The Angiotensin Converting Enzyme Insertion/Deletion Polymorphism Modifies Exercise-Induced Muscle Metabolism

OBJECTIVE A silencer region (I-allele) within intron 16 of the gene for the regulator of vascular perfusion, angiotensin-converting enzyme (ACE), is implicated in phenotypic variation of aerobic fitness and the development of type II diabetes. We hypothesised that the reportedly lower aerobic performance in non-carriers compared to carriers of the ACE I-allele, i.e. ACE-DD vs. ACE-ID/ACE-II genotype, is associated with alterations in activity-induced glucose metabolism and capillarisation in exercise muscle. METHODS Fifty-three, not-specifically trained Caucasian men carried out a one-legged bout of cycling exercise to exhaustion and/or participated in a marathon, the aim being to identify and validate genotype effects on exercise metabolism. Respiratory exchange ratio (RER), serum glucose and lipid concentration, glycogen, and metabolite content in vastus lateralis muscle based on ultra-performance lipid chromatography-mass spectrometry (UPLC-MS), were assessed before and after the cycling exercise in thirty-three participants. Serum metabolites were measured in forty subjects that completed the marathon. Genotype effects were assessed post-hoc. RESULTS Cycling exercise reduced muscle glycogen concentration and this tended to be affected by the ACE I-allele (p = 0.09). The ACE-DD genotype showed a lower maximal RER and a selective increase in serum glucose concentration after exercise compared to ACE-ID and ACE-II genotypes (+24% vs. +2% and -3%, respectively). Major metabolites of mitochondrial metabolism (i.e. phosphoenol pyruvate, nicotinamide adenine dinucleotide phosphate, L-Aspartic acid, glutathione) were selectively affected in vastus lateralis muscle by exercise in the ACE-DD genotype. Capillary-to-fibre ratio was 24%-lower in the ACE-DD genotype. Individuals with the ACE-DD genotype demonstrated an abnormal increase in serum glucose to 7.7 mM after the marathon. CONCLUSION The observations imply a genetically modulated role for ACE in control of glucose import and oxidation in working skeletal muscle. ACE-DD genotypes thereby transit into a pre-diabetic state with exhaustive exercise, which relates to a lowered muscle capillarisation, and deregulation of mitochondria-associated metabolism

Muscle composition in relation to the ACE I/D genotype.

<p>Whisker plots of capillary density (A), capillary-to-fibre ratio (B), and mean cross-sectional area of slow (C) and fast fibre types (D) in <i>vastus lateralis</i> muscle in relation to ACE-I/D genotypes for group 1. $, p < 0.05 vs. ACE-DD (ANOVA with post-hoc test of Fisher). Swung bracket indicates effect for combined ACE-II and ACE-ID genotypes.</p

Genotype effects on exercise induced metabolism.

<p>Whisker box plots visualizing the median + standard error (box and central line) and minima/maxima (whisker) of serum glucose (A) and RER (B) pre and post the exhaustive one leg exercise for group 1. *, p < 0.05 vs. pre; **, p < 0.001 vs. pre; $, p < 0.05 vs. ACE-DD post exercise (repeated ANOVA with post-hoc test of Fisher). Swung bracket indicates effect for combined ACE-II and ACE-ID genotypes.</p

ACE I/D-related alterations in serum after the marathon.

<p>Whisker box plots of glucose (A) and triglyceride concentration (B) before and after the Chester Marathon for each ACE-I/D genotype for group 2. *, p < 0.05 vs. pre; $$ $, p < 0.0001 vs. ACE-DD post exercise (repeated ANOVA with post-hoc test of Fisher).</p

ACE I/D genotype effects on muscle metabolism post exercise.

<p>Whisker box plots visualizing the median + standard error (boxes) and minima/maxima (Whiskers) of muscle glycogen concentration pre and post the exhaustive one leg exercise for group 1. *, p < 0.05 vs. pre; **, p < 0.001 vs. pre; $, p < 0.05 vs. ACE-DD post exercise (repeated ANOVA with post-hoc test of Fisher).</p

Muscle metabolites after exercise in relation to the ACE I/D genotype.

<p>(A-G) Whisker box plots of muscle metabolite levels being associated with pyruvate metabolism (A,B), glutathione metabolism (C,D) and amino acid metabolism (E,F), pre and post exercise per ACE-I/D genotype for group 1. Levels reflect the relative fraction of ion abundance for the respective compound (i.e. metabolite). Respective HMDB entries are provided in brackets. The main function/ ontology of each metabolite is provided in the heading. *, p < 0.05 vs. pre; $, p < 0.05 for fold changes vs. ACE-DD (SAM).</p