Skeletal muscle fibre type determines mitochondrial and metabolic responses to hypoxia and pulmonary inflammation.

BackgroundChronic 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. MethodsAdult male Wistar rats were subjected to chronic hypoxia (FiO2=10%) and/or chronic pulmonary inflammation (induced by bi-weekly intratracheal instillations of lipopolysaccharides). After 4 weeks of exposure, 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, fibre cross-sectional area (fCSA) as well as succinate dehydrogenase (SDH) and glycerol-3-phosphate dehydrogenase (GPDH) activities. ResultsChronic hypoxia led to a decline in adenosine diphosphate-stimulated complex I (CI) respiration (p<0.01), Hydroxyacyl-Coenzyme A dehydrogenase activity (p<0.01), weight (p<0.05) and fCSA of type IIb fibres (p < 0.05) in plantaris. In contrast, chronic hypoxia increased CI-derived ROS emission (p<0.01) without changes in mitochondrial respiration or mass of soleus. No alterations in fibre typology were noticed in either muscle following the hypoxic exposure. Chronic pulmonary inflammation caused a reduction in mitochondrial CRC and an increase in GPDH activity in type IIa fibres of soleus (p<0.001) without any changes in fibre type distribution. Conversely, chronic pulmonary inflammation induced a downregulation of GPDH activity in plantaris type I and type IIa fibres, in parallel with an elevation in the SDH/GPDH ratio across all fibre types and a rise in the proportion of type IIx fibres. ConclusionsOur results demonstrate fundamental differences in the responses to chronic hypoxia and chronic pulmonary inflammation between soleus and plantaris. While 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 mitochondrial alterations seem to occur independently of fibre type shifts highlighting the central role of intrinsic mitochondrial maladaptations in the COPD-associated muscle dysfunction.