Regulation of skeletal muscle ATP catabolism by AMPD1 genotype during sprint exercise in asymptomatic subjects

Deficiency of myoadenylate deaminase, the muscle isoform of AMP deaminase e ncoded by the AMPD1 gene, is a common myopathic condition associated with a lterations in skeletal muscle energy metabolism. However, recent studies ha ve demonstrated that most individuals harboring this genetic abnormality ar e asymptomatic. Therefore, 18 healthy subjects with different AMPD1 genotyp es were studied during a 30-s Wingate test in order to evaluate the influen ce of this inherited defect in AMPD1 expression on skeletal muscle energy m etabolism and exercise performance in the asymptomatic population. Exercise performances were similar across the AMPD1 genotypes, whereas significant differences in several descriptors of energy metabolism were observed. Norm al homozygotes (NN) exhibited the highest levels of AMP deaminase activitie s, net ATP catabolism, and IMP accumulation, whereas intermediate values we re observed in heterozygotes (MN). Conversely, mutant homozygotes (MM) had very low AMP deaminase activities and showed no significant net catabolism of ATP or IMP accumulation. Accordingly, MM also did not show any postexerc ise increase in plasma ammonia. Unexpectedly, MN consistently exhibited gre ater increases in plasma ammonia compared with NN despite the relatively lo wer accumulation of IMP in skeletal muscle. Moreover, time course profiles of postexercise plasma ammonia and blood lactate accumulation also differed across AMPD1 genotypes. Finally, analysis of adenosine in leftover biopsy material revealed a modest twofold increase in MN and a dramatic 25-fold in crease in MM.