Aug 2026· The FEBS Journal· 0 citations· 58 references
Medicine
TL;DR
The epigenetic mechanisms underlying the transition of healthy type IIb myonuclei into Ampd3+ myonuclei, revealing key chromatin remodeling events that drive this phenotypic shift are delineated, helps understand the epigenetic events underlying mammalian skeletal muscle aging.
Abstract
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.
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
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.
Veronica Ruggieri, Andrea Bracaglia, Lorenza Esposito et al.· iScience· 0 citations
Aging is the primary risk factor for most chronic diseases and is characterized in striated muscle by progressive functional decline, mitochondrial dysfunction, and chronic inflammation. The miR-128-1 locus resides within a positively selected haplotype on chromosome 2q21.3 associated with variation in grip strength, pulmonary function, and cardiometabolic traits in humans. Here, we show that antisense oligonucleotide-mediated inhibition of miR-128-3p restores muscle mass and function in aged mice, improves cardiac function while limiting adverse remodeling following myocardial infarction, and ameliorates skeletal and cardiac muscle pathology in mouse and pig models of Duchenne muscular dystrophy. Across these contexts, miR-128-3p inhibition induces a conserved transcriptional response characterized by activation of mitochondrial programs and suppression of inflammatory and fibrotic signaling, resembling the effects of established longevity interventions. These findings identify miR-128-3p as a regulator of a conserved aging-associated program and establish its inhibition as a strategy to restore tissue function across aging-related muscle pathologies. Graphical Abstract Highlights miR-128 loci associate with reduced grip strength; miR-128-1 also with lung function. miR-128-3p drives mitochondrial dysfunction and inflammation in striated muscle. Anti-miR-128 ASO rescues function in aged, infarcted, and dystrophic muscle. Inhibition recapitulates transcriptional effects of longevity interventions.
Aging is a progressive decline in biological function that is proposed to be driven by the accumulation of epigenetic noise and the loss of epigenetic information. Among epigenetic readouts, DNA methylation has been extensively used to develop aging clocks, machine learning models that predict age from molecular data. However, DNA methylation clocks are relatively difficult to interpret and remain distant from gene regulatory networks, a gap that can be complemented by clocks built from another epigenetic layer: chromatin accessibility profiled by ATAC-seq. Existing chromatin accessibility clocks predict age from bulk ATAC-seq data, thereby averaging over the epigenetic heterogeneity across cells that drives aging. We hypothesized that a chromatin accessibility clock trained at the level of individual cell types, using pseudobulk profiles derived from single-nucleus ATAC-seq (snATAC-seq) data, would be particularly useful for characterizing cell type-specific aging. We focused on the brain, a highly heterogeneous tissue whose diverse cell types age asynchronously, and assessed how well cell type-specific accessibility clocks can predict chronological age, capture rejuvenation from genetic perturbation, and detect age acceleration in age-associated neurodegenerative disease. To this end, we introduce a set of cell type-specific and all-cell aging clocks built from snATAC-seq profiles of the prefrontal cortex (PFC) of 357 human donors (15 to 100 years), which generalize to accurately predict age across brain regions and species. Beyond healthy aging, these PFC clocks captured the rejuvenating effects of SIRT6 overexpression in mouse liver and cell type-specific age acceleration in Alzheimer’s disease (AD) and Parkinson’s disease, with microglial age acceleration correlating most strongly with pathology among major cell types, and with female oligodendrocytes and OPCs showing the largest sex differences in age acceleration. Interpreting the clocks further revealed the regulatory elements, genes, pathways, and motifs underlying these signals across species, disease, and perturbation, including repression of the NF-κB pathway in SIRT6 transgenic mice, upregulation of immune and inflammatory pathways in severe AD, and conserved age-predictive peaks related to histone regulation, metabolism, and neuronal survival across brain regions and species. Together, these results establish PFC snATAC-seq aging clocks as a generalizable tool that accurately predicts age and captures cell type-specific perturbation effects of rejuvenation and disease on the epigenetic landscape, providing both a means to evaluate perturbations and insight into the epigenetic mechanisms of aging and disease.
Patrick Z. Yu, Doudou Yu, Yao Xue et al.· bioRxiv· 0 citations
Skeletal muscle aging is a complex biological process that involves coordinated changes in multiple cell types. Recent breakthroughs in single-cell sequencing technology have provided new perspectives regarding this process. Here, we systematically summarize current progress in single-cell technology with respect to skeletal muscle aging. We focused on specific molecular characteristics and interaction networks of muscle fiber, satellite and immune cells during aging. Aging skeletal muscles develop cellular heterogeneity such as a decline in stem cell function, formation of a chronic inflammatory microenvironment, and remodeling the extracellular matrix. We integrated multi-omics data to identify potential intervention targets and explored precise anti-aging strategies using single-cell data. Although this field has significantly progressed, persistent challenges include technical methods, data integration, and clinical translation. Future studies are needed to optimize single-cell analysis techniques, deepen understanding of cell interaction mechanisms, and promote the translation of related findings into clinical applications. These will provide vital references for understanding the molecular basis of muscle aging and developing new intervention methods.
Yanteng Wang, Yichen Yang, W. Guan et al.· Ageing Research Reviews· 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
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