Succinate dehydrogenase–complex II regulates skeletal muscle cellular respiration and contractility but not muscle mass in genetically induced pulmonary emphysema
Reduced skeletal muscle mass and oxidative capacity coexist in patients with pulmonary emphysema and are independently associated with higher mortality. If reduced cellular respiration contributes to muscle atrophy in that setting remains unknown. Using a mouse with genetically induced pulmonary emphysema that recapitulates muscle dysfunction, we found that reduced activity of succinate dehydrogenase (SDH) is a hallmark of its myopathic changes. We generated an inducible, muscle-specific SDH knockout mouse that demonstrates lower mitochondrial oxygen consumption, myofiber contractility, and exercise endurance. Respirometry analyses show that in vitro complex I respiration is unaffected by loss of SDH subunit C in muscle mitochondria, which is consistent with the pulmonary emphysema animal data. SDH knockout initially causes succinate accumulation associated with a down-regulated transcriptome but modest proteome effects. Muscle mass, myofiber type composition, and overall body mass constituents remain unaltered in the transgenic mice. Thus, while SDH regulates myofiber respiration in experimental pulmonary emphysema, it does not control muscle mass or other body constituents.
Authors
- Jason D. Doles (ORCID: https://orcid.org/0000-0002-6830-708X)
- Jack A. Elias (ORCID: https://orcid.org/0000-0002-3124-8557)
- Joseph Balnis (ORCID: https://orcid.org/0000-0003-0894-2839)
- Emily Jackson (ORCID: https://orcid.org/0000-0003-1096-0331)
- Harold A. Singer (ORCID: https://orcid.org/0000-0001-8554-3239)
- David Lacomis (ORCID: https://orcid.org/0000-0001-8646-943X)
- Ariel Jaitovich (ORCID: https://orcid.org/0000-0003-4714-2260)
- Lisa A. Drake (ORCID: https://orcid.org/0000-0002-3217-1715)
- Annie Jen (ORCID: https://orcid.org/0000-0001-5569-8387)
- David Jourd’heuil (ORCID: https://orcid.org/0000-0002-6555-5061)
- Diane V. Singer
- Joshua J. Coon (ORCID: https://orcid.org/0000-0002-0004-8253)
- Chun Geun Lee (ORCID: https://orcid.org/0000-0002-9514-3658)
- Ankita Tufts
- Catherine E. Vincent
- Louis James Maher (ORCID: https://orcid.org/0000-0002-5043-6422)
Institutions
- Mayo Clinic (US)
- University of Wisconsin–Madison (US)
- University of Pittsburgh (US)
- Brown University (US)
- Morgridge Institute for Research (US)
- Institute for Clinical Pharmacodynamics (United States) (US)
- Mayo Clinic in Arizona (US)
- Indiana University School of Medicine
- Indiana University – Purdue University Indianapolis (US)
- Albany Medical Center Hospital (US)
Publication Details
- Journal
- Science Advances
- Published
- 2024-08-21
- DOI
- https://doi.org/10.1126/sciadv.ado8549
- Citations
- 8
- Primary Topic
- Chronic Obstructive Pulmonary Disease (COPD) Research
- Type
- article
- Field-Weighted Citation Impact
- 3.35
Funders
- National Institutes of Health