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
BACKGROUND AND PURPOSE
The molecular mechanisms underlying denervation-induced muscle atrophy remain incompletely understood, and effective therapeutic interventions are currently lacking. Tectorigenin (TG), a natural isoflavonoid, has demonstrated antioxidant and metabolic regulatory activities. This study investigated whether TG also alleviates denervation-induced muscle atrophy via activation of the AMPK/SIRT1/PGC-1α signalling pathway.
EXPERIMENTAL APPROACH
A sciatic nerve transection model was established in ICR mice to evaluate the therapeutic effects of TG. Histomorphology, oxidative stress markers, mitochondrial function and pathway activity were assessed. A nutrient deprivation-induced C2C12 myotube atrophy model was used for in vitro validation. Pathway-specific inhibitors (Compound C, EX-527 and SR18292) were applied both in vivo and in vitro to confirm mechanistic involvement.
KEY RESULTS
TG treatment significantly improved muscle wet weight ratio, myofibre cross-sectional area and myosin heavy chain expression in denervated mice. It reduced levels of atrophy-related ubiquitin ligases, attenuated oxidative stress and improved mitochondrial integrity. TG reversed the denervation-induced suppression of AMPK/SIRT1/PGC-1α signalling and downstream effectors. In C2C12 myotubes, TG dose-dependently ameliorated atrophy and up-regulated SIRT1/PGC-1α. Pharmacological inhibition of AMPK, SIRT1 or PGC-1α abolished TG's protective effects, both in vitro and in vivo.
CONCLUSIONS AND IMPLICATIONS
TG mitigates denervation-induced muscle atrophy through a multi-mechanistic approach involving activation of the AMPK/SIRT1/PGC-1α axis, enhancement of mitochondrial dynamics and restoration of redox homeostasis. This study identifies TG as a promising candidate for clinical translation in the treatment of neurogenic muscle atrophy.
Boya Liu, Fei Xue, Xingxing Fang et al.· British Journal of Pharmacol...· 0 citations
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