Importance of purine nucleotide cycle to energy production in skeletal muscle.

The purpose of this study was to determine the role of the purine nucleotide cycle in aerobic energy production. Rats received either saline or 5-amino-4-imidazolecarboxamide riboside (AICAriboside), a precursor to an inhibitor of adenylosuccinate lyase (AICAR). Muscle tension was quantified during gastrocnemius stimulation, and muscle metabolite content was measured to obtain an estimate of the activity of the enzymes of the cycle. AICAriboside prevented the increase in synthetase and lyase activities observed in control animals during moderate (aerobic) stimulation, and was accompanied by marked muscle dysfunction. Although glycolytic energy production was not impaired in the AICAriboside-treated animals (lactate production occurred), total energy production did not meet energy demand. These results suggest that disruption of the purine nucleotide cycle impairs aerobic energy metabolism. Tetanic (anaerobic) stimulation produced more rapid fatigue in the AICAriboside-treated group. Total energy production was again impaired in the AICAriboside-treated animals, but lactate production was similar in both groups. These findings suggest the loss of the initial aerobic component of energy generation in tetanically stimulated muscle of AICAriboside-treated animals. The results of this study indicate that disruption of the purine nucleotide cycle at the level of the synthetase and lyase reactions is associated with skeletal muscle dysfunction, and suggest that the cycle plays an anapleurotic role in providing citric acid cycle intermediates that enhance aerobic energy production in contracting skeletal muscle.