The dual role of cell death in skeletal muscle homeostasis and disease: Mechanisms and therapeutic targeting.

Abstract

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.