Aug 2026· iScience· Vol 29, pp. 117000· 0 citations· 116 references
Medicine
TL;DR
A spatial transcriptomic atlas of skeletal muscle from young and aged mice is presented, resolving transcriptional reprogramming across fiber types and tissue compartments and revealing alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring.
Abstract
Summary Sarcopenia, the age-related decline in skeletal muscle mass and function, profoundly affects skeletal muscle structure and performance. We present a spatial transcriptomic atlas of skeletal muscle from young and aged mice, resolving transcriptional reprogramming across fiber types and tissue compartments. Our analyses reveal alterations in sarcomeric organization, excitation-contraction coupling, oxidative stress responses, and fiber type-specific metabolic rewiring. Conserved molecular signatures across muscles and species highlight Car3 as a potential biomarker of sarcopenia. We also uncover a selective downregulation of polyamine biosynthetic enzymes, leading to reduced spermidine levels in aged muscle. This decline affects muscle-resident populations, as limiting polyamine metabolic flux in both murine and human fibro-adipogenic progenitors (hFAPs) induces aging-like features, including myofibroblast differentiation, extracellular matrix dysregulation, and impaired ability to support myogenesis. Together, our findings reveal spatially organized, fiber type-specific, and polyamine-linked mechanisms of muscle aging and position the polyamine pathway as a promising therapeutic target.
Skeletal muscle aging is characterized by the deterioration of muscle function, which can lead to negative quality-of-life outcomes including frailty and sarcopenia. While understanding the mechanisms of this process is increasingly important as the global population ages, previous molecular studies of skeletal muscle aging have been limited by statistical power and cell type resolution. In this study, we analyzed single-nucleus gene expression and chromatin accessibility data from 287 human skeletal muscle samples from individuals aged 20-79 years to explore sex- and cell type-specific aging effects. Across 467,126 nuclei from 13 cell types, we identify 384 age-associated genes and 4,061 age-associated chromatin regions. These age-associated molecular features are enriched for functional pathways, including metabolic processes, cell-to-cell communication, and senescence Kyoto Encyclopedia of Genes and Genomes KEGG terms. Age-associated closing chromatin was more common across fiber types and sexes than opening chromatin, and was enriched in active enhancer regions while depleted for active transcription start sites. We observe enrichment for specific transcription factor motifs in closing chromatin, including those of glucocorticoid and androgen receptors, both of which play a key role in the maintenance of healthy skeletal muscle. Together, these findings identify an age-associated regulatory shift, largely invisible in matched transcriptomic data, characterized by closing chromatin which reduces accessibility to hormone receptor binding sites and enhancer regions in the muscle fiber epigenome.
Keagan G. Moo, Peter Orchard, A. Varshney et al.· bioRxiv· 0 citations
Skeletal muscle undergoes a progressive decline in mass and function with aging, a condition that in its extreme form is known as sarcopenia. This is driven by complex cellular and molecular alterations, such as shifts in myonucleus composition, increased fibrosis, and fat or immune cell infiltration. Despite extensive research, effective therapeutic interventions for sarcopenia remain limited. Recent advances in single-cell omics technologies have begun to unravel the cellular and molecular heterogeneity of mouse and human skeletal muscle across the lifespan, identifying age-enriched cell states and dynamic transcriptional changes. However, epigenetic regulation during skeletal muscle aging is less well characterized. To help address this gap, we performed single-nucleus Assay for Transposase-Accessible Chromatin using sequencing (snATAC-seq) on skeletal muscle from young adult and aged male mice, generating chromatin accessibility profiles from over 43,000 nuclei. Among other findings, our analyses reveal an age-enriched pro-atrophy subpopulation of type IIb myonuclei marked by increased chromatin accessibility at the Ampd3 locus. Furthermore, we delineate the epigenetic mechanisms underlying the transition of healthy type IIb myonuclei into Ampd3+ myonuclei, revealing key chromatin remodeling events that drive this phenotypic shift. Moreover, by integrating with an existing single-nucleus RNA sequencing dataset of the same anatomical origin, we identified thousands of cell-type-specific cis-regulatory elements related to aging programs. Within these elements, we observed a broad depletion of binding motifs for transcription factors with roles in cellular identity and muscle regeneration, concomitant with the gain of stress-responsive transcription factors. Our work helps understand the epigenetic events underlying mammalian skeletal muscle aging.
