Molecular mechanisms of skeletal muscle atrophy: clinical challenges and future therapeutic strategies.

Skeletal muscle atrophy, characterized by loss of muscle mass and function, is a debilitating feature of chronic diseases, aging, and disuse.It fundamentally results from a sustained imbalance where rates of protein degradation surpass those of synthesis.Key drivers include the hyperactivation of proteolytic systems: the ubiquitin-proteasome system (UPS), autophagy-lysosome pathway (ALP), and calpain/caspase cascades. These systems are regulated by intricate signaling networks. The anabolic insulin-like growth factor 1/phosphoinositide 3-kinase/protein kinase B/mammalian target of rapamycin (IGF-1/PI3K/Akt/mTOR) pathway promotes protein synthesis, while catabolic pathways-including Forkhead box O (FOXO), myostatin/activin-Smad, nuclear factor-kappa B (NF-κB), and Janus kinase/signal transducer and activator of transcription (JAK/STAT)-enhance protein breakdown. Recent research implicates oxidative stress, mitochondrial dysfunction, chronic inflammation, endoplasmic reticulum stress, epigenetic alterations, and programmed cell death (e.g., ferroptosis, pyroptosis) in a complex pathogenic network. Translating these mechanistic insights into effective therapies faces significant hurdles: the intricate interplay of molecular pathways, disparities between preclinical models and human disease, and limitations of current interventions. While exercise, pharmacology, and nutrition offer benefits, their applicability and efficacy are often constrained.A host ofemergingstrategies-such as stem cell and exosome therapies, mitochondrial quality control, and epigenetic modulation-remain exploratory. Future progress necessitates a multidimensional approach: employing multi-omics to decipher mechanism heterogeneity and identify biomarkers; developing human-relevant disease models; and pioneering combinatorial and precision therapies. Integrating these efforts is crucial for advancing the prevention and treatment of skeletal muscle atrophy, ultimately improving patient outcomes.