substrate utilization, mitochondrial respiration, H2O2 emission, mitochondrial ultrastructure, and molecular markers of biogenesis and mitophagy were assessed.
RESULTS: In humans, active heat acclimation improved ventilatory thresholds, enhanced lactate clearance, and reduced carbohydrate oxidation during submaximal exercise. In mice, active heat acclimation increased mitochondrial biogenesis (PGC-1α, p-p38 MAPK, TFAM), enhanced mitophagy (Pink1, Parkin), improved OXPHOS and ETS capacities, and elevated TRPV1 expression. Pharmacological TRPV1 activation augmented mitochondrial remodeling and improved exercise performance. Conversely, TRPV1 inhibition blunted heat-induced mitochondrial biogenesis, mitophagy activation, and structural remodeling.
CONCLUSION: TRPV1 is an important mediator of mitochondrial adaptations to active heat acclimation, promoting mitochondrial turnover and enhancing respiratory capacity, thereby supporting the improvement of aerobic capacity.

Keywords:  TRPV1; active heat acclimation; mitochondrial turnover; oxidative phosphorylation; skeletal muscle

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.015
NPJ Microgravity. 2026 Jan 12.

Integrated cross-species translation and biophysical multi-scale modeling links molecular signatures and locomotory phenotypes in spaceflight-induced sarcopenia.

Brendan K Ball, Hammad F Khan, Jee Hyun Park, Krishna Jayant, Deva D Chan, Douglas K Brubaker.

Age-related skeletal muscle deterioration, referred to as sarcopenia, poses significant risks to astronaut health and mission success during spaceflight, yet its multisystem drivers remain poorly understood. While terrestrial sarcopenia manifests gradually through aging, spaceflight induces analogous musculoskeletal decline within weeks, providing an accelerated model to study conserved atrophy mechanisms. Here, we introduced an integrative framework combining cross-species genetic analysis with physiological modeling to understand mechanistic pathways in space-induced sarcopenia. By analyzing rodent and human datasets, we identified conserved molecular pathways underlying spaceflight-induced muscle atrophy, revealing shared regulators of neuromuscular signaling including pathways related to neurotransmitter release and regulation, mitochondrial function, and synaptic integration. Building upon these molecular insights, we developed a physiologically grounded central pattern generator model that reproduced spaceflight-induced locomotion deficits in mice. This multi-scale approach established mechanistic connections between transcriptional changes and impaired movement kinetics while identifying potential therapeutic targets applicable to both spaceflight and terrestrial aging-related muscle loss.

DOI: https://doi.org/10.1038/s41526-025-00557-x
Aging Dis. 2026 Jan 05.

Genomic and Epigenomic Landscapes of Sarcopenia: From Molecular Etiology to Precision Interventions.

Ji-Yong Sung, Jung Woo Lee.

Sarcopenia-the age-related loss of skeletal muscle mass and strength-is a major contributor to frailty, disability, and mortality in the elderly. Once considered a physiological consequence of aging, sarcopenia is now recognized as a complex multifactorial syndrome driven by intricate interactions between genetic predispositions, epigenetic regulation, environmental exposures, and lifestyle factors. Recent advances in high-throughput genomics and epigenomics have transformed our understanding of its molecular underpinnings, revealing key genes, signaling pathways, and regulatory networks that govern muscle homeostasis, regeneration, and degeneration. Furthermore, epigenetic alterations such as DNA methylation, histone modifications, and non-coding RNA networks act as critical modulators of muscle aging, bridging genetic risk with environmental and metabolic influences. Here, we review current knowledge of the genomic and epigenomic landscapes of sarcopenia, discuss how they intersect with cellular and systemic processes, and explore how these insights are paving the way for precision diagnostics, risk prediction, and targeted therapeutic interventions.

DOI: https://doi.org/10.14336/AD.2025.1463
Endocr Connect. 2026 Jan 14. pii: EC-25-0801. [Epub ahead of print]

The Impact of Hyperparathyroidism on Skeletal Muscle Pathophysiology and Physical Function.

Michel Kabbash, Stephen D Anton, Christiaan Leeuwenburgh, Aditya S Shirali.

  Primary hyperparathyroidism (PHPT), increasingly diagnosed in its asymptomatic form, is associated with clinically significant neuromuscular dysfunction. Growing evidence indicates that skeletal muscle is a direct target of parathyroid hormone (PTH), with chronic PTH excess impairing mitochondrial bioenergetics, promoting proteolysis, and altering muscle-bone-adipose endocrine crosstalk. Experimental studies confirm PTH receptor (PTHR1) expression in muscle fibers and satellite cells, while transcriptomic analyses of PHPT muscle reveal dysregulation of calcium signaling and oxidative metabolic pathways. Clinically, patients with PHPT, irrespective of hypercalcemia, demonstrate reduced grip strength, slower gait speed, impaired chair-stand performance, and diminished postural stability. Parathyroidectomy improves several of these deficits, with studies reporting increases in grip strength, knee extension force, ambulatory capacity, and, in some cohorts, improved muscle composition and metabolic gene expression. However, available data are heterogeneous and derived primarily from small cohorts with variable functional measures. Current evidence implicates PTH-mediated skeletal muscle dysfunction as a reversible component of PHPT, yet key mechanistic and clinical gaps remain. Standardized functional assessments and larger prospective studies are needed to clarify biological pathways, identify predictors of postoperative recovery, and inform the integration of muscle health into PHPT management. The focus of this review was to explore evidence linking PTH excess and skeletal muscle pathophysiology and review the relationship between PHPT and parathyroidectomy on physical function.

Keywords:  PHPT; hyperparathyroidism; muscle function; phosphorous

DOI:  https://doi.org/10.1530/EC-25-0801
MedComm (2020). 2026 Jan;7(1): e70563

Obestatin Treatment Counteracts Muscle Wasting by Reactivation of Autophagy in Duchenne Muscular Dystrophy.

Icía Santos-Zas, Silvia Costas-Abalde, Andrea C Lodeiro, Fátima Fernández-Barreiro, Tania Cid-Díaz, Saúl Leal-López, Jessica González-Sánchez, Mar García-Lamela, Lucía Debasa-Corral, Carlos S Mosteiro, Kamel Mamchaoui, Vincent Mouly, Xesús Casabiell, Rosalía Gallego, José Luis Relova, Yolanda Pazos, Jesus P Camiña.

  The mechanisms by which muscular dystrophy-related stress is transduced to the autophagic machinery remain poorly characterized. The formulation of strategies should be based on how disruption of these processes results in the deregulation of signaling pathways that contribute to many pathological effects of the disease. In this study, we investigated the molecular mechanism by which the obestatin/GPR39 system, an autocrine signaling with anabolic impact on normal skeletal muscle, restores autophagy in Duchenne muscular dystrophy (DMD). We report that obestatin integrates 5' AMP-activated protein kinase (AMPK) and mammalian target of rapamycin complex 1 (mTORC1) signaling to control ubiquitin proteasome system (UPS), autophagy-lysosome system, and protein synthesis under dystrophic context. The posttranslational modifications of the E3 ligase NEDD4-L emerges as the main switch to activate the autophagy in response to obestatin. This includes NEDD4-L tyrosine phosphorylation and autoubiquitination, which is critical for recruiting the ubiquitin-specific protease 10 to assemble a deubiquitination complex, that orchestrates the unc-51 like autophagy activating kinase 1 (ULK1) and class III PI3K (VPS34) complexes. Reactivation of autophagy through obestatin signaling promotes the recovery of physiological skeletal muscle function. Thus, DMD conditions determine permissiveness to the activation of AMPK that sustain autophagy under anabolic conditions stablished by obestatin signaling through mTORC1.

Keywords:  Duchenne muscular dystrophy; autophagy; neural precursor cell expressed developmentally downregulated protein 4; obestatin; ubiquitin‐specific protease 10

DOI:  https://doi.org/10.1002/mco2.70563
Am J Physiol Endocrinol Metab. 2026 Jan 16.

The Important Role of Fatty Infiltration of Skeletal Muscle in Aging: Skeletal Muscle Function, Pathological Mechanisms and Intervention.

Mei Yang, Fangli Zhou, Cui Wang, Ting Sun, Wanyu Zhao, Lu Liu, Yang Meng, Li Tian.

  This review explores the various biological changes that occur during the aging process, elucidating the fundamental pathological mechanisms leading to a decline in muscle integrity and functionality. A primary focus of the review is the occurrence of fat infiltration within skeletal muscle, a phenomenon that becomes increasingly prevalent with advancing age. The study assesses the implications of fat infiltration on skeletal muscle performance, along with the regulatory signaling mechanisms potentially influenced by fat accumulation. Furthermore, it addresses a variety of intervention strategies aimed at alleviating these age-related changes, including nutritional supplements, exercise regimens, and pharmacological treatments. By integrating current findings in the field and addressing existing challenges, this review aims to conduct an in-depth exploration of the intricate connection between aging and skeletal muscle health, with the goal of guiding future research and clinical practices to improve the quality of life for older adults.

Keywords:  Aging; Fatty infiltration; Intramuscular adipose tissue; Skeletal muscle function; sarcopenia

DOI:  https://doi.org/10.1152/ajpendo.00473.2025
Nat Commun. 2026 Jan 15. 17(1): 546

CHAMP1 is an essential regulator for human myoblast fusion and muscle development.

Haifeng Zhang, Min Zhou, Zheng Zhang, Zhaoning Wang, Ruifeng Shi, Yushu Wang, Xiaolin Wei, Renjie Shang, Jianwen Li, Cuiyu He, Jin Xie, Yarui Diao, Pengpeng Bi.

Human skeletal muscle comprises myofibers formed by fusion of thousands of myoblasts. This process depends on tightly regulated, muscle-specific fusogens, but its genetic control remains poorly understood. Here, we identify CHAMP1 (Chromosome Alignment Maintaining Phosphoprotein 1) as essential for human myoblast fusion in vitro and in vivo. Genomic and protein-interaction assays reveal a noncanonical role for CHAMP1 as a MyoD cofactor that directly activates expression of the key muscle fusogen Myomaker. As established in prior clinical reports, CHAMP1 mutations in patients cause developmental delay, hypotonia, and muscle weakness. Consistently, patient-derived cells show fusion defects that can be fully rescued by restoring Myomaker expression. Structure and function analyses identify C2H2-type zinc-finger motifs on CHAMP1 protein that are both necessary and sufficient for MyoD interaction and Myomaker expression. These findings highlight a cell-autonomous role for CHAMP1 in muscle development and disease and point to therapeutic avenues for treating CHAMP1-related muscle development defects.

DOI: https://doi.org/10.1038/s41467-025-67584-w
Am J Physiol Cell Physiol. 2026 Jan 12.

Ablation of Tumor-Derived IGFBP-3 Attenuates Cancer-Associated Skeletal Muscle Wasting in Murine Pancreatic Cancer.

Zachary R Sechrist, Daniel J Belcher, Nidhi R Patel, Zoe J Pittman, Edward M Schwarz, Calvin L Cole.

  Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer-related deaths, and its incidence is expected to rise. Skeletal muscle wasting (SMW) is a debilitating co-morbidity of PDAC with unknown etiology. Previously our lab demonstrated that systemic increases in Insulin-like Growth Factor Binding Protein-3 (IGFBP-3) is associated with SMW and pathologic myocellular lipid accumulation in an orthotopic murine model of PDAC (Ptf1atm1-cre/+;Krastm4Tyj;Muc1-/-(KCKO)). Here we show that PDAC tumor cells secrete high levels of IGFBP-3 and that genetic ablation of IGFBP-3 in the KCKO and Ptf1atm1(cre)Cvw/WT;Krastm4Tyj/WT;Trp53tm5Tyj/tm5Tyj (KP2) orthotopic models of PDAC increases survival by at least 30 days in both models without affecting tumor progression. Mice with IGFBP-3-/- tumors lost 10- and 3-fold less appendicular lean mass, and experienced a 5- and 6-fold decrease in myocellular lipid accumulation vs mice with parental KCKO and KP2 tumors, respectively, at failure to thrive endpoints. Gene expression studies demonstrated increases in the ubiquitin proteasome pathway (fbxo32 and trim32), autophagy (ULK1 and LC3bII), and TGF-βR signaling (tgfβr1 and FoxO1) in skeletal muscle of mice inoculated with parental PDAC tumors, which was absent in mice with IGFBP-3-/- tumors. In vitro studies confirmed a role for IGFBP-3 in stimulating TGF-β receptors and regulating SMAD3 nuclear localization. Moreover, IGFBP-3 deletion in tumor cells and small molecule inhibition of TGF-βR1/2 attenuated myotube wasting. Collectively, these results suggest that PDAC derived IGFBP-3 promotes SMW via non-canonical binding of TGF-βRs, warranting formal investigation of IGFBP-3 as a potential therapeutic target for PDAC-related SMW through a novel pathway.

Keywords:  Cancer Cachexia; IGFBP-3; PDAC; Skeletal Muscle

DOI:  https://doi.org/10.1152/ajpcell.00421.2025
Am J Physiol Heart Circ Physiol. 2026 Jan 12.

Endurance Exercise Induces Distinct Skeletal and Cardiac Mitochondrial Adaptations in Racehorses.

