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 10muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the 102 LACE study. 103 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, 114 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, 116 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.
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 10muscle mass, strength, in sarcopenia or contributed to the lack of response to treatment in the 102 LACE study. 103 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, 114 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, 116 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.
| Original language | English |
|---|---|
| Article number | e0292402 |
| Number of pages | 17 |
| Journal | PloS ONE |
| Volume | 18 |
| Issue number | 10 |
| Early online date | 20 Oct 2023 |
| DOIs | |
| Publication status | Published - 20 Oct 2023 |
Bibliographical note
FundingThe LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership.
Acknowledgements
The authors would also thank the efforts of all the research nurses and other site research staff who recruited participants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial