Endurance exercise training in pulmonary hypertension increases skeletal muscle electron transport chain supercomplex assembly

Abstract

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

Exercise intolerance in pulmonary arterial hypertension: insight into central and peripheral pathophysiological mechanisms

“…However, the absence of paired control subjects, the lack of measurements of the ATP cost of contraction or the limited details regarding the exercise done to measure phosphocreatine recovery time preclude confident conclusions to be made from that study. Interestingly, MCCULLOUGH et al [145] demonstrated plasticity in mitochondrial function after endurance exercise training in Sugen/hypoxia PAH rat model, especially for mitochondrial complex I and III.…”

Skeletal muscle deficits are associated with worse exercise performance in pediatric pulmonary hypertension

“…Functional impairment can manifest as reduced muscle strength, decreased muscular endurance, impaired oxygenation in the microcirculation, reduced type I fiber tension, and sarcomeric dysfunction ( 6 , 8 , 9 , 44 , 45 ). Molecular abnormalities have been described including reduced oxidative capacity, increased protein degradation and decreased protein synthesis, impaired angiogenesis, and impaired mitochondrial function ( 11 , 46 , 47 ). The spectrum of muscular abnormalities in children with PH is unknown.…”

Skeletal muscle dysfunctions in pulmonary arterial hypertension: Effects of aerobic exercise training

“…In fact, PAH decreases exercise tolerance. On the other hand, it was verified that aerobic physical exercise increases the maximum consumption of oxygen ( McCullough et al, 2020 ), as well as increases the cross-sectional area of the skeletal muscle, which improves exercise tolerance ( Moreira-Gonçalves et al, 2015a ).…”

“…The study by Kue et al (2017) reported that the soleus muscle of animals with PAH showed a reduction in the expression of the coactivator-1 alpha of the receptor activated by gamma peroxisome proliferators (PGC1α) and mitochondrial DNA (mtDNA), without alteration in OPA1, thus, impairing mitochondrial biogenesis. Additionally, McCullough et al ( McCullough et al, 2020 ) demonstrated that PAH induced by Sugen/Hypoxia promoted negative changes in the expression of electron transport chain supercomplexes in the gastrocnemius of rats. Mitochondrial supercomplexes are dynamic sets of individual complexes in the electron transport chain that can lead to more efficient respiration ( Genova and Lenaz, 2014 ).…”

“…Concerning muscle metabolism, McCullough et al ( McCullough et al, 2020 ), reported recently that AET after experimental PAH induced by Sugen/Hypoxia increased mitochondrial supercomplexes in the electron transport chain in the oxidative portion of the gastrocnemius in rats. Thus, it is suggested that AET enhances both function and structure of mitochondria.…”