Simon Libak Haugaard, Mélodie J Schneider, Sarah Dalgas Nissen, Arnela Saljic, Peter Fruergaard Andersen, Helena Carstensen, Charlotte Hopster-Iversen, Thomas Jespersen, Steen Larsen, Rikke Buhl.

  Mitochondrial respiration sustains the high energy demands of endurance exercise, yet the extent to which atrial, ventricular and skeletal muscle mitochondria adapt remains uncertain. At the same time, endurance athletes face an increased risk of atrial fibrillation (AF), but the role of cardiac metabolism in arrhythmia susceptibility is poorly understood. Here, we compared mitochondrial respiration in skeletal muscle and across all four cardiac chambers between trained and untrained racehorses (n=34) to investigate adaptations associated with long-term endurance exercise. We further examined whether cardiac metabolism was linked to AF propensity. All horses underwent treadmill performance testing, and mitochondrial respiration was assessed in permeabilised skeletal and cardiac muscle fibres. Cardiac RNA-sequencing and in vivo AF inducibility testing were performed in a subset of horses. Mitochondrial function varied by region: the left ventricle showed the greatest oxidative capacity, and the ventricles exceeded the atria in mitochondrial content. Trained horses showed improved skeletal complex I- and II-linked respiration, and skeletal muscle respiration correlated with aerobic performance. In contrast, cardiac mitochondrial content and mass-specific respiration were unchanged by endurance exercise, despite enrichment of mitochondrial complex I pathways on transcriptomic analysis. A greater cardiac capacity for fatty acid oxidation, but not mitochondrial respiration, was associated with protection against AF induction. These findings reveal tissue-specific mitochondrial adaptations to endurance exercise and implicate cardiac substrate preference, rather than respiratory capacity, as a potential determinant of AF vulnerability. This raises new questions about how different tissues adapt metabolically to exercise and the potential role of cardiac energetics in arrhythmogenesis.

Keywords:  High resolution respirometry; athlete's heart; atrial fibrillation; large animal model

DOI:  https://doi.org/10.1152/ajpheart.00833.2025
Exp Physiol. 2026 Jan 11.

Impacts of exercise, renin-angiotensin system modulation or both on skeletal muscle circadian gene expression.

Emily L Zumbro, Liliana C Baptista, Taylor Taylor, Abbi R Hernandez, Anisha Banerjee, Yi Sun, YouFeng Yang, Qiuhong Li, Thomas W Buford.

  Ageing negatively affects quality of life and healthspan, and interventions are needed to slow this progressive decline. Previously, we have demonstrated the potential functional benefits of combining a genetically modified probiotic (GMP) targeting the non-canonical arm of the renin-angiotensin system (RAS) with exercise training. Initial RNAseq studies indicated the potential of the interventions to influence circadian physiology. Therefore, the objective of this study was to evaluate the expression of circadian-related genes in the tibialis anterior and soleus muscles in male and female aged rats in response to the administration of the GMP, exercise training and multiple controls. Following 12 weeks of the intervention, circadian-related genes were differentially expressed in male and female aged rats and between tissues, primarily influenced by the exercise intervention, with potential additive effects of the GMP. Several genes were also significantly associated with measures of physical performance. Thus, combining exercise with a RAS-related GMP may have potential functional benefits in late life, potentially related to circadian-related impacts within skeletal muscle.

Keywords:  circadian rhythm; exercise; probiotic; skeletal muscle

DOI:  https://doi.org/10.1113/EP092318
Sci Rep. 2026 Jan 16.

Transcriptomic characterization of the aberrant alternative splicing in skeletal muscles of sarcopenia patients.

Yuanyuan Li, Xiaoxuan Guo, Sujun Li, Xiaowen Wei, Tianyi Li.

  Sarcopenia represents a substantial health risk for the expanding elderly population globally, characterized by a progressive decline in skeletal muscle mass and strength as people age. To investigate the potential role of the alternative splicing change in sarcopenia pathogenesis, we conducted a re-analysis of previously published RNA-seq data from muscle biopsies of sarcopenia patients, age-matched healthy controls, and individuals exhibiting partial symptoms (either low muscle mass or reduced muscle function). Our results revealed 2260 differential alternative splicing events (DASEs) in 1686 genes (DASGs, differentially alternatively spliced genes) in sarcopenia samples, which included CD38, PARP, sirtuins involved in NAD biosynthesis and metabolism. These DASGs were significantly enriched in functional pathways critical for skeletal muscle development and sarcopenia pathogenesis, such as FoxO, neurotrophin and AMPK signaling. Notably, approximately half of these DASGs were also present in individuals with partial symptoms. Furthermore, we developed a sarcopenia mouse model by administering dexamethasone to C57BL/6 mice. RNA-seq and RT-qPCR analysis of differential alternative splicing in the transcriptomes of this mouse model revealed that some sarcopenia-related DASEs, including those in AKT2, MNL2, TCF7L2, and USP40, were conserved between humans and mice. Additionally, nearly 20% of the DASGs identified in sarcopenia mice overlapped with those from sarcopenia patients. Our integrated analyses reveal a core set of conserved alternative splicing abnormalities in sarcopenia that are shared between humans and mice, highlighting their potential as cross-species therapeutic targets.

Keywords:  Alternative splicing; Enriched pathways; RNA-seq; Sarcopenia; Sarcopenic mice model

DOI:  https://doi.org/10.1038/s41598-026-35002-w
Free Radic Biol Med. 2026 Jan 11. pii: S0891-5849(26)00026-2. [Epub ahead of print]246 107-125

USP47 stabilizes HDAC2 to ameliorate cigarette smoke-induced skeletal muscle atrophy by suppressing CYP1A1/ROS-mediated autophagy.

Chao Li, MingZhi Ou, GuiXian Zheng, Gang Jiang, Xiao Hu, YongLiang Jiang.

  Skeletal muscle atrophy, a debilitating complication of COPD, is closely linked to cigarette smoke (CS) exposure. The epigenetic regulator HDAC2 has been implicated, but the upstream regulatory mechanisms and precise downstream pathways are unclear. Using a CS-induced mouse atrophy model and C2C12 myotubes treated with cigarette smoke extract (CSE), we systematically investigated the role of USP47/HDAC2/CYP1A1/ROS axis through gain/loss-of-function studies, RNA-seq, ChIP-qPCR, co-immunoprecipitation, and ubiquitination assays. HDAC2 was downregulated in atrophic muscle, and its overexpression mitigated CS-induced atrophy, improved grip strength, and enhanced muscle regeneration. HDAC2 acted as a transcriptional repressor of CYP1A1 by deacetylating H3K9 and H3K27 at the promoter, thus curtailing ROS-driven excessive autophagy. We further discovered that the deubiquitinase USP47 is the key upstream regulator of HDAC2. USP47 directly interacted with HDAC2, promoted its deubiquitination, and enhanced its protein stability. Consequently, USP47 overexpression phenocopied the benefits of HDAC2 overexpression, which were effectively nullified by restoring CYP1A1 expression. In conclusion, we delineate a previously unrecognized signaling axis wherein USP47 stabilizes HDAC2 to inhibit the CYP1A1/ROS/autophagy cascade, ultimately protecting against CS-induced skeletal muscle atrophy. Targeting the USP47-HDAC2 interface presents a novel therapeutic strategy for combating muscle wasting in COPD.

