Contribution of proton leak to oxygen consumption in skeletal muscle during intense exercise is very low despite large contribution at rest

A computer model was used to simulate the dependence of protonmotive force (Δp), proton leak and phenomenological (involving proton leak) ATP/O(2) ratio on work intensity in skeletal muscle. Δp, NADH and proton leak decreased with work intensity. The contribution of proton leak to oxygen consumption ([Image: see text] ) decreased from about 60% at rest to about 3 and 1% at moderate and heavy/severe exercise, respectively, while the ATP/O(2) ratio increased from 2.1 to 5.5 and 5.7. A two-fold increase in proton leak activity or its decrease to zero decreased/increased the ATP/O(2) ratio by only about 3 and 1% during moderate and heavy/severe exercise, respectively. The low contribution of proton leak to [Image: see text] in intensively working skeletal muscle was mostly caused by a huge increase in ATP usage intensity during rest-to-work transition, while OXPHOS, and thus oxidative ATP supply and [Image: see text] related to it, was mostly stimulated by high each-step activation (ESA) of OXPHOS complexes. The contribution of proton leak to [Image: see text] and ATP/O(2) ratio in isolated mitochondria should not be directly extrapolated to working muscle, as mitochondria lack ESA, at least in the absence of Ca(2+), and therefore [Image: see text] cannot be elevated as much as in intact muscle.