Mitochondria to motion: optimizing oxidative phosphorylation to improve exercise performance

Abstract

Mitochondria oxidize substrates to generate the ATP that fuels muscle contraction and locomotion. This review focuses on three steps in oxidative phosphorylation that have independent roles in setting the overall mitochondrial ATP flux and thereby have direct impact on locomotion. The first is the electron transport chain, which sets the pace for oxidation. New studies indicate that the electron transport chain capacity per mitochondria declines with age and disease, but can be revived by both acute and chronic treatments. The resulting higher ATP production is reflected in improved muscle power output and locomotory performance. The second step is the coupling of ATP supply from O2 uptake (mitochondrial coupling efficiency). Treatments that elevate mitochondrial coupling raise both exercise efficiency and the capacity for sustained exercise in both young and old muscle. The final step is ATP synthesis itself, which is under dynamic control at multiple sites to provide the 50-fold range of ATP flux between resting muscle and exercise at the mitochondrial capacity. Thus, malleability at sites in these subsystems of oxidative phosphorylation has an impact on ATP flux, with direct effects on exercise performance. Interventions are emerging that target these three independent subsystems to provide many paths to improve ATP flux and elevate the muscle performance lost to inactivity, age or disease.

Keywords: Exercise capacity; Exercise efficiency; Magnetic resonance spectroscopy; Mitochondrial coupling; Muscle energetics; P/O.

Fig. 1.

Diagram of the inner mitochondrial membrane, showing three processes that underlie oxidative phosphorylation. (1) The electron transport chain, which involves NADH oxidation; (2) the uncoupling of oxidation from phosphorylation by leaking H⁺ across the inner mitochondrial membrane (Leak); and (3) phosphorylation to generate ATP (ATP synthesis). F₀-F₁ denotes the ATP synthase, UCP is uncoupling protein and ANT is the adenine nucleotide transporter.

Fig. 2.

Muscle ultrastructure, leg performance and whole-body adaptations to endurance training in adults. (A) Comparison of changes in capillary density [N_A(c,f)], volume density of mitochondria [V̇_V(mt,f)], mass-specific maintained power, and mass-specific maximal O₂ consumption (V̇_O2,max/M_b). (B) Comparison of the absolute increases in mass-specific maintained power and V̇_O2,max/M_b. Error bars indicate ±95% confidence intervals. From Hoppeler et al. (1985), reprinted with permission from the American Physiological Society.

Fig. 3.

Mitochondrial ATP production capacity and leg performance improvements with endurance training in the elderly. Average increases in mitochondrial ATP production capacity (ΔATP_max) of the quadriceps muscles and in leg power output at the aerobic capacity (ΔP_max) after a 6-mo endurance-training (ET) program. The red horizontal line separates the relative contribution of ΔV̇_O2,max versus Δexercise efficiency to ΔP_max. This line also provides estimates of the contribution of ΔETC flux (ΔO₂ uptake) versus Δmitochondrial coupling efficiency to ΔATP_max. The Δexercise efficiency at the whole-body level is likely due to Δmitochondrial efficiency because muscle fiber types were unchanged with ET. In addition, only half of the change in ΔV̇_O2,max is accounted for by Δmitochondrial volume density [ΔV̇_V(mt,f)] in muscle, which points to increased ΔETC flux per mitochondrion (ΔETC flux?) to account for the other half of the increased O₂ flux. The question marks (?) indicate likely changes at the mitochondrial level based on the measured changes in whole-body and leg performance.