The ageing microenvironment in sarcopenia: early alterations and targeted therapeutic strategies

Abstract

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.