High CO2 downregulates skeletal muscle protein anabolism via AMPKα2-mediated depressed ribosomal biogenesis.

Abstract

High CO2 retention, or hypercapnia, is associated with worse outcomes in patients with chronic pulmonary diseases. Skeletal muscle wasting is also an independent predictor of poor outcomes in patients with acute and chronic pulmonary diseases. While previous evidence indicates that high CO2 accelerates skeletal muscle catabolism via AMPK-FoxO3a-MuRF1, little is known about the role of high CO2 in regulating skeletal muscle anabolism. In the present study we investigated the potential role of high CO2 in attenuating skeletal muscle protein synthesis. We found that locomotor muscles from patients with chronic CO2 retention demonstrate depressed ribosomal gene expression in comparison with non-CO2 retaining individuals, and analysis of muscle proteome from normo- and hypercapnic mice indicates reduction of important components of ribosomal structure and function. Indeed, mice chronically kept under a high CO2 environment show evidence of skeletal muscle downregulation of ribosomal biogenesis; and decreased protein synthesis as measured by the incorporation of puromycin to skeletal muscle. Hypercapnia did not regulate mTOR pathway and rapamycin-induced deactivation of mTOR did not cause decrease in ribosomal gene expression. Loss-of-function studies in cultured myotubes showed that AMPKα2 regulates CO2-mediated reductions in ribosomal gene expression and protein synthesis. While previous evidence has implicated transcription factor TIF-1A and the lysin demethylase KDM2A in AMPK-driven regulation of ribosomal gene expression, we found that these mediators are not required in the high CO2-induced depressed protein anabolism. Our research supports future studies targeting ribosomal biogenesis and protein synthesis to alleviate the effects of high CO2 on skeletal muscle turnover.