title: Disruption of the purine nucleotide cycle by inhibition of adenylosuccinate lyase produces skeletal muscle dysfunction.
abstract: Controversy exists as to whether the purine nucleotide cycle is important in normal skeletal muscle function. Patients with disruption of the cycle from a deficiency of AMP deaminase exhibit variable degrees of muscle dysfunction. An animal model was used to examine the effect of inhibition of the purine nucleotide cycle on muscle function. When the compound 5-amino-4-imidazolecarboxamide riboside (AICAriboside) is phosphorylated to the riboside monophosphate in the myocyte it is an inhibitor of adenylosuccinate lyase, one of the enzymes of the purine nucleotide cycle. AICAriboside was infused in 28 mice, and 22 mice received saline. Gastrocnemius muscle function was assessed in situ by recording isometric tension developed during stimulation. The purine nucleotide content of the muscle was measured before and after stimulation. Disruption of the purine nucleotide cycle during muscle stimulation was evidenced by a greater accumulation of adenylosuccinate, the substrate for adenylosuccinate lyase, in the animals receiving AICAriboside (0.60 +/- 0.10 vs. 0.05 +/- 0.01 nmol/mumol total creatine, P less than 0.0001). There was also a larger accumulation of inosine monophosphate in the AICAriboside vs. saline-treated animals at end stimulation (73 +/- 6 vs. 56 +/- 5 nmol/mumol total creatine, P less than 0.03). Inhibition of flux through the cycle was accompanied by muscle dysfunction during stimulation. Total developed tension in the AICAriboside group was 40% less than in the saline group (3,023 +/- 1,170 vs. 5,090 +/- 450 g . s, P less than 0.002). An index of energy production can be obtained by comparing the change in total phosphagen content per unit of developed tension in the two groups. This index indicates that less high energy phosphate compounds were generated in the AICAriboside group, suggesting that interruption of the purine nucleotide cycle interfered with energy production in the muscle. We conclude from these studies that defective energy generation is one mechanism whereby disruption of the purine nucleotide cycle produces muscle dysfunction.
mesh_terms: D000264:Adenylosuccinate Lyase / Q000037:antagonists & inhibitors*; D000620:Aminoimidazole Carboxamide / Q000031:analogs & derivatives / Q000378:metabolism / Q000494:pharmacology; D000818:Animals; D008190:Lyases / Q000037:antagonists & inhibitors*; D051379:Mice; D008810:Mice, Inbred C57BL; D009119:Muscle Contraction / Q000187:drug effects; D009132:Muscles / Q000187:drug effects / Q000378:metabolism / Q000503:physiopathology*; D010725:Phosphocreatine / Q000378:metabolism; D011685:Purine Nucleotides / Q000096:biosynthesis / Q000378:metabolism*; D012263:Ribonucleosides / Q000494:pharmacology; D012265:Ribonucleotides / Q000378:metabolism
chemical_list: D011685:Purine Nucleotides; D012263:Ribonucleosides; D012265:Ribonucleotides; D010725:Phosphocreatine; D000620:Aminoimidazole Carboxamide; C011651:acadesine; D008190:Lyases; D000264:Adenylosuccinate Lyase; C031143:AICA ribonucleotide