Targeting ubiquitin-dependent mitochondrial autophagy and apoptosis in sarcopenia: the therapeutic potential of phytochemicals.

Sarcopenia is a progressive degenerative disease of skeletal muscle closely associated with aging, disuse, and chronic diseases, affecting approximately 10-16% of the global older adult population. Its core pathological basis lies in the disruption of skeletal muscle cell proteostasis and mitochondrial dysfunction. At the molecular level, excessive degradation of structural proteins mediated by the ubiquitin-proteasome system forms an intertwined vicious cycle with the inability of ubiquitin-dependent mitophagy to clear damaged organelles, ultimately triggering irreversible cell death programmes within an oxidative stress and inflammatory microenvironment. Due to the high complexity and molecular crosstalk within this cell fate-determining network, traditional single-target interventions often yield limited therapeutic efficacy. In recent years, phytochemicals (such as polyphenols, flavonoids, alkaloids, and coumarins) have demonstrated significant therapeutic potential in the field of sarcopenia due to their unique multi-target, multi-pathway synergistic regulatory advantages. This article reviews the dual-faceted regulatory mechanisms of ubiquitination in skeletal muscle mitochondrial quality control, protein hydrolysis, and apoptosis escape and provides an analysis of how phytochemicals achieve autophagy-promoting, anti-apoptotic, and anti-degradative skeletal muscle protection. However, oral bioavailability is often below 1%, microbiota-dependent metabolism, and the absence of phase III clinical trials have hindered the translational application of phytochemicals. This paper explores the use of nano-delivery systems to overcome the bioavailability bottleneck of phytochemicals, as well as translational application strategies based on the gut-muscle axis to reshape the in vivo metabolism of natural products. This review aims to provide a solid theoretical foundation for the development of novel phytochemical-derived drugs targeting ubiquitination and apoptosis networks and to chart a course for reversing skeletal muscle ageing and enhancing human healthspan.