Regulation of ATP supply in mammalian skeletal muscle during resting state→intensive work transition Original Research Article

In the present debating paper, the problem how the rate of ATP supply by oxidative phosphorylation in mitochondria is adjusted to meet a greatly increased demand for ATP during intensive exercise of skeletal muscle is discussed. Different experimental results are collected from different positions of the literature and confronted with five conceptual models of the regulation of the oxidative phosphorylation system. The previously performed computer simulations using a dynamic model of oxidative phosphorylation are also discussed in this context. The possible regulatory mechanisms considered in the present article are: (A) output activation: an external effector activates directly only the output of the system (ATP turnover); (B) input/output activation: an external effector activates directly the output (ATP usage) and input (substrate dehydrogenation) of the system; (C) removal of substrate shortage: only ATP consumption and substrate supply by blood are directly activated; (D) removal of oxygen shortage: only ATP consumption and oxygen supply by blood are directly activated; (E) each step activation: an external effector activates both the ATP-consuming subsystem and all the steps in the ATP-producing subsystem (particular enzymes/carriers/blocks of oxidative phosphorylation, substrate supply, oxygen supply). The performed confrontation of the considered mechanisms with the presented results leads to the conclusion that only the each step activation model is quantitatively consistent with the whole set of experimental data discussed. It is therefore postulated that a universal effector/regulatory mechanism of a still unknown nature which activates all steps of oxidative phosphorylation should exist and be discovered. A possible nature of such an effector is shortly discussed.