Wnt and Hh signaling in skeletal development and homeostasis

Experimental results on fast-twitch muscle of rainbow trout following exercise and during subsequent recovery lead us to a reinterpretation for the function of the components of the purine nucleotide cycle (PNC). Exhaustive exercise depletes tissue ATP by more than 90% and results in a stoichiometric gain in IMP and ammonium ions. Simultaneously, white-muscle aspartate decreases by half, but its maximum contribution can account for less than 2% of the accumulated ammonium. Of the three enzymes of the purine nucleotide cycle, AMP deaminase, adenylosuccinate synthetase and adenylosuccinate lyase, only AMP deaminase is functional during exhaustive exercise. During the slow (>15 hour) recovery, AMP deaminase is effectively shut off, while the other two enzymes replenish the adenylate pool. At all times, a tight inverse correlation exists between ATP and IMP concentrations. Tissue ammonium and malate supply the required aspartate. Theoretical treatment with speciai attention to proton dynamics in a potentially anaerobic tissue also leads to the conclusion that rather than constituting a true cycle, distinct parts of the PNC are temporally segregated. We hypothesize that during periods of high energy demand, exclusively AMP deaminase is activated as a means (1) to push the myokinase reaction toward ATP synthesis, (2) to supply allosteric effectors, and (3) to remove some of the accumulating protons through the formation of ammonium, all at the expense of the adenylate pool. The process leading to its replenishment, which involves the production of two protons and the consumption of a high-energy phosphate, can be active during aerobic recovery only. Full PNC activity during anaerobic muscle work would outweigh any metabolic advantages of the AMP deaminase reaction, and severely aggravate the problem of acid-base regulation.