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Mechanisms of Ageing and Development
Volume 202, 2022, 111630

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

Yixuan Qiua,b,c,1, Jiaming Yua,b,c,1, Xueying Jia,b,c,1, Huiyuan Yua,b,c

Department of Gerontology, Huadong Hospital Affiliated to Fudan University, Shanghai, 200000, China.

Abstract

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.

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