The angiotensin converting enzyme insertion/deletion polymorphism alters the response of muscle energy supply lines to exercise

Abstract

The presence of a silencing sequence (the I-allele) in the gene for the upstream regulator of blood flow, angiotensin I-converting enzyme (ACE), is associated with superior endurance performance and its trainability. We tested in a retrospective study with 36 Caucasian men of Swiss descent whether carriers of the ACE I-allele demonstrate a modified adaptive response of energy supply lines in knee extensor muscle, and aerobic fitness, to endurance training based on 6 weeks of supervised bicycle exercise or 6 months of self-regulated running (p value <Bonferroni-corrected 5 %). Body weight related maximal oxygen uptake and capillary density in vastus lateralis muscle before training were 20 and 23 % lower, respectively, in carriers of the I-allele. Bicycle (n = 16) but not running type endurance training (n = 19) increased the volume content of subsarcolemmal mitochondria (2.5-fold) and intramyocellular lipid (2.1-fold). This was specifically amplified in I-allele carriers after 6 weeks of bicycle exercise. The enhanced adjustment in myocellular organelles of aerobic metabolism with bicycle training corresponded to ACE I-allele dependent upregulation of 23 muscle transcripts during recovery from the bicycle stimulus and with training. The majority of affected transcripts were associated with glucose (i.e. ALDOC, Glut2, LDHC) and lipid metabolism (i.e. ACADL, CPTI, CPTII, LIPE, LPL, FATP, CD36/FAT); all demonstrating an enhanced magnitude of change in carriers of the ACE I-allele. Our observations suggest that local improvements in mitochondrial metabolism, through a novel expression pathway, contribute to the varying trainability in endurance performance between subjects with genetically modified expression of the regulator of vascular tone, ACE.

Gene-Pharmacologial Effects on Exercise-Induced Muscle Gene Expression in Healthy Men

“…More recently, we have shown ACE-I/D dependent responses of serum levels of angiotensin 2 and capillary perfusion to intense cycling exercise [8]. These results suggest a critical role of ACE-modulated vascular tone, which is important for the regulation of response to exercise [13,12]. test, breath-by-breath respiratory data were collected using a calibrated spirometry system (JAEGER Oxycon alpha, CareFusion, Höchberg, Germany) and heart rate was monitored using a heart rate chest belt (Accurex Plus, Polar Electro Oy, Kempele, Finland).…”

“…It was therefore suggested that several processes downstream of ACE activity contribute to elevated endurance performance and trainability in subjects carrying the ACE I-allele [10,11]. In this context, we recently identified an ACE I-allele dependent up-regulation of muscle transcripts associated with glucose and lipid metabolism during recovery from endurance exercise [12]. Additionally subjects carrying at least one I-allele, were found to show reduced capillarity at rest, but amplified mitochondrial biogenesis after cycling-type endurance exercise.…”

Diagnostics of endurance performance on the level of gene expression

“…All of these relate to metabolic fitness. This is shown for genotyping of the ACE I/D polymorphism based on mucosal samples, as well as for the quantification of changes in angiotensin 2, arterial oxygen saturation, serum lactate and glucose in blood serum after a maximal aerobic workout [28,38,41]. While the prospective power and robustness of these molecular candidates as biomarkers for muscle performance and its malleability remains to be evaluated; the current data indicate that the step from diagnosis to prognosis may be in close reach.…”

“…Towards this end we recently pointed out that exercise-induced transcript expression provides a mechanistic connection between heritable factors and inter-individual variability in the phenotypic response to endurance exercise [38]. The investigation shows that the polymorphism for a 287bp gene insertion in intron 16 (the I-allele) of the gene for the producer of the major vasoconstrictor angiotensin 2, angiotensin-converting enzyme (ACE), affects plasticity of aerobic metabolism in skeletal muscle.…”

“…It was originally identified after a search of genetic elements conferring risk to coronary hypertension and stroke and is understood to occur in a frequency of nearly 50% ration in Caucasian populations [40]. Specifically, the presence of the I-allele is associated with 2-fold larger local improvements in subsarcolemmal mitochondria and intramyocellular lipids in knee extensor muscle compared to subjects being homozygous for the absence of the I-allele [38]. The latter genotype holds the D-allele, which is characterized by the absence of a control sequence known to reduce ACE gene transcript levels.…”