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Cited by 137Muscle Physiology and DisordersMetabolism, Diabetes, and CancerMuscle metabolism and nutrition

High CO2 Levels Cause Skeletal Muscle Atrophy via AMP-activated Kinase (AMPK), FoxO3a Protein, and Muscle-specific Ring Finger Protein 1 (MuRF1)

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Jaitovich, Ariel, Angulo, Martín, Lecuona, Emilia, Dada, Laura A., Welch, Lynn C., Cheng, Yuan, Gusarova, Galina, Ceco, Ermelinda +6 more·2015·Journal of Biological Chemistry
DOI 10.1074/jbc.m114.625715PMC PMC4423704
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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.

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References 63 · Cited by 137

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Authors
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.
Affiliations
  • Northwestern University (US)
  • Karolinska Institutet (SE)
  • Universitat Pompeu Fabra (ES)
  • University of North Carolina at Chapel Hill (US)
Corresponding author
Sznajder, Jacob I.
ORCID
Venue
Journal of Biological Chemistry
Publisher
Elsevier BV
Published
2015-04
Volume
290
Issue
14
Pages
9183-9194
ISSN
0021-9258 (ISSN-L)
DOI
10.1074/jbc.m114.625715
PMC
PMC4423704
OpenAlex
W2048084454
Cited by
137
References
63
Citations by year
2026: 6 · 2025: 15 · 2024: 4 · 2023: 8 · 2022: 9 · 2021: 14 · 2020: 23 · 2019: 12 · 2018: 12 · 2017: 18 · 2016: 11 · 2015: 5
FWCI
6.66
Type
journal article
Language
en
Open access
Licence
Locations
  • Journal of Biological Chemistry (publishedVersion, cc-by)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • RECERCAT (Consorci de Serveis Universitaris de Catalunya) (acceptedVersion)
  • Carolina Digital Repository (University of North Carolina at Chapel Hill) (submittedVersion)
  • Repositori digital de la UPF (Universitat Pompeu Fabra) (submittedVersion)
  • UNC Libraries
Funders
National Institutes of Health (CA060553)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Muscle metabolism and nutrition
Keywords
hypercapnia, elevated CO2, skeletal muscle atrophy, AMPK, AMPKα2, FOXO3, MuRF1, muscle fiber size, myotube atrophy, chronic obstructive pulmonary disease, acute lung injury, muscle dysfunction
MeSH terms
Tripartite Motif Proteins, Forkhead Box Protein O3, Adenylate Kinase, Animals, Base Sequence, Carbon Dioxide, Cell Line, Male, Mice, Inbred C57BL, Muscle Proteins, Muscular Atrophy, Up-Regulation, DNA Primers, Muscle, Skeletal, Ubiquitin-Protein Ligases, Mice, Forkhead Transcription Factors, Real-Time Polymerase Chain Reaction

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