title: High CO2 levels cause skeletal muscle atrophy via AMP-activated kinase (AMPK), FoxO3a protein, and muscle-specific Ring finger protein 1 (MuRF1).
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.
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Ariel
authors.initials: A
authors.lastname: Jaitovich
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, Departamento de Fisiopatología, Facultad de Medicina, Universidad de la República, Montevideo, Uruguay.
authors.forename: Martín
authors.initials: M
authors.lastname: Angulo
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Emilia
authors.initials: E
authors.lastname: Lecuona
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Dada
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Lynn C
authors.initials: LC
authors.lastname: Welch
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Yuan
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Galina
authors.initials: G
authors.lastname: Gusarova
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Ermelinda
authors.initials: E
authors.lastname: Ceco
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Chang
authors.initials: C
authors.lastname: Liu
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611.
authors.forename: Masahiko
authors.initials: M
authors.lastname: Shigemura
authors.affiliation: Pulmonology Department-Muscle and Respiratory System Research Unit, Molecular Mechanisms of Lung Cancer Predisposition Research Group (IMIM)-Hospital del Mar-IMIM, Department of Experimental and Health Sciences, Universitat Pompeu Fabra, The Barcelona Biomedical Research Park, Barcelona, Spain, and Centro de Investigación en Red de Enfermedades Respiratorias (CIBERES), Instituto de Salud Carlos III (ISCIII), Madrid, Spain, and.
authors.forename: Esther
authors.initials: E
authors.lastname: Barreiro
authors.affiliation: McAllister Heart Institute, University of North Carolina, Chapel Hill, North Carolina.
authors.forename: Cam
authors.initials: C
authors.lastname: Patterson
authors.affiliation: Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden.
authors.forename: Gustavo A
authors.initials: GA
authors.lastname: Nader
authors.affiliation: From the Division of Pulmonary and Critical Care Medicine, Northwestern University, Chicago, Illinois 60611, j-sznajder@northwestern.edu.
authors.forename: Jacob I
authors.initials: JI
authors.lastname: Sznajder
mesh_terms: D000263:Adenylate Kinase / Q000378:metabolism*; D000818:Animals; D001483:Base Sequence; D002245:Carbon Dioxide / Q000378:metabolism*; D002460:Cell Line; D017931:DNA Primers; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009124:Muscle Proteins / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000209:etiology*; D060888:Real-Time Polymerase Chain Reaction; D000070584:Tripartite Motif Proteins; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D015854:Up-Regulation
chemical_list: D017931:DNA Primers; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D009124:Muscle Proteins; D000070584:Tripartite Motif Proteins; D002245:Carbon Dioxide; C499084:Trim63 protein, mouse; D044767:Ubiquitin-Protein Ligases; D000263:Adenylate Kinase
keywords: AMP-activated Kinase (AMPK); Chronic Obstructive Pulmonary Disease (COPD); E3 Ubiquitin Ligase; FOXO; Skeletal Muscle