High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific ring finger protein 1 (MuRF1)

Ariel Jaitovich, Martín Angulo, Emilia Lecuona, Laura A. Dada, Lynn C. Welch, Yuan Cheng, Galina Gusarova, Ermelinda Ceco, Chang Liu, Masahiko Shigemura, Esther Barreiro, Cam Patterson, Gustavo A. Nader, Jacob I. Sznajder

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Abstract

Patients with chronic obstructive pulmonary disease, 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 ratios, and anabolic capacity. High CO2 induced the expression of MuRF1 in vivo and in vitro, whereas MuRF1-/- mice exposed to high CO2 did not develop muscle atrophy. AMP-activated kinase (AMPK), a metabolic sensor, was activated in myotubes exposed to high CO2, and loss-of-function studies showed that the AMPKα2 isoform is necessary for muscle-specific ring finger protein 1 (MuRF1) up-regulation and myofiber size reduction. High CO2 induced AMPKα2 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 AMPKα2-FoxO3a-MuRF1, which is of biological and potentially clinical significance in patients with lung diseases and hypercapnia.

Original languageEnglish (US)
Pages (from-to)9183-9194
Number of pages12
JournalJournal of Biological Chemistry
Volume290
Issue number14
DOIs
StatePublished - Apr 3 2015

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All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Biology
  • Cell Biology

Cite this

Jaitovich, A., Angulo, M., Lecuona, E., Dada, L. A., Welch, L. C., Cheng, Y., Gusarova, G., Ceco, E., Liu, C., Shigemura, M., Barreiro, E., Patterson, C., Nader, G. A., & Sznajder, J. I. (2015). High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific ring finger protein 1 (MuRF1). Journal of Biological Chemistry, 290(14), 9183-9194. https://doi.org/10.1074/jbc.M114.625715