Keywords:  CYP1A1; HDAC2; Skeletal muscle atrophy; USP47; cigarette smoke

DOI:  https://doi.org/10.1016/j.freeradbiomed.2026.01.018
Autophagy. 2026 Jan 14. 1-3

Muscle meets Lysosomes: emerging strategies in muscular dystrophy.

Abbass Jaber, David Israeli.

  Duchenne muscular dystrophy (DMD) is caused by the loss of DMD (dystrophin), leading to sarcolemmal fragility and progressive muscle degeneration. Although adeno-associated viral (AAV) microdystrophin (µDMD) therapies have advanced clinically, their benefits remain partial, highlighting the need to identify secondary cellular defects that limit therapeutic efficacy. In our recent study, we demonstrated that lysosomal dysfunction is a conserved, intrinsic, and persistent feature of DMD pathology. Using mouse, canine, and human dystrophic muscle, we show marked lysosomal membrane permeabilization (LMP), impaired acidification, defective proteolysis, and inefficient membrane repair, all hallmarks of compromised lysosomal integrity. Cholesterol accumulation within dystrophic myofibers further exacerbates these defects, linking lipid dysregulation to lysosomal injury and accelerated muscle degeneration. We find macroautophagy/autophagy impairment in DMD stems in part from reduced autophagosome-lysosome fusion, reframing autophagy failure as a downstream consequence of lysosomal damage. µDMD gene therapy only partially corrects these abnormalities and does not fully restore lysosomal stability. In contrast, combining µDMD with the lysosome-activating disaccharide trehalose produces synergistic benefits, improving muscle strength, architecture, and molecular signatures beyond either treatment alone. These findings position lysosomal dysfunction as a central driver of DMD pathophysiology and support therapeutic strategies that pair gene restoration with lysosomal enhancement.Abbreviation: AAV: adeno-associated virus; DAGC: DMD-associated glycoprotein complex; DMD: Duchenne muscular dystrophy; FDA: Food and Drug Administration; LMP: lysosome membrane permeabilization; MTOR: mechanistic target of rapamycin kinase; µDMD: microdystrophin.

Keywords:  Autophagy; Duchenne muscular dystrophy; galectin-3; lysosome; microdystrophin

DOI:  https://doi.org/10.1080/15548627.2026.2615985
Sci Rep. 2026 Jan 11.

Sepsis-associated skeletal muscle wasting is ameliorated by pharmacological inhibition of the STAT3 signaling pathway in mice.

Yuko Ono, Masafumi Saito, Ikumi Yoshihara, Yutaka Kondo, Kazuho Sakamoto, Jun Sugiyama, Nobuto Nakanishi, Shigeaki Inoue, Joji Kotani.



Keywords:  Autophagy; Cytokine storm; Interleukin-6; Psoas muscle index; Skeletal muscle atrophy; Ubiquitin–proteasome pathway

DOI:  https://doi.org/10.1038/s41598-026-35815-9
Exp Gerontol. 2026 Jan 09. pii: S0531-5565(26)00006-9. [Epub ahead of print] 113028

Irisin and the muscle-brain axis: Mechanisms and translational potential.

Beatrice Arosio, Anna Picca.

  The muscle-brain axis integrates peripheral metabolic activity with central nervous system function. Among the endocrine signaling molecules regulating such crosstalk, the peptide hormone irisin released during muscle contraction seems to play relevant roles. Irisin is generated by the proteolytic cleavage of the fibronectin type III domain-containing protein FNDC5 and has emerged as a key regulator of neurotrophic and metabolic adaptation. Although initially described as a myokine, irisin is also expressed in adipose and neural tissues, acting through autocrine, paracrine, and endocrine mechanisms. Irisin binds to the αV/β5 integrin receptor complex and activates a network of signaling pathways which promote mitochondrial biogenesis, autophagy, oxidative stress resistance, and modulation of inflammatory responses. Within the central nervous system, irisin induces brain-derived neurotrophic factor expression and contributes to synaptic plasticity, neurogenesis, and cognitive preservation. Experimental models show that irisin reduces amyloid burden, limits α-synuclein pathology, suppresses neuroinflammation, and stabilizes blood-brain barrier integrity, supporting a disease-modifying role in neurodegenerative conditions. In skeletal muscle, irisin stimulates myogenesis, enhances anabolic signaling, and improves metabolic efficiency, suggesting broader relevance for sarcopenia and age-related metabolic decline. Herein, we discuss irisin as a promising biomarker and a candidate therapeutic target for disorders characterized by concurrent muscle deterioration and cognitive impairment.

Keywords:  Brain-derived neurotrophic factor; Cognition; Myokine; Neurodegeneration; Neuroinflammation; Oxidative stress; Skeletal muscle

DOI:  https://doi.org/10.1016/j.exger.2026.113028
Mol Neurobiol. 2026 Jan 12. 63(1): 357

Muscle Fibrosis in Amyotrophic Lateral Sclerosis: Molecular Mechanisms, Diagnostic Advances, and Therapeutic Strategies.

Yumeng Sun, Chao Huang, Yan Pan, Xudong He, Hao Zhang.

  Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder primarily characterized by the degeneration of motor neurons. However, the pathological process of ALS extends beyond the central nervous system, with dynamic changes in skeletal muscle playing a crucial role in the progression of the disease. Recent research has shown that muscle fibrosis, marked by the abnormal accumulation of extracellular matrix (ECM), leads to reduced muscle elasticity, compromised contractile function, and impaired regeneration of neuromuscular junctions (NMJs). This condition represents not only the final stage of muscle atrophy in ALS but also a significant factor accelerating disease progression through "neuromuscular interactions." We conducted a systematic review of the molecular mechanisms of muscle fibrosis in ALS. This included examining the dysregulation of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF/CCN2), and the Wnt/β-catenin signaling pathways. We also considered key cellular contributors, such as fibro-adipogenic precursor cells and macrophages. The review also covers the use of non-invasive imaging techniques, such as MRI and muscle ultrasound, for early detection and monitoring. We also evaluate potential therapeutic approaches, ranging from anti-fibrotic drugs and gene therapy to physical interventions. In summary, muscle fibrosis is a promising therapeutic target that could complement strategies focused on motor neurons, ultimately improving functional outcomes in patients with amyotrophic lateral sclerosis.

