Ileal FXR-FGF15/19 signaling activation improves skeletal muscle loss in aged mice.

Sarcopenia is the age-related decrease in skeletal muscle mass, and current therapies for this disease are ineffective. We previously showed that ileal farnesoid X receptor (FXR)-fibroblast growth factor 15/19 (FGF15/19) signaling acts as a regulator of gut microbiota to mediate host skeletal muscle. However, the therapeutic potential of this pathway for sarcopenia is unknown. This study showed that ileal FXR-FGF15/19 signaling was downregulated in older men and aged male mice due to changes in the gut microbiota and microbial bile acid metabolism during aging. In addition, the intestine-specific FXR agonist fexaramine increased skeletal muscle mass and improve muscle performance in aged mice. Ileal FXR activation increased skeletal muscle protein synthesis in a FGF15/19-dependent way, indicating that ileal FXR-FGF15/19 signaling is a potential therapeutic target for sarcopenia.