Skeletal muscle mitochondrial oxidative phosphorylation capacity is associated with aerobic capacity and neuromuscular performance in patients with heart failure with preserved ejection fraction
A Martinez-Dominguez, M Gutierrez-Garcia, S Oscoz-Ochandorena, R Ramirez-Velez, M IzquierdoAbstract
Background
Functional capacity is a major determinant of quality of life and prognosis in heart failure with preserved ejection fraction (HFpEF). Although exercise intolerance has been traditionally attributed to central hemodynamic limitations, accumulating evidence implicates peripheral skeletal muscle abnormalities, including impaired mitochondrial oxidative phosphorylation (OXPHOS), as key contributors. However, the association between skeletal muscle OXPHOS capacity and both cardiorespiratory fitness and neuromuscular performance in HFpEF is not well defined.
Purpose
To examine the association between skeletal muscle OXPHOS capacity with exercise performance, including peak oxygen uptake and peripheral muscle strength and power, in patients with HFpEF.
Methods
This secondary analysis used a subsample of baseline data from 40 patients with HFpEF (mean [SD] age, 66.6 [9.6] years) completed a symptom-limited cycle ergometer cardiopulmonary exercise testing with breath-by-breath gas exchange. Peripheral muscle performance was assessed by 1-repetition maximum knee extension strength and knee extension power using an E-GYM machine. Vastus lateralis muscle biopsies were obtained for high-resolution respirometry, and skeletal muscle OXPHOS capacity was quantified in permeabilized fibers using a standardized substrate–uncoupler–inhibitor titration protocol. Body composition was assessed by dual-energy X-ray absorptiometry. Associations between OXPHOS capacity and exercise performance outcomes were examined using simple linear regression. Participants were additionally stratified into tertiles of OXPHOS capacity, and differences across tertiles in peak oxygen uptake (VO₂peak/kg), maximal CPET power output, maximal strength, and mean muscle power were evaluated using ANCOVA adjusted for age and sex.
Results
After adjustment for age and sex, OXPHOS tertiles differed significantly across aerobic and neuromuscular outcomes (all P≤.001; partial η², 0.33–0.41). Higher OXPHOS capacity was associated with greater peak oxygen uptake (β=0.56; adjusted R²=0.66; P≤.001) and higher maximal cycle ergometer power output (β=0.48; adjusted R²=0.73; P≤.001). OXPHOS capacity was also associated with greater knee extension mean power (β=0.30; adjusted R²=0.79; P≤.001) and maximal strength (β=0.29; adjusted R²=0.79; P≤.001).
Conclusion(s)
In patients with HFpEF, skeletal muscle OXPHOS capacity was independently associated with aerobic capacity, muscle power, and maximal strength. These findings reinforce the relevance of peripheral skeletal muscle bioenergetic dysfunction in HFpEF and support mitochondrial oxidative capacity as a potential therapeutic target to improve functional capacity in this population. ClinicalTrials.gov: NCT07251361.