EXPRESS: Endurance Exercise Training in Pulmonary Hypertension increases Skeletal Muscle Electron Transport Chain Supercomplex Assembly

Introduction: Pulmonary hypertension (PH) is associated with pronounced exercise intolerance (decreased V̇ O2 max) that can significantly impact quality of life. The cause of exercise intolerance in PH remains unclear. Mitochondrial supercomplexes (SC) are large respiratory assemblies of individual electron transport chain (ETC) complexes which can promote more efficient respiration. In this study, we examined PH and exercise-induced changes in skeletal muscle ETC protein expression and SC assembly. Methods: PAH was induced in rats with the Sugen/Hypoxia model (10% FiO2, 3 weeks). PAH and control rats were assigned to an exercise training protocol (EXT group) or kept sedentary (SED) for 1 month. Cardiac function and V̇ O2 max were assessed at the beginning and end of EXT. Red (RG: Type 1-oxidative muscle) and white (WG: Type 2–glycolytic muscle) gastrocnemius were assessed for changes in ETC complex protein expression and SC assembly via SDS- and Blue Native (BN)-PAGE. Results: PAH caused a significant decrease in V̇ O2 max via treadmill testing that was improved with exercise (P<0.01). Decreases in cardiac output (CO) and pulmonary acceleration time (PAT) due to PAH were not improved with exercise. PAH reduced expression in individual ETC complex protein expression (NDUFB8(CI), SDHB(CII), CoxIV (CIV), but not UQCRC2(CIII), or ATP5a(CV)) in RG muscle. Both RG and WG ETC expression was unaffected by exercise. However, non-denaturing BN-PAGE analysis of mitochondrial supercomplexes demonstrated increases with EXT in PAH in the RG but not WG muscle. Conclusion: PAH-induced exercise intolerance is improved with exercise and is associated with muscle type specific alteration in mitochondrial SC assembly and expression of mitochondrial ETC proteins.