The ACE I/D gene variant predicts ACE enzyme activity in the blood but not the expression of ACE protein in skeletal muscle in the Gene SMART study

X. Yan,^1,2 N. Dvir,¹ L. Cavalcante,¹ M. Jacques,¹ I.D. Papadimitriou,¹ F. Munson,¹ A.P. Garnham,¹ L. O'Keefe,¹ O. Tirosh,³ D.J. Bishop,¹ S. Voisin¹ and N. Eynon,¹ ¹Institute of Sport, Exercise & Active Living, Victoria University, Melbourne, VIC 8001, Australia, ²College of Health and Biomedicine, Victoria University, Melbourne, VIC 8001, Australia and ³School of Health Sciences, Swinburne University of Technology, Hawthorn, VIC 3122, Australia.

Background: Both environmental and genetic factors are important determinants of adaptations to exercise training. One gene variant that has been associated with exercise performance across multiple cohorts is the Angiotensin Converting Enzyme (ACE) Insertion/Deletion (I/D). This variant has also been associated with the activity of the ACE enzyme. It is, however, unclear if it is associated with changes in ACE enzyme in response to exercise.

Aims: To investigate whether: 1) the ACE I/D gene variant is associated with changes in ACE enzyme activity in the blood and ACE protein content muscle, at baseline and following a session of High-Intensity Interval Exercise (HIIE); and 2) whether the ACE I/D variant is associated with physiological (VO_2max, Lactate Threshold, mitochondrial respiration) characteristics at baseline.

Methods: These analyses are part of the Gene SMART (Skeletal Muscle Adaptive Response to Training) study, investigating the influence of genetic variants on muscle metabolism and adaptation to exercise. Genotyping for the ACE I/D variant was performed using Taq-Man method. The ACE enzyme levels in the blood (serum) pre, immediately after, and 3 hours post HIIE were measured using an ELISA kit, and the ACE protein expression in the muscle was measured by western blots at the same time points.

Results: At baseline, DD participants had 68% higher ACE activity levels in the serum compared with II participants (adj. p-value = 0.0009). However, II and DD participants had similar levels of ACE protein content in the muscle (all adj. p-value> 0.05). Immediately post-exercise, serum ACE levels increased by 15.1% (adj. p-value=0.004). Three hours post-HIIE, ACE levels in blood returned to baseline levels (adj. p-value = 0.34). ACE levels in muscle were unchanged following HIIE (adj. p-values > 0.05). These changes were independent of the ACE I/D genotype. There were also no genotype differences in age, BMI, Lactate Threshold, VO_2max or mitochondrial respiration (all adj. p-values > 0.05)

Conclusion: The ACE I/D variant is associated with serum ACE content at baseline, but not with ACE protein expression in the muscle, and physiological characteristics at baseline. Further research is required to assess the association between other genetic variants in the Renin-Angiotensin System (RAAS) and ACE content in the muscle.