Regulation of metabolism: the rest-to-work transition in skeletal muscle

Abstract

Wilson DF. Regulation of metabolism: the rest-to-work transition in skeletal muscle. Am J Physiol Endocrinol Metab 309: E793-E801, 2015. First published September 22, 2015; doi:10.1152/ajpendo.00355.2015.-Mitochondrial oxidative phosphorylation is programmed to set and maintain metabolic homeostasis, and understanding that program is essential for an integrated view of cellular and tissue metabolism. The behavior predicted by a mechanism-based model for oxidative phosphorylation is compared with that experimentally measured for skeletal muscle when work is initiated. For the model, initiation of work is simulated by imposing a rate of ATP utilization of either 0.6 (equivalent of 13. [CrP], and the increase in oxygen consumption are dependent on the PO2 in the inspired gas (experimental) or tissue PO2 (model). The metabolic behavior predicted by the model is consistent with available experimental measurements in muscle upon initiation of work, with the model providing valuable insight into how metabolic homeostasis is set and maintained. muscle work; metabolic control; metabolic homeostasis; rest-to-work transition; skeletal muscle IN CELLS, METABOLISM CHANGES CONTINUOUSLY AND RAPIDLY in response to alterations in the cellular environment or intracellular and extracellular functions, and this can involve large changes in metabolite levels and enzymatic activity. These metabolic responses can occur within seconds and include all aspects of metabolism: ion transport, mechanical work, protein synthesis, etc. Integrated metabolism, however, counters these metabolic displacements and on a time average basis operates near a particular set point (metabolic homeostasis), and this set point is very similar for all eukaryotic cells. Real-time control of metabolism and maintaining metabolic homeostasis requires a metabolic unit that is programmed with that set point and is connected to the rest of metabolism through a network of regulatory pathways through which the set point is maintained (49,50,55). In eukaryotic cells, mitochondrial oxidative phosphorylation is programmed with a set point for the energy state To better understand how oxidative phosphorylation is able to set and maintain metabolic homeostasis, it is necessary to understand the mechanism(s) by which oxidative phosphorylation is regulated and to construct a model that quantifies the dependence on each of the regulatory parameters. The rate of oxidative phosphorylation is determined by the flux through cytochrome c oxidase, so a mechanism-based model has been built for the cytochrome c oxidase (55, 56). The steady-state rate expression derived for that model fits the observed dependences on energy state, PO 2 , pH, and level of reduction of cytochrome c (51, 52, 55). The rate expression for cytochrome c oxidase can then be extended to overall oxidative phosphorylation, with the first two sites of oxidative phosphorylation added (without the pH dependence of ATP hydrolysis): NADH ϩ 2 P i ϩ 2 ADP ϩ2 cyt c 3ϩ ϭ NAD ϩ ϩ H ϩ ϩ 2 ATP ϩ 2 cyt c 2ϩ (1). The reactio...

Each‐step activation of oxidative phosphorylation is necessary to explain muscle metabolic kinetic responses to exercise and recovery in humans

“…Recently Wilson (Wilson, ) presented a modified dynamic version of his previous static model (Wilson et al . ), involving, for example, the CK system.…”

The ‘Critical Power’ Concept: Applications to Sports Performance with a Focus on Intermittent High-Intensity Exercise

“…The mean rate at which representative indices of metabolic perturbation such as [PCr], [ P i ], and pH change during exercise will therefore determine the tolerable duration of exercise; during intermittent exercise, the mean rate of change of these indices as well as their sequelae (e.g., adenosine and inosine monophosphate [AMP], [IMP], [Ca 2+ ], and [K + ] will naturally be influenced by P W , D W , P R , and D R . It is important to note that several substrates and metabolites that have been linked with the process of muscle fatigue are also known to stimulate mitochondrial respiration [14, 53]. Therefore, rates of change of these substrates and metabolites will be causally and temporally related to the rate of change of during severe-intensity exercise, with, for example, the minimum value of [PCr] and the maximum value of [ P i ], coinciding with the attainment of close to the limit of tolerance.…”

Oxidative phosphorylation: regulation and role in cellular and tissue metabolism

“…The transitions between resting and work in skeletal muscle gives rise to the widest range of rates of ATP utilization of any tissue, over 100‐fold (Wilson et al . ; Wilson & Vinogradov, ; Wilson, ,b, ). In addition, skeletal muscle of vertebrates includes creatine kinase, an enzyme which catalyses a reaction in which ATP reacts with creatine (Cr) to form ADP and creatine phosphate (CrP): i.e.…”

“…, ; Wilson et al . , , ; Erecinska & Wilson, ; Wilson, , ,b, , ; Wilson & Vinogradov, ), most notably the extensive data on exercising muscle (Wilson, , , ). The current review, therefore, focuses on understanding how the unique metabolic and regulatory properties of oxidative phosphorylation, as exemplified in the model, had a central role in the evolutionary development of higher animals and plants.…”

“…; Wilson et al . , ; Erecinska & Wilson, ; Forman & Wilson, ; Greenbaum & Wilson, ; Wilson, , ,b, , ) and using known equilibrium constants (no additional fitting required). (5)It has been shown to predict behaviour of oxidative phosphorylation that is consistent with the measured energy state and respiratory rates in many tissues as well as with changes that occur during the work‐to‐rest (Wilson, ) and rest‐to‐work (Wilson, ) transitions in oxidative skeletal muscle.…”