The Importance of ATPase Microenvironment in Muscle Fatigue: A Hypothesis

A broadly held opinion is that fatigue is not due to an insufficient supply of ATP to the energy consuming mechanisms because tissue [ATP] always remains at least one order of magnitude higher than K_m for ATP of any ATPase. In general these findings also suggest that ATP consumption is well balanced with ATP regeneration even in the fatigued muscles. This balance is achieved by down-regulation of ATP consumption. Potentially this down-regulation could be accomplished by any product of the ATPase reaction and the role of Pi and H⁺ accumulation in this regulation has been discussed in the literature. The purpose of this paper is to describe known compartmentalization of ATP regeneration systems in muscle cell, their importance in the regulation of [adenine nucleotide] in the vicinity of ATPases and how such local ATP regeneration maybe important in the etiology of muscle fatigue. Available experimental evidence suggests that the binding of creatine kinase and glycolytic enzymes in the vicinity of sites where ATP is hydrolyzed and functional coupling between these ATP regenerating mechanisms and ATPase can generate ATPase microenvironments that have an important role in the regulation of ATPase function. Main function of this ATP regeneration is to keep the local ADP/ATP ratios favorable for ATPase function, which seems to be especially important when ATPase turnover is high. Unfortunately, the maximum rate of local ATP regeneration relative to that of ATP hydrolysis in vivo is not known, mainly because in vitro determinations underestimate this value due to a decrease in the fraction of loosely bound enzyme to the preparation during isolation procedure. Indirect evidence suggests that the ability to maintain a microenvironment favorable for ATPase function could be depressed in fatigued muscle. So far the most convincing evidence comes from experiments with single fibers, where changes in the relaxation rate and myoplasmic [Ca²⁺] during high-frequency fatigue and recovery can be best explained by a depression of Ca²⁺ pump function due to changes in substrate/product concentrations in ATPase microenvironment. These local changes may represent a sensitive mechanism through which ATP consumption is controlled and significant changes in cellular [adenine nucleotide] are avoided.

Key words

ATPase function - microenvironment - ATPase-creatine kinase coupling - fatigue