Keywords:  Amyotrophic lateral sclerosis; Biomarker; Extracellular matrix; Fibrosis; Targeted therapies

DOI:  https://doi.org/10.1007/s12035-025-05658-y
bioRxiv. 2026 Jan 05. pii: 2026.01.05.697715. [Epub ahead of print]

Regenerative Index reveals declining muscle regeneration in paediatric patients with Duchenne muscular dystrophy.

Johnathan K Smid, Charis A McPherson, Jacob G Monast, Shanti S S Rayagiri, Steven A Moore, Michael A Rudnicki.

Background: Duchenne muscular dystrophy (DMD) is a devastating disease manifested in skeletal muscle by repetitious myonecrosis and regeneration. Because the regenerative process is closely linked to the cumulative severity of muscle damage, which is variably distributed within and between muscle groups, accurately quantifying muscle regeneration has remained a significant challenge.
Methods: Myofibers are delineated by immunostaining for laminin, and subsequent image analysis employed to generate a masked outline precisely within each myofiber boundary. Morphometric parameters including minimal Feret's diameter, cross-sectional area, and circularity were measured for each myofiber. In addition, the number of Pax7-expressing satellite cells were quantified. To evaluate regenerative activity, newly formed myofibers were identified by immunostaining for expression of embryonic myosin heavy chain (eMHC). Necrotic myofibers were enumerated by immunofluorescent detection of immunoglobulin G (IgG) infiltration. The Regenerative Index (RI) was calculated as the number of regenerating (eMHC + ) myofibers divided by the number of necrotic (IgG + ) myofibers. Determination of RI was performed on muscle biopsies from 10 boys with DMD and 3 non-DMD controls of similar age.
Results: A trend toward an increasing minimal Feret's diameter, cross-sectional area and circularity was observed with increasing age in DMD boys, with circularity showing the strongest trend. Furthermore, compared to DMD boys 7- to 8-years old, the boys 9- to 11-years old had significantly increased myofiber circularity. Pax7-expressing cells were significantly elevated in DMD boys compared to control boys of similar ages, without any observation of age-related changes. Notably, the Regenerative Index in DMD boys exhibited a pronounced decline between 7-11 years of age, and a significant inverse correlation between RI and age was observed.
Conclusions: Using eMHC and IgG immunostaining to calculate RI accurately assesses regeneration despite the variation in histopathologic severity between biopsies. This methodology demonstrated a significant negative correlation between RI and age of DMD boys from 7 to 11 years of age.

DOI: https://doi.org/10.64898/2026.01.05.697715
Adv Sci (Weinh). 2026 Jan 12. e14363

HMGB2-RAD21 Axis Promotes Fibro/Adipogenic Progenitor Proliferation and Regulates Fat Infiltration.

Xian Tong, Ziyun Liang, Tianqi Duo, Liping Pan, Qi Zhu, Jiete Liang, Xianyao Luo, Qingcai Feng, Rong Xu, Yihao Liu, Xu Chen, Luxi Chen, Xiaohong Liu, Yaosheng Chen, Delin Mo.

  Intermuscular fat (IMF) infiltration is not only associated with myopathies and insulin resistance, but also serves as a key determinant of meat quality in the livestock industry. However, the molecular and cellular mechanisms influencing the intermuscular adipocyte abundance remain poorly understood. Based on porcine samples, we confirmed that the differentiation of intermuscular preadipocytes begins after birth, which prompted us to focus on the changes in the number of fibro/adipogenic progenitors (FAPs) during the embryonic stage. Using single-cell sequencing (ScRNA-seq) analysis of pig embryonic muscle, we constructed the first developmental atlas of embryonic FAPs and identified a distinct HMGB2+ subpopulation (FAPsHMGB2+) as a key determinant of FAP pool size. When HMGB2 is knocked out, both heterozygous and homozygous mice exhibit a remarkable reduction in the number of FAPs and impaired adipogenic potential. Correspondingly, the FAPsHMGB2+ were also found during muscle regeneration in mice. Unlike targeting C/EBPβ in vitro, HMGB2 governs FAP proliferation in vivo through targeting RAD21, a gene involved in DNA replication. Collectively, these findings provide novel insights into analyzing differences in IMF content and highlight potential targets for enhancing pork quality and mitigating pathological fat infiltration in skeletal muscles.

Keywords:  HMGB2; adipogenic differentiation; fibro/adipogenic progenitors; intermuscular fat; single‐cell RNA sequencing

DOI:  https://doi.org/10.1002/advs.202514363
Nat Commun. 2026 Jan 15. 17(1): 547

Development of a split-toxin CRISPR screening platform to systematically identify regulators of human myoblast fusion.

Haifeng Zhang, Renjie Shang, Zheng Zhang, Min Zhou, Anne Bigot, Yanqing Cai, Yanran Zhao, Yushu Wang, Aaryahi Deshmukh, Elena Kudryashova, Dmitri S Kudryashov, Cuiyu He, Vincent Mouly, Pengpeng Bi.

Muscle defects are common in human developmental disorders and often cause severe functional impairment. These defects arise from intricate tissue crosstalk and rare genetic mutations, underscoring the need to systematically identify cell-autonomous mechanisms regulating human myogenesis. Here we show a rationally designed, high-throughput genetic screening platform that integrates human myoblast models, customized CRISPR libraries, and a split-toxin strategy that enables quantitative selection of fusion-defective myocytes. Leveraging this platform, our initial screen uncovers a large group of hits essential for human myoblast fusion. The majority of these hits converge into 23 protein complexes. Notably, mutations in 41 screen hits are associated with human diseases marked by abnormal skeletal-muscle morphology. Applying a new single-cell CRISPR & RNA-seq approach, we show that majority of these hits control human myoblast fusion as well as influence early-stage myogenic differentiation. This work establishes a scalable approach to identify cell-autonomous regulators of human muscle differentiation and fusion.

DOI: https://doi.org/10.1038/s41467-025-67583-x
Free Radic Biol Med. 2026 Jan 09. pii: S0891-5849(26)00002-X. [Epub ahead of print]

MOTS-c improves intrinsic muscle mitochondrial bioenergetic health and efficiency in a PGC-1α/AMPK-dependent manner.

Anders Gudiksen, Camilla Collin Hansen, Thibaux van der Stede, Amalie Hertz Daugaard, Josefine H Schmidt, Stine Ringholm, Manal Merimi, Fatima Raad Al-Obaidi, Amanda Takamiya Kristoffersen, Egija Zole, Birgitte Regenberg, Rasmus Kjøbsted, Jørgen Wojtaszewski, Ylva Hellsten, Henriette Pilegaard.

