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

Area of Science:

• Microbiology
• Metabolomics
• Muscle Physiology

Background:

• The gut-muscle axis highlights the role of gut microbiota metabolites in skeletal muscle regulation.
• 3-phenylpropionic acid (3-PPA) is a gut microbial metabolite abundant in circulation, with its skeletal muscle functions largely unexplored.

Purpose of the Study:

• To investigate the effects of 3-phenylpropionic acid (3-PPA) on skeletal muscle growth and development.
• To elucidate the underlying molecular mechanisms of 3-PPA's action in muscle tissue.

Main Methods:

• In vivo and in vitro studies using C2C12 myotubes and chick embryo primary skeletal muscle cells.
• Analysis of protein degradation, protein acetylation, NAD+ synthesis, and gene expression (SIRT1/3).
• Investigation of potential direct binding of 3-PPA to Foxo3.

Main Results:

• 3-PPA demonstrated beneficial effects on increasing muscle mass and promoting myotube hypertrophy.
• 3-PPA inhibited protein degradation and enhanced protein acetylation in skeletal muscle cells.
• Mechanistically, 3-PPA reduced NAD+ synthesis, suppressed the tricarboxylic acid cycle and SIRT1/3 expression, leading to increased protein and Foxo3 acetylation, potentially via direct Foxo3 inhibition.

Conclusions:

• This study is the first to reveal the impact of 3-PPA on skeletal muscle growth and development.
• A novel interaction between 3-PPA, Foxo3, and NAD+ was identified, mechanistically promoting myotube hypertrophy.
• Findings enhance the understanding of how gut microbiota metabolites regulate skeletal muscle physiology via the gut-muscle axis.