Succinate dehydrogenase (SDH)-Complex II regulates skeletal muscle cellular respiration and fatigue but not muscle mass in genetically induced pulmonary emphysema [3 wk]
Skeletal muscle wasting and reduced oxidative capacity coexist in patients with COPD/pulmonary emphysema and are independently associated with higher mortality. Whether reduced respiration contributes to muscle atrophy in that setting remains unknown. We have previously shown that a mouse with genetically induced COPD/pulmonary emphysema recapitulates muscle dysfunction features present in patients' muscles, including reduced expression and activity of succinate dehydrogenase (SDH), which are partially reversed by genetic gain of SDH function. Previous research suggests that succinate accumulation, a by-product of SDH inhibition, can increase respiratory capacity of skeletal muscle. Here, we generated an inducible, muscle-specific SDH-C knockout mouse which demonstrates lower mitochondrial oxygen consumption and oxidative fibers' contractility, associated with overall reduced exercise endurance. These changes are partially offset by mitochondrial complex I-dependent respiration, a respiratory pattern replicated in the muscles from the COPD/pulmonary emphysema genetic model. Moreover, while mice skeletal muscle SDH-C knockout causes an early succinate accumulation associated with a downregulated transcriptome, these changes do not correlate with the proteomic landscape; and animals muscle mass, fiber-type composition, and dry body mass constituents remain unaltered. We preset the first conditional, skeletal muscle-specific SDH-C knockout animal and demonstrate that while SDH-C regulates fibers respiration in genetically induced pulmonary emphysema, it does not control muscle mass. Overall design: Differential expression of genes (mRNA) isolated from tibialis anterior (TA) skeletal muscle; 3 wk post induction WT vs. skeletal muscle SDHC-KO mice.