Simulations carried out using a previously-developed model of the skeletal muscle bioenergetic system, involving the "Pi double-threshold" mechanism of muscle fatigue, lead to the conclusion that a decrease in the oxidative phosphorylation (OXPHOS) activity, caused by mutations in mitochondrial or nuclear DNA, is the main mechanism underlying the changes in the kinetic properties of the system in mitochondrial myopathies (MM). These changes generally involve the very-heavy-exercise-like behavior and exercise termination because of fatigue at low work intensities. In particular, a sufficiently large (at a given work intensity) decrease in OXPHOS activity leads to slowing of the primary phase II of the V̇O2 on-kinetics, decrease in V̇O2max, appearance of the slow component of the V̇O2 on-kinetics, exercise intolerance and lactic acidosis at relatively low power outputs encountered in experimental studies in MM patients. Thus, the "Pi double-threshold" mechanism of muscle fatigue is able to account, at least semi-quantitatively, for various kinetic effects of inborn OXPHOS deficiencies of the skeletal muscle bioenergetic system. Exercise can be potentially lengthened and V̇O2max elevated in MM patients through an increase in peak Pi (Pipeak), at which exercise is terminated because of fatigue. Generally, a mechanism underlying the kinetic effects of OXPHOS deficiencies on the skeletal muscle bioenergetic system in MM is proposed that was absent in the literature.
