Solving the common problem: matching ATP synthesis to ATP demand during exercise.

Abstract

Biologists have long known that rates of adenosine triphosphate utilization and production need to be extremely closely balanced in all cells at all work rates. To put it in molecular rather than molar terms, in human muscle engaged in a 15-min work protocol, some 3.3 x 10(20) ATP molecules g-1 are used and resynthesized at close to 100 times the resting cycling rates before fatigue occurs. However, during this interval only a 20-25% decrease in the ATP pool is sustained. Review of recent studies as to how such remarkable regulatory precision is achieved suggests that in resting muscle, myosin behaves as a latent catalyst for which the full catalytic capacity is (a) realized with the arrival of its activator signal (Ca2+) and (b) attenuated with reaction products. These proactive controls, initiated at the onset of ATP utilization, set the required flux through ATP-producing pathways. For any given enzyme step in ATP-producing pathways, reaction velocity (upsilon) becomes the independent parameter, whereas substrate concentration ([s], the dependent parameter) must be adjusted accordingly. Because the dynamic range for muscles (change from resting to maximum ATP turnover rates) can exceed 100-fold, in many studies of working muscle the percentage change in ATP turnover rate usually greatly exceeds the percentage change in substrate concentrations. These kinds of observations are not easily explained by current metabolic regulation models, but are consistent with pathway enzymes behaving as latent catalysts in resting muscle. In this view, the unmasking of such latent catalytic potential is the main explanation for how large changes in upsilon can be achieved with modest (sometimes immeasurable) changes in [s]. In terms of the basic enzyme velocity equation, Vmax = kcat.e0 for pathways of ATP utilization and of ATP synthesis, the dominant (coarse level) regulation is achieved through e0 adjustments, whereas fine-tuning of flux is achieved by effective kcat adjustment.