J. An, Guang-Shun Lai, Jing Zuo et al.· The FEBS Journal· 0 citations
Sarcopenia is characterized by progressive decline in skeletal muscle mass and function, driven in part by impaired mitochondrial homeostasis and redox imbalance. However, the upstream regulators that integrate metabolic resilience with muscle integrity during ageing remain poorly defined. Here, we identify the cell adhesion molecule Cdon as a conserved determinant of adult muscle maintenance whose expression declines with human aging, sarcopenia and muscle-wasting disease. Reduced Cdon expression was associated with transcriptional atrophy signatures, metabolic insufficiency and reduced myofibre size. Using a Cdon promoter-based screen, we identified meloxicam (Mcam) as a small molecule inducer of Cdon that enhances myogenic differentiation, increases muscle mass and function in young mice and mitigates age-related muscle atrophy. Mcam treatment also improved neuromuscular conduction and systemic metabolic parameters, including blood glucose regulation and hepatic lipid accumulation. In aged muscle, Mcam normalized cysteine accumulation, restored redox balance, improved mitochondrial metabolism and reduced oxidative stress. Mechanistically, Mcam activated Ampk signalling to preserve Cdon expression under oxidative challenge and support antioxidant and mitochondrial quality control pathways. Together, these findings identify Cdon decline as a hallmark of muscle ageing and demonstrate that Mcam preserves muscle integrity by reestablishing redox and metabolic homeostasis through Ampk-dependent maintenance of Cdon. Age-related decline of Cdon is a key molecular feature of skeletal muscle dysfunction. In this study, meloxicam restored Cdon expression through Ampk activation, thereby preserving muscle integrity and functional capacity in aged muscle. Mechanistically, meloxicam normalized cysteine metabolism and elevates Gpx4 expression, improving glutathione buffering and suppressing excessive reactive oxygen species accumulation. Activation of the Ampk-Cdon axis was associated with maintenance of mitochondrial homeostasis and redox balance. Together, these findings identify Cdon as a potential therapeutic target for age-associated skeletal muscle degeneration.
Ju-Hyeon Bae, Hyun-Kyung So, Yideul Jeong et al.· Experimental and Molecular M...· 0 citations
Resistance exercise (RE) improves strength and muscle mass, with multiple benefits for human health. However, intense RE also induces acute myofibrillar damage. The molecular mechanisms that preserve, mark, degrade, and restore damaged proteins to keep skeletal muscle working under RE are incompletely understood. Based on repeated sampling of human skeletal muscle, we show here that acute, repeated and interrupted RE induce dynamic changes of the protein landscape associated with the sarcomeric cytoskeleton. These changes correlate with changes in phosphorylation indicative of adaptation and deadaptation signaling footprints. Regulation mainly affects the protein network linked to the muscle maintenance protein BAG3, which includes mechanosensory proteins, small heat shock proteins, and a lipid droplet associated protein. All network components exhibit altered phosphorylation and increased cytoskeletal association after damaging RE. Moreover, network components cooperate to recognize strained skeletal muscle structures and mediate their degradation through chaperone-assisted selective autophagy (CASA). Our study thus identifies key regulators of skeletal muscle homeostasis in humans. This study reveals molecular responses of untrained, adapted and deadapted human skeletal muscle to resistance exercise, which identifies a network of mechanosensory proteins and molecular chaperones that ensures skeletal muscle homeostasis.
Maithreyan Kuppusamy, D. Jacko, Yamini Gupta et al.· Nature Communications· 0 citations
Ageing is a major risk factor for degenerative diseases, including sarcopenia, which is characterized by a progressive loss of skeletal muscle mass and function, frailty, and is associated with increased mortality. Skeletal muscle regeneration relies on muscle stem cells and efficient communication with cellular microenvironment. With ageing, skeletal muscle regenerative capacity declines, and sarcopenia results from complex, multitissue dysregulation involving mitochondrial dysfunction, immune ageing, chronic inflammation, senescence, extracellular matrix modification, disruption of neuromuscular junctions and muscle‐specific vulnerability. This review summarizes current knowledge contributing to sarcopenia and inefficient muscle repair during ageing from cell‐autonomous metabolic dysregulation to age‐associated changes in the local and systemic cellular environment. We also explore recent insights into important role of exercise on muscle tissue health. Overall, emerging technologies, including human muscle atlases and spatial transcriptomics, together with exercise‐based interventions, will help to identify of novel biomarkers and therapeutic targets to better prevent and treat sarcopenia.
J. D. Hernández-Camacho, Marielle Saclier· Journal of Cellular Physiolo...· 0 citations
Exercise training confers broad health benefits, yet molecular regulators of skeletal muscle adaptation, particularly sex-specific mechanisms, remain incompletely understood. Integrating new and previously published multi-omics data from the molecular transducers of physical activity consortium (MoTrPAC), we characterized metabolomic, epigenomic, transcriptomic, proteomic, and post-translational modification (PTM) responses to 1-8 weeks of endurance exercise training in male and female rat gastrocnemius. While transcriptomic and proteomic responses were largely sex-concordant, there were distinct sex-specific training-induced PTM signatures, particularly in the redox proteome. Females exhibited decreased mitochondrial protein cysteine oxidation alongside increased oxidation of glycolytic proteins relative to males, suggesting sex-biased subcellular reactive oxygen species (ROS) dynamics. Multi-omic factor analysis (MOFA) identified coordinated sex-concordant molecular programs and further supported female-specific mechanisms of redox buffering with training. Together, these findings indicate that sex-specific skeletal muscle exercise adaptations are particularly evident at the PTM level in rats, and identify future avenues for precision exercise health and medicine.
Gina M. Many, C. Jin, N. Day et al.· Cell Reports· 0 citations