Importance of purine nucleotide cycle to energy production in skeletal muscle

Abstract

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.

Biochemical and structural analysis of 14 mutant adsl enzyme complexes and correlation to phenotypic heterogeneity of adenylosuccinate lyase deficiency

“…ADSL acts in two pathways of purine nucleotide metabolism: the de novo purine synthesis pathway and the purine nucleotide cycle. Although both pathways are constitutively active during development and throughout life [Flanagan et al, 1986;Swain et al, 1984;Van den Berghe et al, 1992;Watts, 1983], their activity must be precisely regulated and coordinated to meet the entirely different nucleotide demands of dividing, differentiating and fully differentiated cells. The regulation of purine metabolism certainly takes place at various levels as demonstrated by the distinct compartmentalization of the purinosome within cells and the entirely different downstream regulatory effects of various intermediates of both of the pathways.…”

Muscle function during repetitive moderate-intensity muscle contractions in myoadenylate deaminase-deficient Dutch subjects

“…What might have caused the reduced capacity for repetitive submaximal contractions of MAD-deficient muscle, if we assume that the impaired muscle function in our subjects was indeed due to the deficiency ? MAD is an enzyme of the purine nucleotide cycle, and an important role of this cycle could be the provision of tricarboxylic acid cycle intermediates, which would be important for optimal aerobic energy production [1,18,29,30]. Therefore it could be hypothesized that failure to provide sufficient tricarboxylic acid cycle intermediates in MAD-deficient muscle, particularly during the first 5-10 min of exercise when levels of these intermediates have been found to increase substantially in healthy muscle [31][32][33], would lead to a shift of energy production towards anaerobic sources and early fatigue.…”

“…Indeed, the symptoms reported by MAD-deficient subjects often develop during daily tasks of only moderate, submaximal intensity [11]. Moreover, in isolated rat muscle, disruption of the purine nucleotide cycle reduced force output during repetitive submaximal contractions [17,18]. Therefore the purpose of the present study was to investigate whether the capacity for repetitive submaximal muscle contractions is reduced in MADdeficient subjects.…”

Muscle function during fatigue in myoadenylate deaminase-deficient Dutch subjects

“…The underlying reasoning was that, if the deficiency of the enzyme did not affect muscle function under our extreme conditions, it would be unlikely that MAD dysfunction by itself was the direct cause of the clinical symptoms of the MAD-deficient subjects. However, there is evidence that, at least in rat muscle, the purine nucleotide cycle is also active during moderate-intensity exercise, when it may play an anapleurotic role in providing citric acid cycle intermediates, and in that situation IMP accumulation would not occur because IMP is re-aminated to AMP [24,25]. Such a metabolic function of MAD during moderate-intensity exercise may explain why some of our MAD-deficient subjects also reported problems during basically aerobic activities such as gardening and having a 10 min telephone conversation.…”