ACE I/D genotype associates with strength in sarcopenic men but not with response to ACE inhibitor therapy in older adults with sarcopenia: Results from the LACE trial

Abstract

Background Angiotensin II (AII), has been suggested to promote muscle loss. Reducing AII synthesis, by inhibiting angiotensin converting enzyme (ACE) activity has been proposed as a method to inhibit muscle loss. The LACE clinical trial was designed to determine whether ACE inhibition would reduce further muscle loss in individuals with sarcopenia but suffered from low recruitment and returned a negative result. Polymorphic variation in the ACE promoter (I/D alleles) has been associated with differences in ACE activity and muscle physiology in a range of clinical conditions. This aim of this analysis was to determine whether I/D polymorphic variation is associated with muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the LACE study. Methods Sarcopenic individuals were recruited into a 2x2 factorial multicentre double-blind study of the effects of perindopril and/or leucine versus placebo on physical performance and muscle mass. DNA extracted from blood samples (n = 130 72 women and 58 men) was genotyped by PCR for the ACE I/D polymorphism. Genotypes were then compared with body composition measured by DXA, hand grip and quadriceps strength before and after 12 months’ treatment with leucine and/or perindopril in a cross-sectional analysis of the influence of genotype on these variables. Results Allele frequencies for the normal UK population were extracted from 13 previous studies (I = 0.473, D = 0.527). In the LACE cohort the D allele was over-represented (I = 0.412, D = 0.588, p = 0.046). This over-representation was present in men (I = 0.353, D = 0.647, p = 0.010) but not women (I = 0.458, D = 0.532, p = 0.708). In men but not women, individuals with the I allele had greater leg strength (II/ID = 18.00 kg (14.50, 21.60) vs DD = 13.20 kg (10.50, 15.90), p = 0.028). Over the 12 months individuals with the DD genotype increased in quadriceps strength but those with the II or ID genotype did not. Perindopril did not increase muscle strength or mass in any polymorphism group relative to placebo. Conclusion Our results suggest that although ACE genotype was not associated with response to ACE inhibitor therapy in the LACE trial population, sarcopenic men with the ACE DD genotype may be weaker than those with the ACE I/D or II genotype.

Association of bradykinin receptor 2 (BDKRB2) variants with physical performance and muscle mass: Findings from the LACE sarcopenia trial

“…We performed a post hoc subgroup analysis between perindopril and no perindopril groups to test if the medication may have affected this outcome and found that this persisted in the no perindopril group, but was negated by the presence of perindopril. This is a similar finding to that seen in our recent study of ACE gene variants, where perindopril negated the improvement in SPPB score seen among ID/II genotypes who were not taking perindopril [ 9 ]. The findings in the both studies may be explained by the effect of being recruited into a trial leading to increased activity and physical improvement–those taking perindopril suffered a higher rate of adverse events and poorer quality of life as reported in the trial [ 16 ], which may have reduced their motivation to remain active, and this could be most capitalised among +9+9 genotypes.…”

“…The ACE I allele has been associated with a higher proportion of type I muscle fibres which may explain its link with enhanced endurance performance [ 8 ]. We have also recently shown that the I allele is under-represented in sarcopenic men and that sarcopenic men with the I allele had higher leg strength than DD individuals suggesting a role for the RAS in sarcopenia, at least in men [ 9 ].…”