Microbiota-derived 3-phenylpropionic acid promotes myotube hypertrophy by Foxo3/NAD+ signaling pathway.

Background: Gut microbiota and their metabolites play a regulatory role in skeletal muscle growth and development, which be known as gut-muscle axis. 3-phenylpropionic acid (3-PPA), a metabolite produced by colonic microorganisms from phenylalanine in the gut, presents in large quantities in the blood circulation. But few study revealed its function in skeletal muscle development.

Results: Here, we demonstrated the beneficial effects of 3-PPA on muscle mass increase and myotubes hypertrophy both in vivo and vitro. Further, we discovered the 3-PPA effectively inhibited protein degradation and promoted protein acetylation in C2C12 and chick embryo primary skeletal muscle myotubes. Mechanistically, we supported that 3-PPA reduced NAD⁺ synthesis and subsequently suppressed tricarboxylic acid cycle and the mRNA expression of SIRT1/3, thus promoting the acetylation of total protein and Foxo3. Moreover, 3-PPA may inhibit Foxo3 activity by directly binding.

Conclusions: This study firstly revealed the effect of 3-PPA on skeletal muscle growth and development, and newly discovered the interaction between 3-PPA and Foxo3/NAD⁺ which mechanically promote myotubes hypertrophy. These results expand new understanding for the regulation of gut microbiota metabolites on skeletal muscle growth and development.