Impact of Angiotensin Converting Enzyme Activity on Exercise Training Sensitivity

The phenotype based on the insertion/deletion (I/D) polymorphism of the human angiotensin converting enzyme (ACE) gene has been associated with individual training response. Briefly, intervention studies have demonstrated an 11-fold greater training-induced improvement in muscular endurance for ACE I/I homozygotes compared to ACE D/D homozygotes. Importantly, the ACE I/D polymorphism causes large inter-individual differences in serum ACE activity. Because the ACE D/D genotype is characterized by high plasma ACE activity and potentially blunted endurance exercise training response, it appears likely that ACE inhibitors (ACEi) have the potential to improve the outcome of exercise training for ACE D/D homozygotes. Thus, in the present study the investigators apply a randomized double-blind placebo-controlled longitudinal design to investigate whether pharmacological inhibition of ACE activity can amplify the exercise training response in healthy humans carrying either the ACE D/D or ACE I/I genotype. The study hypothesis is that inhibition of ACE activity in healthy humans with the ACE D/D genotype will amplify the health beneficial effects of exercise training while this is not the case in ACE I/I homozygotes.

Adaptation, Physiological, Genotype, Polymorphism, Genetic, Enalapril, Physiological Effects of Drugs

The present study is double-blinded with regard to ACE genotype and study medication and the blinding is kept until completion of the trial

Participants will be assigned to daily administration of ACE inhibitors (Initially 5 mg Corodil® 'Enalapril' daily followed by up to 20 mg daily dependent on the blood pressure response) combined with an 8-week training period.

Participants will be assigned to daily administration of placebo (5-20 mg CaCO3) combined with an 8-week training period.

Training-induced changes in maximal systemic oxygen uptake (L/min) is evaluated with an incremental maximal cycle protocol on a cycle ergometer

Training-induced changes in muscle endurance evaluated as changes in duration (sec) of a repetitive elbow-flexion exercise

Training-induced changes in total blood volume (mL) is measured using the Carbon-monoxide rebreathing method.

Training-induced changes in endurance performance is determined by a 2000 meter time trial on an indoor rowing ergometer

Training-induced changes in muscle oxidative capacity is evaluated as maximal citrate synthase and 3- hydroxy-acetylCoa-dehydrogenase activity (µmol/g/min)

Expression of complex I-V will be analyzed in order to evaluate if the applied training induced mitochondrial biogenesis.

Training-induced changes in resting MAP (mmHg) will be estimated using this formula: MAP = diastolic pressure + 1/3 (systolic pressure - diastolic pressure)

Training-induced changes in steady-state systemic oxygen uptake (mL/min) is determined by indirect calorimetry during a submaximal cycle protocol on a cycle ergometer

Training-induced changes in fat mass (kg) is determined by dual-energy x-ray absorptiometry (DXA)-scan

LV stroke volume (mL) and LV end-diastolic volume (mL) will be used to measure training-induced changes in LV ejection fraction (%)

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Montgomery HE, Marshall R, Hemingway H, Myerson S, Clarkson P, Dollery C, Hayward M, Holliman DE, Jubb M, World M, Thomas EL, Brynes AE, Saeed N, Barnard M, Bell JD, Prasad K, Rayson M, Talmud PJ, Humphries SE. Human gene for physical performance. Nature. 1998 May 21;393(6682):221-2. doi: 10.1038/30374. No abstract available.

Sjuretharson T, Bejder J, Breenfeldt Andersen A, Bonne TC, Kyhl K, Thomassen M, Prats J, Oddmarsdottir Gregersen N, Skoradal MB, Weihe P, Nordsborg NB, Mohr M. Robust arm and leg muscle adaptation to training despite ACE inhibition: a randomized placebo-controlled trial. Eur J Appl Physiol. 2023 Feb;123(2):325-337. doi: 10.1007/s00421-022-05072-5. Epub 2022 Oct 22.