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.

Figures

Fig. 1

ACE I-allele dependent effects on muscle-related parameters of fitness. Representative micrograph indicating the assessed ultra-structural parameters in vastus lateralis muscle

Fig. 2

ACE I-allele dependent muscle adjustments to endurance training. Bar graph of mean + SE of fold changes in muscle parameters and VO2max in carriers and non-carriers of the ACE I-allele after bicycle training. n = 9 with no I-allele, 7 with I-allele. Vv volume density. *, p < Bonferroni-corrected 0.05 for post versus pre changes (paired T-test). # denotes a significant interaction effect between the fold-changes (‘post vs. pre-training’) and the ‘ACE I-allele’ at p < Bonferroni-corrected 0.05 (repeated ANOVA)

Fig. 3

Genotype dependent expression changes to endurance exercise. a Heat map visualizing the regulation of the 15 gene transcripts and their functional ontology demonstrating level differences between carriers and non-carriers of the ACE I-allele in vastus lateralis muscle during recovery from bicycle exercise and after bicycle training. Colour code denotes the scale of fold changes 1, 8, 24 h after endurance exercise and training versus baseline in carriers of the I-allele, non-carriers of the I-allele, and the corresponding ratio between the two genotypes. b Bar graph of mean + SE for fold changes in training-induced expression for 8 transcripts which distinguished between ACE genotypes after training. #, q-value <5 %/231 for differences in fold changes between genotypes. n = 12. For abbreviations see legend to Fig. 4

Fig. 4

Summary of ACE I-allele affected pathways Genmapp visualizing the metabolic pathways holding gene transcripts with ACE I/D genotype dependent expression post exercise/training. The assessed transcripts are given in boxes with the colour coding indicting a significant genotype effect. ACADL long chain acyl-CoA dehydrogenase, ACTN1 actinin alpha 1, ALDOC aldolase C, COL4A1 collagen type IV alpha 1, CPTI carnitine palmitoyltransferase I, CPTII Carnitine palmitoyltransferase II, CD36/FAT cluster of Differentiation 36)/fatty acid translocase, ETC. electron transport chain, FATP fatty acid transport protein, GIP glucose-dependent insulinotropic peptide, Glut2 Glucose transporter 2, HIF-1a subunit alpha of hypoxia-inducible factor 1, HO-1 heme oxygenase 1, IGF-II insulin-like growth factor II, IL-6 interleukin 6, Il-6RST interleukin 6 receptor signal transducer, LDHC lactate dehydrogenase C, LIPE hormone sensitive lipase transcript, LPL lipoprotein lipase, MMP-10 metalloproteinase 10, PDHA2 pyruvate dehydrogenase alpha 2, PGF placental growth factor, PPARA Peroxisome proliferator-activated receptor alpha, VHL von Hippel Landau tumour suppressor. For further abbreviations consult www.expasy.org