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.
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2023
2023
Historique:
received:
06
06
2023
accepted:
19
09
2023
medline:
1
11
2023
pubmed:
20
10
2023
entrez:
20
10
2023
Statut:
epublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 37862321
doi: 10.1371/journal.pone.0292402
pii: PONE-D-23-17472
pmc: PMC10588903
doi:
Substances chimiques
Perindopril
Y5GMK36KGY
Peptidyl-Dipeptidase A
EC 3.4.15.1
Leucine
GMW67QNF9C
Angiotensin-Converting Enzyme Inhibitors
0
Types de publication
Randomized Controlled Trial
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0292402Subventions
Organisme : Medical Research Council
Pays : United Kingdom
Organisme : Department of Health
Pays : United Kingdom
Organisme : Chief Scientist Office
Pays : United Kingdom
Informations de copyright
Copyright: © 2023 Rossios et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Déclaration de conflit d'intérêts
The authors have declared that no competing interests exist.
Références
J Appl Physiol (1985). 2018 May 1;124(5):1377-1384
pubmed: 29345962
Eur Respir J. 2007 Mar;29(3):482-8
pubmed: 17107992
Stroke. 1995 Aug;26(8):1329-33
pubmed: 7631331
J Clin Med. 2018 Apr 08;7(4):
pubmed: 29642478
Nucleic Acids Res. 1992 Mar 25;20(6):1433
pubmed: 1313972
J Nutr Health Aging. 2008 Aug-Sep;12(7):480-5
pubmed: 18615230
Nat Genet. 1999 Jan;21(1):71-2
pubmed: 9916793
CMAJ. 2007 Oct 9;177(8):867-74
pubmed: 17923654
Chron Respir Dis. 2019 Jan-Dec;16:1479973119843650
pubmed: 31131626
Arch Med Res. 2006 Oct;37(7):890-4
pubmed: 16971231
J Med Genet. 2005 Jan;42(1):26-30
pubmed: 15635071
J Sports Sci. 2021 Jan;39(2):200-211
pubmed: 32856541
Circulation. 1997 Aug 5;96(3):741-7
pubmed: 9264477
Physiol Rep. 2022 Jul;10(13):e15382
pubmed: 35822425
F1000Res. 2021 Mar 5;10:184
pubmed: 34354813
J Hypertens. 1995 Dec;13(12 Pt 2):1597-601
pubmed: 8903617
Chest. 2014 Oct;146(4):932-940
pubmed: 24556825
Exp Gerontol. 2018 Aug;109:82-89
pubmed: 28645696
Compr Physiol. 2012 Oct;2(4):2829-70
pubmed: 23720267
Front Rehabil Sci. 2021 Nov;2:
pubmed: 34901931
Trials. 2018 Jan 04;19(1):6
pubmed: 29301558
Cells. 2021 Jul 06;10(7):
pubmed: 34359878
Lancet. 2000 Feb 5;355(9202):434-42
pubmed: 10841123
Int J Sports Med. 2010 Jan;31(1):65-71
pubmed: 20029740
Physiology (Bethesda). 2015 Jan;30(1):30-9
pubmed: 25559153
Int J Environ Res Public Health. 2021 Jun 19;18(12):
pubmed: 34205250
Stroke. 1996 Mar;27(3):435-40
pubmed: 8610309
J Hypertens. 1999 May;17(5):657-64
pubmed: 10403609
Endocrinology. 2001 Apr;142(4):1489-96
pubmed: 11250929
Scand J Med Sci Sports. 2020 Aug;30(8):1298-1317
pubmed: 32281690
Circulation. 1998 Oct 27;98(17):1742-9
pubmed: 9788828
Genes (Basel). 2021 Jul 29;12(8):
pubmed: 34440352
Int J Mol Sci. 2023 Feb 08;24(4):
pubmed: 36834822
BMJ Open Respir Res. 2017 Mar 8;4(1):e000165
pubmed: 28321311
Biol Reprod. 2019 Jan 1;100(1):139-148
pubmed: 30102356
J Hum Hypertens. 1994 Aug;8(8):639-40
pubmed: 7990101
J Aging Res. 2018 Feb 19;2018:8491092
pubmed: 29670769
Lancet. 2019 Jun 29;393(10191):2636-2646
pubmed: 31171417
Exp Ther Med. 2020 Oct;20(4):3407-3411
pubmed: 32905120
Kobe J Med Sci. 2018 Nov 12;64(3):E119-E125
pubmed: 30666042
J Am Coll Cardiol. 1996 Aug;28(2):338-44
pubmed: 8800107
Age Ageing. 2010 Jul;39(4):412-23
pubmed: 20392703
Int J Environ Res Public Health. 2020 Feb 14;17(4):
pubmed: 32075076
J Cachexia Sarcopenia Muscle. 2022 Apr;13(2):858-871
pubmed: 35174663
Kidney Int. 1996 Feb;49(2):534-7
pubmed: 8821841
J Sports Med Phys Fitness. 2022 Jun;62(6):795-802
pubmed: 34028240
J Renin Angiotensin Aldosterone Syst. 2009 Jun;10(2):77-84
pubmed: 19502254
Am J Respir Crit Care Med. 2016 Dec 1;194(11):1349-1357
pubmed: 27248440
Front Med (Lausanne). 2020 Jan 22;6:327
pubmed: 32039215
Clin Genet. 2003 Feb;63(2):139-44
pubmed: 12630962
J Appl Physiol (1985). 2009 Jul;107(1):346-53
pubmed: 19407247
Muscle Nerve. 2013 Oct;48(4):488-97
pubmed: 23553751
J Appl Physiol (1985). 2019 Jun 1;126(6):1550-1562
pubmed: 30946636
J Renin Angiotensin Aldosterone Syst. 2011 Sep;12(3):202-7
pubmed: 21330423
J Gerontol A Biol Sci Med Sci. 2014 Jun;69(6):736-43
pubmed: 24201696
Phys Ther. 2019 Aug 1;99(8):998-1009
pubmed: 31087072
Clin Chim Acta. 2020 Nov;510:455-458
pubmed: 32791137
Atherosclerosis. 2001 Jan;154(1):123-8
pubmed: 11137090
J Med Genet. 2000 Sep;37(9):695-7
pubmed: 10978362
Ann Rehabil Med. 2012 Aug;36(4):433-46
pubmed: 22977768
Pharmacogenet Genomics. 2005 Feb;15(2):75-81
pubmed: 15861031
Circ Res. 2015 Aug 14;117(5):424-36
pubmed: 26137861
J Am Geriatr Soc. 2000 Jun;48(6):625-30
pubmed: 10855597
Am J Respir Crit Care Med. 2004 Aug 15;170(4):395-9
pubmed: 15117739
Exp Physiol. 2000 Sep;85(5):575-9
pubmed: 11038409
Eur J Clin Invest. 2000 Dec;30(12):1076-82
pubmed: 11122322
Eur J Appl Physiol. 2012 Jul;112(7):2409-20
pubmed: 22045415
JAMA. 2005 Aug 10;294(6):691-8
pubmed: 16091571