Skeletal Muscle Fibre Type Determines Mitochondrial and Metabolic Responses to Hypoxia and Pulmonary Inflammation in Young Adult Rats
Angelos Gavrielatos, Cécile Cottet‐Rousselle, Noé Brocker, Cindy Tellier, Amel Achouri, Alexandre Prola, Hervé Dubouchaud, Clovis ChabertABSTRACT
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 < 0.01), Hydroxyacyl‐Coenzyme A dehydrogenase activity (−27%; p < 0.01), weight (−17%; p < 0.05) and fCSA of Type IIb fibres (−16%; p < 0.05) in plantaris. In contrast, chronic hypoxia increased ROS emission (+74%; p < 0.01) without changes in mitochondrial respiration or mass in soleus. No alterations in fibre typology were observed in either muscle following the hypoxia exposure. Chronic pulmonary inflammation caused a reduction in mitochondrial CRC (−29%; p < 0.001) and an increase in GPDH activity in Type IIa fibres of soleus (+17%; p < 0.001) without any changes in fibre type distribution. Conversely, chronic pulmonary inflammation induced a downregulation of GPDH activity in plantaris types I and IIa fibres (−27% and −32%, respectively; p < 0.05), in parallel with an elevation in the SDH/GPDH ratio across all fibre types (+73%; p < 0.05) and a rise in the proportion of Type IIx fibres (+12%; p < 0.05).
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.