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.
Abstract
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.
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.
J. An, Guang-Shun Lai, Jing Zuo et al.· The FEBS Journal· 0 citations
Objectives Sarcopenia, characterized by age-associated loss of skeletal muscle mass, function, and physical performance, is a major challenge in aging societies because of its association with a decreased lifespan. Existing gene expression-based diagnostic methods often rely on large gene sets, requiring high costs and analytical complexity. In this study, we developed a machine learning-driven framework to identify senescence-associated cell states in skeletal muscle tissue. Methods Publicly available single-cell RNA sequencing data from 2- and 24-month-old C57BL/6J male mice from single-cell and single-nucleus RNA sequencing datasets comprising over 365,000 cells from skeletal muscle were obtained from the DRYAD Repository and consolidated into 15 cell populations. Candidate genes for machine learning were selected from differential expression analysis. Multiple machine learning algorithms, including logistic regression, support vector machines, and random forest, were trained with recursive feature elimination. Model performance was evaluated using the area under the receiver operating characteristic curve. Results Differential expression analysis across 15 distinct cell populations yielded 30 candidate genes, to which five machine learning models were applied to select biomarkers. Using our approach, we identified a four-gene panel (Malat1, Wdr89, Zfp36, and Jund) exhibiting high predictive accuracy. This panel was validated using additional aging datasets and compared with existing models, which highlighted its potential as a reliable tool for detecting senescence-associated cells. Conclusions In this study, we established a four-gene biomarker panel for detecting senescence-associated cells in skeletal muscle, providing a practical tool for investigating sarcopenia pathophysiology and identifying therapeutic targets.
Taro Kunitomi, Yuri Yamashita, Eri Arikawa-Hirasawa· Juntendo Medical Journal· 0 citations
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
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.
Melissa A. Boldridge, Lei Xu, Xiaoyin Wang et al.· bioRxiv· 0 citations
