Patients with chronic obstructive pulmonary disease (COPD), acute lung injury and critical care illness may develop hypercapnia. Many of these patients often have muscle dysfunction which increases morbidity and impairs their quality of life. Here, we investigated whether hypercapnia leads to skeletal muscle atrophy. Mice exposed to high CO2 had decreased skeletal muscle wet weight, fiber diameter, and strength. Cultured myotubes exposed to high CO2 had reduced fiber diameter, protein/DNA ratio and anabolic capacity. High CO2 induced the expression of MuRF1 in vivo and in vitro, while MuRF1-/- mice exposed to high CO2 did not develop muscle atrophy. AMPK, a metabolic sensor, was activated in myotubes exposed to high CO2 and loss-of-function studies showed that AMPK-a2 isoform is necessary for MuRF1 up-regulation and myofiber size reduction. High CO2 induced AMPK-a2 activation, triggering the phosphorylation and nuclear translocation of FoxO3a, and leading to an increase in MuRF1 expression and myotube atrophy. Accordingly, we provide evidence that high CO2 activates skeletal muscle atrophy via AMPKa2-FoxO3a-MuRF1, which is of biological and potentially clinical significance in patients with lung diseases and hypercapnia.

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