THE IMPORTANCE OF ATPASE MICROENVIRONMENT IN MUSCLE FATIGUE - A HYPOTHESIS

A broadly held opinion is that fatigue is not due to an insufficient s upply of ATP to the energy consuming mechanisms because tissue [ATP] a lways remains at least one order of magnitude higher than K-m for ATP of any ATPase. In general these findings also suggest that ATP consump tion is well balanced with ATP regeneration even in the fatigued muscl es. This balance is achieved by down-regulation of ATP consumption. Po tentially this down-regulation could be accomplished by any product of the ATPase reaction and the role of Pi and H+ accumulation in this re gulation has been discussed in the literature. The purpose of this pap er is to describe known compartmentalization of ATP regeneration syste ms in muscle cell, their importance in the regulation of [adenine nucl eotide] in the vicinity of ATPases and how such local ATP regeneration maybe important in the etiology of muscle fatigue. Available experime ntal evidence suggests that the binding of creatine kinase and glycoly tic enzymes in the vicinity of sites where ATP is hydrolyzed and funct ional coupling between these ATP regenerating mechanisms and ATPase ca n 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, wh ich seems to be especially important when ATPase turnover is high. Unf ortunately, the maximum rate of local ATP regeneration relative to tha t of ATP hydrolysis in vivo is not known, mainly because in vitro dete rminations 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 microenviro nment favorable for ATPase function could be depressed in fatigued mus cle. So far the most convincing evidence comes from experiments with s ingle 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/produc t concentrations in ATPase microenvironment. These local changes may r epresent a sensitive mechanism through which ATP consumption is contro lled and significant changes in cellular [adenine nucleotide] are avoi ded.