Inotodiol prevents age-related muscle wasting by restoring mitochondrial function through liver X receptor beta signaling.

Sarcopenia is characterized by a progressive decline in muscle mass and strength and represents a major contributor to increased mortality in the elderly population. Mitochondrial dysfunction, which leads to impaired energy metabolism and elevated oxidative stress, is a key driver of muscle wasting and associated metabolic disorders. Thus, mitochondrial targeting is a promising strategy for combating sarcopenia. In this study, we investigated the therapeutic potential of the mycosterol inotodiol (Ino) in mitigating age-related muscle wasting and metabolic dysfunction. Ino treatment significantly improved muscle mass and function in aged mice and prevented dexamethasone (DEX)-induced muscle atrophy. Ino enhanced mitochondrial function and restored muscle metabolism, as evidenced by increased mitochondrial content, elevated oxidative capacity, reduced lipid accumulation, and decreased oxidative stress. In addition, Ino attenuated palmitic acid (PA)-induced lipotoxicity in muscle cells by restoring lipid metabolism. Further investigation revealed that Ino activates liver X receptor β (LXRβ) and promotes its interaction with peroxisome proliferator-activated receptor δ (PPARδ), thereby increasing sirtuin 3 (Sirt3) transcription. Consequently, Ino activates the LXRβ/SIRT3/peroxisome proliferator-activated receptor gamma coactivator 1-α (PGC-1α) signaling pathway, a central regulator of mitochondrial function and metabolic homeostasis. Collectively, these findings identify Ino as a promising therapeutic candidate for preserving mitochondrial function and alleviating age-associated muscle dysfunction.