Mitochondrial-derived peptides are a small class of regulatory peptides encoded by short open reading frames in mitochondrial DNA. One such peptide, mitochondrial open reading frame of the 12S rRNA-c (MOTS-c), has been shown to exert numerous beneficial effects on whole-cell and systemic metabolic parameters when administered exogenously. However, potential MOTS-c-mediated effects on mitochondrial bioenergetics have been largely overlooked. Therefore, the primary aim of the present study was to elucidate whether and, if so, how MOTS-c regulates skeletal muscle (SkM) mitochondrial function. We demonstrate, using two distinct transgenic mouse strains, that administration of MOTS-c augments/augmented muscle mitochondrial bioenergetic performance through reliance on both the transcriptional coactivator, Peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α), and cellular energy-sensing kinase, 5' adenosine monophosphate-activated protein kinase (AMPK). These effects seem to be exerted without apparent impact on mitochondrial respiratory protein content, alluding to intrinsic mitochondrial changes rather than changes in volume. Furthermore, MOTS-c treatment lowers mitochondrial reactive oxygen species (ROS) emission and ROS-related protein damage indicating substantial alleviation of cellular oxidative stress. RNA-sequence data reveal the effects of MOTS-c treatment to potentially be exerted subtly across a number of mitochondrial parameters such as redox handling, mitochondrial integrity and OXPHOS efficiency, jointly indicating a mechanistic basis for the observed functional improvements in mitochondrial bioenergetics. Despite increased interstitial MOTs-c levels no change was observed in the arterio-venous difference during one-legged knee extensor exercise in humans. This suggests that SkM may not be the source of circulating MOTS-c in response to exercise.

DOI: https://doi.org/10.1016/j.freeradbiomed.2026.01.002
Small. 2026 Jan 12. e11234

Genotype-Dependent Morpho-Mechanical Profiling of Patient-Derived Human Myotubes on Nanogrooved Substrates.

Raphaël Crépin, Anissa Aït Ouailal, Pierre Joanne, Onnik Agbulut, Vincent Mouly, Olek Maciejak, Michel Malo, Juan Pelta, Clément Campillo, Sid Labdi, Guillaume Lamour.

  Muscle disorders such as myofibrillar myopathies and Duchenne muscular dystrophy involve mutations in key cytoskeletal proteins and lead to progressive muscle degeneration. Yet, the mechanical characterization of affected muscle cells has relied mainly on immature or non-human models. Here, we introduce a human in vitro platform based on patient-derived immortalized myoblasts differentiated into myotubes on nanogrooved substrates, which promote alignment and organotypic maturation. Using immunostaining and atomic force microscopy (AFM), we show that desmin- and dystrophin-mutated myotubes exhibit distinct morphological and mechanical phenotypes compared to wild-type myotubes. We developed an AFM stiffness pipeline to quantify cell body stiffness across myotubes of variable thickness. Desmin- and dystrophin-mutated myotubes are stiffer than controls, with desmin mutants also displaying cytoskeletal disorganization. A dynamic fatigue assay (cyclic AFM indentations over time) further revealed impaired stiffening and faster mechanical fatigue in desmin mutants, while dystrophin mutants preserved resilience. This set of results establishes a reproducible and human-relevant system to probe muscle mechanics in disease, offering a unique intermediate model between conventional immortalized lines and complex iPSC-derived tissues, and enabling future quantitative screening and translational applications.

Keywords:  atomic force microscopy (AFM); duchenne muscular dystrophy (DMD); human muscle cell model; myofibrillar myopathies; myotube biomechanics

DOI:  https://doi.org/10.1002/smll.202511234
Commun Med (Lond). 2026 Jan 16.

Skeletal muscle transcriptional dysregulation of genes involved in senescence is associated with prognosis in severe heart failure.

Eric Rullman, Alen Lovric, Michael Melin, Rodrigo Fernandez-Gonzalo, Thomas Gustafsson.

BACKGROUND: The skeletal muscle hypothesis refers to a vicious cycle of successive deterioration of left ventricular function, skeletal muscle remodeling, and functional capacity in patients with heart failure. Despite extensive research, the regulatory mechanisms and their associations with clinical status and prognosis are still largely unclear.
METHODS: To identify mechanisms and characterize underlying processes involved in the disease pathophysiology, we performed RNA sequencing and network analysis using human skeletal muscle samples from 58 patients with severe symptomatic heart failure. A co-expression network with communities involved in established biological processes within human skeletal muscle was identified and validated in two independent cohorts.
RESULTS: Here, we show network communities associated with mitochondrial beta-oxidation, extracellular matrix remodeling, oxidative phosphorylation, and contractile elements with lower expression in heart failure patients than in age-matched controls. Based on the strong correlation with clinical features and prognosis, extracellular matrix remodeling, mitochondrial beta-oxidation, and p53 signalling communities are identified as key underlying processes. The former two communities are highly enriched with genes regulated by physical (in)activity, i.e., bed rest and exercise, and associated weakly with prognosis. Community related to p53 signalling, with CDKN1A as a key regulator, is increased in heart failure patients relative to age-matched controls and associated with worse prognosis.
CONCLUSION: The current work differentiates previously proposed factors underlying heart failure-induced skeletal muscle dysfunction, emphasizing the p53 signalling community and importance of biological age in this process. The distinct association with clinical status and prognosis furthermore supports pathophysiological significance and clinical potential of this community.

DOI: https://doi.org/10.1038/s43856-025-01362-z
Mol Biol Rep. 2026 Jan 12. 53(1): 278

Emerging therapeutic strategies in muscular dystrophy: an updated review on pathogenesis and treatment advances.

Shahid Parwez, Khurshid Ahmad, Eun Ju Lee, Inho Choi.

  Muscular dystrophy (MD) comprises a class of genetic conditions characterized by the progressive degeneration and weakness of skeletal muscle. Genetic etiologies differ among the major muscular dystrophies: myotonic dystrophy type 1 (DM1) is linked to CTG repeat expansion in DMPK whereas DM2 is linked to CCTG repeat expansion in CNBP; facioscapulohumeral muscular dystrophy (FSHD1) is linked to contraction of the D4Z4 repeat to cause inappropriate DUX4 expression whereas FSHD2 is linked to mutations in chromatin modifier SMCHD1 that derepress DUX4 expression. Despite advancements in investigations into the molecular mechanisms, effective treatments for MD remain limited. This review study aims to elaborate on the pathogenesis of each type of MD, including the underlying genetic mutations, cellular dysfunction, and pathway deregulation. We also conduct comprehensive research on various breakthroughs in treatment strategies, including protein replacement therapies, stem-cell-based, exon skipping, gene therapy, and recently discovered drugs for MD. Furthermore, this study focuses on the artificial intelligence (AI)-based improvement in the diagnosis, management, and treatment of MD. The AI-based discovery of compounds has provided novel treatment modalities that hold potential for managing MD conditions.

