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.
Abstract
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.
Sarcopenia is a progressive skeletal muscle disorder associated with ageing and characterized by declines in muscle strength, mass and function. Increasing evidence suggests that its development is not driven solely by myofiber atrophy or impaired protein metabolism, but also by early remodeling of the ageing skeletal muscle microenvironment. This Review summarizes key early alterations in sarcopenia, including dysregulated immune homeostasis, cellular senescence and the senescence-associated secretory phenotype, depletion and dysfunction of muscle satellite cells, disruption of the regenerative niche, mitochondrial dysfunction, impaired proteostasis and neuromuscular junction degeneration. In aged skeletal muscle, chronic low-grade inflammation, oxidative stress, extracellular matrix stiffening and reduced regenerative capacity reinforce one another, establishing a self-amplifying cycle of inflammation, senescence and regeneration failure. This cycle may first impair muscle quality and contractile performance, resulting in early muscle weakness, and subsequently promote myofiber atrophy, fibrosis, fatty infiltration and overt functional decline. Accordingly, therapeutic strategies for sarcopenia should move beyond interventions aimed only at end-stage muscle loss and instead target the ageing microenvironment at earlier, potentially reversible stages. Potential approaches include exercise and nutritional interventions, modulation of inflammation, senescent cell clearance or suppression of the senescence-associated secretory phenotype, improvement of mitochondrial function and restoration of the muscle satellite cell niche. Biomarker- and omics-based population stratification may further support early detection, precision intervention and individualized management of sarcopenia.
Liang-Ping Zhang, Guang-Yang Li, Long Long et al.· Frontiers in Immunology· 0 citations
Sarcopenia is an age-related progressive degenerative disorder of skeletal muscle characterized by declining muscle mass, strength, and function. Increasing evidence indicates that chronic low-grade inflammation plays an important contributory role in its pathogenesis. The inflammatory microenvironment contributes to sarcopenia through complex interactions involving cellular senescence, mitochondrial dysfunction, and sustained inflammatory signaling, forming a self-reinforcing pathological cycle within skeletal muscle. This review synthesizes current evidence on the molecular mechanisms underlying inflammation-driven sarcopenia, with particular emphasis on how inflammatory signaling disrupts protein turnover and satellite cell metabolism. In addition, exercise is examined as a precision "hormone-like" intervention tailored to different sarcopenia phenotypes, highlighting the distinct mechanisms through which resistance training, aerobic exercise, and combined training modulate the senescence-associated phenotype and inflammatory responses. The review further evaluates anti-inflammatory therapeutic strategies, including nutritional interventions, pharmacotherapy, and acupuncture. These approaches improve muscle health by restoring immune balance, enhancing mitochondrial function, modulating the gut-muscle axis, reducing oxidative stress, and promoting the clearance of senescent cells. Finally, emerging precision medicine frameworks and multi-omics strategies that may support individualized sarcopenia management are discussed. Overall, this review provides an integrated perspective on inflammatory signaling in sarcopenia and outlines potential therapeutic strategies targeting the inflammatory microenvironment, offering insights for future research and clinical management.
Xuesong Wang, Shannah Erasmus, Zewen Chu et al.· Aging and Disease· 0 citations
Meloxicam (Mcam) is identified 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, and is identified 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
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, Arushi Varshney et al.· bioRxiv· 0 citations
Skeletal muscle, the largest organ system in the body, plays essential roles in movement, metabolism, and systemic homeostasis. Its dysfunction is implicated in a wide range of conditions, including sarcopenia, cancer cachexia, inflammatory myopathies, and neuromuscular disorders. Diverse forms of regulated cell death-including apoptosis, necroptosis, ferroptosis, pyroptosis, cuproptosis, and autophagy-dependent cell death-contribute to both skeletal muscle homeostasis and pathology through complex and interconnected signaling networks. This review summarizes the molecular mechanisms underlying major cell death pathways and discusses their context-dependent roles in skeletal muscle physiology, including development, adaptation, regeneration, and aging, as well as in disease progression. We further examine emerging therapeutic strategies targeting cell death signaling, including pharmacological agents, exercise and nutritional interventions, and gene- or cell-based approaches, with emphasis on their translational potential and current limitations. Finally, we discuss unresolved challenges in the field, including pathway crosstalk, spatiotemporal heterogeneity, and limited human validation, and highlight future directions for developing more precise therapeutic strategies for skeletal muscle diseases.
Jiahuan Gong, Hong-Yi Xu, Yun-Tian Shen et al.· European Journal of Pharmaco...· 2 citations
Skeletal muscle retains adaptive information from previous mechanical loading, enabling faster responses to subsequent training and regenerative challenges. This review synthesizes current evidence on the cellular and epigenetic mechanisms underlying skeletal muscle memory and examines how these mechanisms are modified by aging and post-injury regeneration. Muscle memory emerges from complementary structural and molecular components, including myonuclear retention, persistent DNA methylation changes, chromatin remodeling, transcriptional priming, non-coding RNA regulation, and mitochondrial epigenetic adaptations. These mechanisms interact with muscle satellite cells (MuSCs), fibro-adipogenic progenitors (FAPs), immune cells, and extracellular matrix remodeling to maintain regenerative competence. During aging, epigenetic drift, chronic low-grade inflammation, altered macrophage states, MuSC dysfunction, persistent FAP activity, fibrosis, mitochondrial impairment, and anabolic resistance progressively reduce this plasticity, thereby contributing to sarcopenia. Training–detraining–retraining studies indicate that parts of the exercise-induced epigenetic landscape remain detectable after training cessation and can be reactivated during renewed loading, although the persistence and functional importance of individual molecular signatures remain incompletely defined. Physical exercise remains the most established intervention for preserving muscle function and epigenetic responsiveness, whereas caloric restriction, modulation of nutrient-sensing pathways, senolytic strategies, and direct targeting of epigenetic regulators remain promising but translationally less mature approaches. Overall, the preservation of epigenetic plasticity may be a key determinant of healthy skeletal muscle aging and effective regeneration.
Antoni Godlewski, M. Wróblewski, Julia Kuk et al.· Genes· 0 citations
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