Genetic and other determinants of AMP deaminase activity in healthy adult skeletal muscle

Abstract

AMPD1 genotype, relative fiber type composition, training status, and gender were evaluated as contributing factors to the reported variation in AMP deaminase enzyme activity in healthy skeletal muscle. Multifactorial correlative analyses demonstrate that AMPD1 genotype has the greatest effect on enzyme activity. An AMPD1 mutant allele frequency of 13.7 and a 1.7% incidence of enzyme deficiency was found across 175 healthy subjects. Homozygotes for the AMPD1 normal allele have high enzyme activities, and heterozygotes display intermediate activities. When examined according to genotype, other factors were found to affect variability as follows: AMP deaminase activity in homozygotes for the normal allele exhibits a negative correlation with the relative percentage of type I fibers and training status. Conversely, residual AMP deaminase activity in homozygotes for the mutant allele displays a positive correlation with the relative percentage of type I fibers. Opposing correlations in different homozygous AMPD1 genotypes are likely due to relative fiber-type differences in the expression of AMPD1 and AMPD3 isoforms. Gender also contributes to variation in total skeletal muscle AMP deaminase activity, with normal homozygous and heterozygous women showing only 85-88% of the levels observed in genotype-matched men.

AMPD1 gene polymorphism and the vasodilatory response to ischemia

“…The genotype frequencies did not differ from HardyWeinberg equilibrium (χ 2 = 0.105, P = 0.75), and the rare allele frequency of 11% was consistent with previous studies (Norman et al, 1998). There were no subjects with the TT genotype; therefore, statistical analyses compared the CC and CT genotypes.…”

“…This may account for the limitations in exercise capacity previously observed in individuals with the T allele (Fishbein, 1985;Rico-Sanz et al, 2003) and a limited response to exercise training (Rico-Sanz et al, 2003). This decreased exercise capacity appears to be due to reduced AMPD activity (Kalsi et al, 2003;Norman et al, 1998), which is vital to regenerate ATP from AMP via the purine nucleotide cycle. In individuals with decreased AMPD activity, instead of entering the purine nucleotide cycle, AMP is converted to adenosine (Sala-Newby et al, 1999).…”

“…Sabina and Holmes (1995) reported an increased production of adenosine in skeletal muscle samples from individuals heterozygous for the T allele. Moreover, Norman et al showed that the C34T locus influences AMPD activity, as well as muscle ATP catabolism and adenosine production during exercise (Norman et al, 1998(Norman et al, , 2001. Previous studies have shown that individuals with a T allele had increased adenosine production during high intensity exercise (Norman et al, 2001;Sabina and Holmes, 1995), a time when skeletal muscle oxygen homeostasis is disrupted.…”

Polimorfismos genéticos determinantes da performance física em atletas de elite

“…A nonsense mutation, transition of the nucleotide C → T in the 34 position of the exon 2 of the AMPD1 gene, converts the CAA codon (glutamine) into a stop codon (TAA), resulting in an early interruption of the protein synthesis (23) . Consequently, individuals who present the polypeptidic mutant sequence, TT homozygote or CT heterozygote, respectively, present lower and intermediate enzymatic activity of myoadenylate deaminase, when compared with the CC homozygote individuals (24) . According to some authors (25)(26) , part of the population which expresses the mutant gene (2% of the Caucasian population is homozygote and approximately 20% is heterozygote) is vulnerable to muscular cramps, pain and premature fatigue during exercises.…”

Neuromuscular implications in left ventricular hypertrabeculation/noncompaction

“…At least 10 AMPD1 mutations combine with other major mutations on opposite alleles to produce MADD [56]. Though the frequency of the mutant allele is reported 12-19% in the white and 0.5% in the black population [54,57], only 0.1-2% are homozygous for the mutation [58]. Among the latter only 25% develop symptomatic myopathy [53].…”