Keywords:  Artificial intelligence; Duchenne muscular dystrophy; Dystrophin; Machine learning; Muscular dystrophies

DOI:  https://doi.org/10.1007/s11033-025-11418-x
Physiol Genomics. 2026 Jan 16.

Systems Genomics Reveals Age- and Sex-Dependent Metabolic Dysregulation from Glo1 Reduction in Mice.

Ingrid Cely, Montgomery Blencowe, Le Shu, Graciel Diamante, In Sook Ahn, Guanglin Zhang, Jonnby LaGuardia, Ruoshui Liu, Owen Briscoe, Zara Saleem, Susanna Wang, Richard C Davis, Hongxiu Qi, Aldons J Lusis, Xia Yang.

  Objectives:Glyoxalase 1 (Glo1) detoxifies reactive dicarbonyl compounds such as methylglyoxal, a precursor of advanced glycation end products (AGEs), which contribute to metabolic disorders. However, the contribution of AGE-independent mechanisms to Glo1-related metabolic dysfunction remains unclear. Methods: We conducted a longitudinal study in male and female Glo1 heterozygous knockdown (Glo1+/-) mice (~50% Glo1 expression). Metabolic phenotypes, including body weight, adiposity, glycemic control, and plasma lipid levels, were assessed over time. Atherosclerotic burden, AGE levels, and gene expression profiles in liver, adipose, muscle, kidney, and aorta were examined to identify pathway alterations and regulatory genes affected by Glo1 reduction. Results: Partial Glo1 loss resulted in obesity, hyperglycemia, dyslipidemia, and altered lipid metabolism in an age- and sex-dependent manner, with most phenotypes emerging after ~14 weeks. Glo1+/- females exhibited impaired glycemic control and elevated triglycerides, along with perturbations in adipogenesis, PPARγ signaling, insulin signaling, and fatty acid metabolism in liver and adipose tissue. Glo1+/- males displayed increased skeletal muscle mass and visceral adiposity with changes in lipid metabolic pathways. Methylglyoxal-derived AGE accumulation was altered only in male skeletal muscle and did not explain broader phenotypes. Transcriptomic analyses suggest altered glucose and lipid metabolism may be partially driven by alternative detoxification of methylglyoxal to metabolites such as pyruvate. Transcription factor analysis identified Hnf4a (across tissues) and Arntl (in aorta, liver, and kidney) as female-biased regulators altered by Glo1 deficiency. Conclusions: Glo1 reduction disrupts metabolic health through sex- and age-dependent pathways largely independent of AGE accumulation, involving tissue-specific metabolic reprogramming and transcriptional regulation.

Keywords:  Aging; Glyoxalase 1; Metabolic syndrome; Sex Differences; Transcriptome

DOI:  https://doi.org/10.1152/physiolgenomics.00106.2025
PLoS One. 2026 ;21(1): e0340647

Sex differences in cachexia outcomes and branched-chain amino acid metabolism following chemotherapy in aged mice.

Stephen Mora, Gagandeep Mann, Olasunkanmi A J Adegoke.

Cachexia is a complex muscle wasting syndrome that affects the majority of hospitalized cancer patients receiving chemotherapy. It is often unresponsive to nutritional interventions, including provision of branched-chain amino acids (BCAAs: leucine, isoleucine and valine). BCAAs are anabolic for skeletal muscle. We wondered whether their ineffectiveness in managing cachexia might be related to altered metabolism of these amino acids, a subject that has received minimal attention. Because estrogen limits BCAA catabolism, we hypothesized that the effects of chemotherapy on cachexia in old mice would be worse in males compared to females, and that this would be related to greater tissue release of the BCAAs in males. To better reflect the age population for which cachexia is an issue, we treated aged male and female mice (18 ± 2 months) with the chemotherapy drug cocktail FOLFIRI (50 mg/kg 5-fluorouracil (5FU), 90 mg/kg Leucovorin, and 24 mg/kg CPT11) or vehicle twice per week for 6 weeks. This cocktail is used in treating colon cancer. Metabolism and concentrations of the BCAAs and their metabolites were measured in plasma and tissues. There was a main effect of chemotherapy, reflected in reduced body weight, skeletal muscle, myofibrillar protein content, anabolic signalling and protein synthesis. In response to chemotherapy, males showed worsened outcomes for skeletal muscle weight and ubiquitinated proteins; they also had higher total plasma BCAAs but reduced muscle BCAAs. There was a main effect of chemotherapy in reducing the expression of the BCAA transporter LAT1. In response to chemotherapy, gastrocnemius muscle of males but not females had reduced inhibitory phosphorylation of BCKD-E1αser293, corresponding with increased activity of this enzyme. Chemotherapy reduced muscle and liver ketoacids of the BCAAs only in females. These data suggest that sex differences in BCAA catabolism may be linked to the severity of chemotherapy-induced muscle damage and interventions against cachexia need to take this into account.

DOI: https://doi.org/10.1371/journal.pone.0340647
JBMR Plus. 2026 Feb;10(2): ziaf193

Single-cell transcriptional mapping of Mustn1 exhibits consistent mural cell localization across musculoskeletal tissues.

Christopher J Janton, Anne Nichols, Michael Hadjiargyrou.

  The musculoskeletal temporally activated novel gene (Mustn1) is a 9.2-kDa microprotein that has been extensively studied within musculoskeletal tissues. Utilizing open-source, single-cell RNA sequencing datasets, we used a top-down, transcriptional approach that combines systems-wide and targeted-tissue mapping of Mustn1. In doing so, we observed robust mural cell-state colocalization of Mustn1 and Acta2 (encoding alpha smooth muscle actin [aSMA]) within bone, synovium, muscle, and tendon tissues. Mapping Mustn1 within recently documented, uncharacterized cell clusters of Sox9 lineage also revealed overlap with musculoskeletal fibroadipogenic progenitors (FAPs) and mural cells. Overall, these findings demonstrate that aSMA-expressing cells of the periosteum and tendon sheath provide a highly selective cell population to leverage the study of Mustn1 during musculoskeletal development and repair.

Keywords:  alpha smooth muscle actin (aSMA); bone; fibroadipogenic progenitors (FAPs); mural cell; musculoskeletal temporally activated novel gene (Mustn1); perivascular cell; single-cell RNA sequencing (scRNA-seq); skeletal muscle; tendon; vascular smooth muscle cell (vSMC)

DOI:  https://doi.org/10.1093/jbmrpl/ziaf193
Commun Biol. 2026 Jan 14.

