Skeletal Muscle Fibre Type Determines Mitochondrial and Metabolic Responses to Hypoxia and Pulmonary Inflammation in Young Adult Rats

ABSTRACT Background Chronic obstructive pulmonary disease (COPD) patients often experience skeletal muscle dysfunction that may result from a complex combination of mitochondrial dysfunction, metabolic reprogramming and fibre type transitions. Among other factors, pulmonary inflammation and hypoxia contribute to the COPD‐associated muscle defects. Nevertheless, the precise molecular mechanisms and their effects across muscles with distinct metabolic profiles remain elusive. This study investigated the independent and combined effects of chronic pulmonary inflammation and chronic hypoxia on mitochondrial function, metabolic enzyme activity and fibre‐type composition in oxidative (soleus) and glycolytic (plantaris) muscles. Methods Adult male Wistar rats were subjected to 4 weeks of chronic hypoxia (FiO 2  = 10%) and/or chronic pulmonary inflammation (induced by 1 mg/kg biweekly intratracheal instillations of lipopolysaccharides). Mitochondria from both soleus and plantaris were isolated to measure oxygen consumption rates, reactive oxygen species (ROS) emission, calcium retention capacity (CRC), respiratory complex activities and fatty acid oxidation capacity. Cross‐sections from both muscles were analysed for fibre typology and fibre cross‐sectional area (fCSA) as well as succinate dehydrogenase (SDH) and glycerol‐3‐phosphate dehydrogenase (GPDH) activities. Results Chronic hypoxia led to a decline in adenosine diphosphate‐stimulated complex I (CI)–mediated respiration (−37%; p  p  p  p  p  p  p  p  p  p   Conclusions Our results demonstrate fundamental differences in the responses to chronic hypoxia and chronic pulmonary inflammation between soleus and plantaris. Although hypoxia affects predominantly the mitochondrial function and mass of plantaris, pulmonary inflammation drives metabolic reprogramming in both muscles that opposes their intrinsic functional specialisation. Additionally, soleus appears more vulnerable to permeability transition pore opening following pulmonary inflammation. Notably, these alterations occurred independently of fibre type transitions, suggesting a role for qualitative mitochondrial alterations in COPD‐associated muscle dysfunction.