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.
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.
| 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
Funding Information:The LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The Principal Investigator of the award was MW with PK, AS, AA, PD as co applicants. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care. AAS, TA, and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit, which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme. These organisations had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2023 Rossios et al.
Keywords
- Angiotensin converting enzyme
- polymorphism
- sarcopenia