WDR62 is required for proper proliferation and early differentiation of skeletal myoblasts.

Uda Y Ho, Belal Shohayeb, Hinako Kamei, Matthew J Morris, Yvonne Y Yeap, Dominic Richards, Melissa E Reichelt, Walter G Thomas, Peter G Noakes, S Sean Millard, Dominic C H Ng.

WDR62, a centrosome and microtubule associated protein, regulates mitotic spindle formation and centrosome integrity in progenitor cells during development. While its role in neural progenitor differentiation is known, its function in myogenesis remains unclear. Here, we show that WDR62 deficient mice possess smaller skeletal muscles. Following cardiotoxin injury to the tibialis anterior muscle, WDR62 deficient mice show normal satellite cell activation, but display a higher percentage of immature myofibers at day 7 post injury, suggesting premature differentiation. In Drosophila larvae, Wdr62 knockdown in the wing disc increases asymmetric myoblast division resulting in premature differentiation. In C2C12 mouse myoblasts, WDR62 loss leads to decreased myoblast proliferation due to increased centriole numbers and centriole cohesion, and a slight increase in myoblast fusion at day 3 differentiation, which supports premature differentiation. These data implicate WDR62 in maintaining centrosome integrity that is critical for myoblast proliferation and preventing premature differentiation during early stages of myogenesis.

DOI: https://doi.org/10.1038/s42003-026-09537-7
Nat Metab. 2026 Jan 15.

Multi-omics profiling of cachexia-targeted tissues reveals a spatio-temporally coordinated response to cancer.

Pauline Morigny, Michaela Vondrackova, Honglei Ji, Kristyna Brejchova, Monika Krakovkova, Konstantinos Makris, Radka Trubacova, Tuna F Samanci, Doris Kaltenecker, Su-Ping Ng, Vignesh Karthikaisamy, Sophia E Chrysostomou, Anna Bidovec, Mariana Ponce-de-Leon, Tanja Krauss, Claudine Seeliger, Olga Prokopchuk, Marc E Martignoni, Melina Claussnitzer, Hans Hauner, Martina Schweiger, Laure B Bindels, Mauricio Berriel Diaz, Stephan Herzig, Dominik Lutter, Ondrej Kuda, Maria Rohm.

Cachexia is a wasting disorder associated with high morbidity and mortality in patients with cancer. Tumour-host interaction and maladaptive metabolic reprogramming are substantial, yet poorly understood, contributors to cachexia. Here we present a comprehensive overview of the spatio-temporal metabolic reprogramming during cachexia, using integrated metabolomics, RNA sequencing and 13C-glucose tracing data from multiple tissues and tumours of C26 tumour-bearing male mice at different disease stages. We identified one-carbon metabolism as a tissue-overarching pathway characteristic for metabolic wasting in mice and patients and linked to inflammation, glucose hypermetabolism and atrophy in muscle. The same metabolic rewiring also occurred in five additional mouse models, namely Panc02, 8025, ApcMin, LLC and KPP, and a humanised cachexia mouse model. Together, our study provides a molecular framework for understanding metabolic reprogramming and the multi-tissue metabolite-coordinated response during cancer cachexia progression, with one-carbon metabolism as a tissue-overarching mechanism linked to wasting.

DOI: https://doi.org/10.1038/s42255-025-01434-3
Clin Exp Med. 2026 Jan 14.

Multi-omics and molecular testing: A new insight into the genetic mechanisms of sarcopenia and arthritis.

Zhonghai Wang, Meiling Yu, Han Wang.

  Sarcopenia and arthritis, characterized by age-related progressive loss of skeletal muscle mass and function, profoundly impact the well-being of older adults. Our study endeavors to explore the unclear genetic structure between them. Using advanced statistical genetic approaches and genome-wide association study (GWAS) summary statistics, we explored the shared genetic basis among multiple manifestations of sarcopenia and four distinct arthritic conditions: osteoarthritis, rheumatoid arthritis, psoriatic arthritis, and gouty arthritis. We employed global and local genetic methods to gain potential shared biological mechanisms and determine binary local genetic correlations. Cross-phenotype association GWAS studies have revealed many genetic variations associated with complex traits. Transcriptome-wide association studies were conducted using weights from various human tissues to identify risk loci. We functionally annotated genomic multi-markers and fine-mapping colocalization by conducting the whole-genome unified testing of molecular characteristics. Significant correlations between sarcopenia and arthritis were detected through comprehensive and local genetic correlation analyses. At the genomic level, we identified 19 unique bivariate regions, including chr3q27.3, chr5q35.3, and chr12q13.2-q13.3, involving multiple human genes such as KBM7, GM12878, and IMR90. Gene enrichment analyses revealed that the selected loci primarily signaled through elementary pathways, including central nervous system neuron axonogenesis, glutamatergic synapse, and beta-catenin binding. Specifically, GDF5 and DNAJC27 were prioritized as the most probable candidate genes via transcriptomics. Our study has identified pleiotropic genomic regions linking sarcopenia and arthritis, providing novel insights into their genetic mechanisms.

Keywords:  Arthritis; Genetic architecture; Phenotypic loci; Sarcopenia

DOI:  https://doi.org/10.1007/s10238-025-01985-5
Proc Natl Acad Sci U S A. 2026 Jan 20. 123(3): e2511722123

Multiple modes of AFM reveal distinct mechanical properties for dystrophin and utrophin not manifest by small fragments.

Cailong Hua, Joseph Vavra, Jacob Powers, Joseph M Muretta, James M Ervasti, Murti V Salapaka.

  Duchenne muscular dystrophy (DMD) is a lethal muscle disease caused by the absence of the protein dystrophin. Dystrophin is hypothesized to work as a molecular shock absorber that limits myofiber membrane damage when undergoing reversible unfolding upon muscle stretching and contraction. Here, we report the mechanical characterization of single full-length dystrophin (Dys) molecules using two operational modes of atomic force microscopy; constant speed and constant force as well as Monte Carlo simulations. Furthermore, we have compared Dys with large fragments encoding the N-terminus through spectrin repeat 10 (DysN-R10), the C-terminal retinal isoform of dystrophin (Dp260), and full-length utrophin (Utr). Our comprehensive data reveal that Dys, DysN-R10, and Dp260, all show a uniform, brittle unfolding behavior, whereas Utr demonstrates more complex unfolding dominated by a stiffening spring behavior. These fundamentally different mechanical behaviors in vitro suggest different in vivo functions for Dys and Utr with implications for the potential efficacy of Utr upregulation to substitute for Dys deficiency in DMD.

Keywords:  constant speed and constant force experiments; dystrophin; force spectroscopy; mechanical properties; utrophin

DOI:  https://doi.org/10.1073/pnas.2511722123