Reduced energy metabolism contributing to aging of skeletal muscle by serum metabolomics and gut microbiota analysis

Sarcopenia is an age-related syndrome characterized by a gradual loss of the muscle mass, strength, and function. It is associated with a high risk of adverse consequences such as poorer quality of life, falls, disability and mortality among the elderly. The aim in this study is to investigate the pathological mechanism of sarcopenia.The aging of skeletal muscle was investigated by the D-galactose induced accelerated aging model combining with constrained motion. After 10 weeks, muscle function and gastrocnemius muscle index, and morphology of muscle fibers were evaluated, and myostatin, IGF-1 and ATP in skeletal muscle were also determined. Then the mechanism of aging-related skeletal muscle dysfunctions was investigated based on untargeted serum metabolomics and 16S rRNA gene sequencing. Four key metabolites were validated by the D-galactose-induced C2C12 senescent cell model in vitro.Results showed that gastrocnemius muscle mass was decreased significantly, morphology of muscle fibers was altered, and muscle function was damaged in the aged group. Furthermore, increased MSTN, and decreased IGF-1 and ATP were also observed in the aging skeletal muscle. Importantly, alteration of the key pathways including riboflavin biosynthesis and energy metabolism contributed to the aging of skeletal muscle. Four key metabolites, including riboflavin, α-ketoglutaric acid and two dicarboxylic acids, which were involved in these metabolic pathways, could promote the proliferation of C2C12 cells.These findings provide novel insights into pathological mechanism of sarcopenia, and will facilitate the development of therapeutic and preventive strategies for sarcopenia.