Microvascular O delivery and O utilization during metabolic transitions in skeletal muscle. One-hundred years after the pioneering work by August Krogh.

Upon a sudden rise in work rate, ATP turnover increases immediately, whereas the adjustment of ATP resynthesis from oxidative phosphorylation is substantially slower. An "O deficit" (energy borrowed from substrate level phosphorylation) is therefore generated. A greater O deficit represents an epiphenomenon of a lower "metabolic stability" during the transition, a circumstance directly related to impaired exercise tolerance. In the search for factors responsible for the delayed adjustment of oxidative phosphorylation, we performed studies in the surgically isolated canine gastrocnemius muscle in situ. Enhancement of convective and diffusive microvascular O delivery, with respect to a "normal" condition, did not affect skeletal muscle V̇O kinetics during transitions to submaximal metabolic rates. V̇O kinetics, however, was slowed after experimentally impairing convective O delivery, a condition frequently encountered in pathological conditions. Among potential metabolic factors (pyruvate dehydrogenase activation, nitric oxide inhibition of cytochrome oxidase) a limiting role in V̇O kinetics was observed only for creatine kinase (CK) mediated phosphocreatine (PCr) breakdown. Following CK inhibition, faster muscle V̇O kinetics was observed. Thus, in skeletal muscle CK-catalysed PCr breakdown at contractions onset slows the increase of oxidative phosphorylation. By acting as a high-capacitance energy buffer, PCr breakdown delays or attenuates the increased concentrations of metabolites (such as ADP, Pi, Cr) mediating the V̇O increase. Upon sudden increases in ATP turnover, skeletal muscle fibers rely first on the bioenergetic pathway (PCr breakdown), which is fast to adjust to increased metabolic needs. Metabolites related to PCr breakdown regulate, but inevitably slow down, the adjustment of oxidative phosphorylation.