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. Although previous evidence indicates that high CO2 
accelerates skeletal muscle catabolism via AMPK (AMP-activated protein 
kinase)-FoxO3a-MuRF1 (E3-ubiquitin ligase muscle RING finger protein 1), 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 demonstrated depressed ribosomal gene expression in 
comparison with locomotor muscles from non-CO2-retaining individuals, and 
analysis of the muscle proteome of 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 into skeletal muscle. Hypercapnia did 
not regulate the mTOR pathway, and rapamycin-induced deactivation of mTOR did 
not cause a 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. Although previous evidence has 
implicated TIF1A (transcription initiation factor-1α) and KDM2A (lysine-specific 
demethylase 2A) in AMPK-driven regulation of ribosomal gene expression, we found 
that these mediators were 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.