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• W2149204650 abstract "ViewpointPerspectivesEpigenetic regulation of the ACE gene might be more relevant to endurance physiology than the I/D polymorphismStuart M. RaleighStuart M. RaleighDivision of Health and Life Science, University of Northampton, Northampton, United KingdomPublished Online:15 Mar 2012https://doi.org/10.1152/japplphysiol.00828.2011This is the final version - click for previous versionMoreSectionsPDF (39 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the renin-angiotensin system (RAS) is a complex pathway initiated by the renin dependent catalysis of liver derived angiotensinogen to angiotensin I (ANG I) (21). ANG 1 is then converted to the effector metabolite angiotensin II (ANG II) by angiotensin converting enzyme (ACE), a peptidyl carboxypeptidase (21). Subsequent interaction of ANG II with membrane bound AT-1 receptors can promote a hypertensive response mediated by vasoconstriction and the reabsorption of both sodium and water (21, 33). Although the classic RAS was originally thought to involve ANG II generation only in the circulation where it acted in an endocrine manner it is now known that both local tissue and cellular versions of the RAS exist that are postulated to work by intracrine, autocrine, or paracrine mechanisms (33). In addition to blood pressure regulation, different tissue RASs are thought to be important for other cellular functions (21, 33).The activity of ACE is germane to the effective function of the RAS, and it is constitutively expressed in a range of tissue (11). The structural organization of the ACE gene was determined in 1991 (18). It resides on chromosome 17 (19) and harbors a 287-base pair intronic insertion/deletion (I/D) polymorphism that associates with circulating ACE (11, 15) and the expression of ACE from various tissues like T-lymphocytes and the heart (10, 13). Interestingly, the ACE I/D polymorphism has been, and continues to be, the focus of much research from sports physiologists who are trying to understand whether the polymorphism influences a broad spectrum of physiological traits related to endurance and athletic prowess. A number of excellent reviews documenting the extensive research in this area have recently been published (26, 27, 31). Although it seems that most reports suggest that the I allele predisposes to human endurance (26) the literature also contains some contrary evidence (2, 20). A plethora of mechanisms have been suggested for how the I/D polymorphism influences performance phenotypes (reviewed in 26, 31). For example, muscle fiber type (32) and relative anabolic response to training (26) have been associated with the I allele. However, muscle function and contractile properties (22) and the conversion of ANG I to ANG II within the forearm and leg are independent of the genotype (12). Interestingly, ACE levels within individuals have been reported to remain fairly constant over time (11) and seem unchanged following different exercise interventions (14). Although it is rightly recognized by researchers that such factors as heterogeneous sporting cohorts (26) and modest sample sizes (27) may explain some of the discrepant findings between ACE I/D genotype and endurance phenotypes, it is acknowledged that additional molecular mechanisms related to the ACE gene will also have a part to play (26).Epigenetic mechanisms (discussed subsequently) may influence sports and exercise performance (8, 5, 7, 29). However, as far as the author is aware, there have not been any reports that address whether epigenetic regulation of the ACE gene is specifically involved in modifying human endurance. Epigenetic factors such as histone acetylation and CpG island methylation are processes that the cell uses to modify the expression of genes without alteration to the DNA coding sequence (1, 23). As a general rule hypermethylation of a gene's promoter CpG regions tends to silence gene expression (1). The opposite can occur when CpG islands become hypomethylated (1). Importantly, the human ACE gene promoter has been shown to harbor CpG islands (28). Indeed the methylation status of these CpG regions, along with the acetlyation status of histones, strongly influences the activity of the ACE promoter in driving transcription in a cell type-specific manner (28). Therefore the viewpoint of the author is that future studies on the ACE gene, in relation to human endurance, would benefit if the recently identified epigenetic factors that regulate ACE expression (28) were considered in addition to the I/D genotype. Indeed the DNA methylation status of other genes relevant to endurance related traits, such as blood pressure, have been studied (16).Another compelling reason for encouraging research to focus on possible epigenetic mechanisms that might be related to the ACE gene and endurance performance is that environmental factors such as nutrition (9), training (24), muscle unloading (25), and mechanical stimulation (4) have also been associated with modifying a gene's epigenetic status. It is well established that some of these environmental factors significantly impact on performance (17, 30, 36), and epigenetics relevant to sports have been suggested as a pathway whereby the environment interacts with the genome (8). Hence it is conceivable that some of the factors mentioned previously might influence the CpG islands within the ACE promoter and affect functionality. Likewise, could inconsistencies reported for the I/D polymorphism and endurance phenotypes be partially explained by unmeasured environmentally induced changes in methylation and/or histone acetylation status leading to spurious or unexpected association? Under this scenario, one might envisage a situation in which possession of the D/D genotype, generally associated with strength (26) and increased ACE levels(13, 15) be temporarily reversed if both copies of the ACE gene were transiently methylated. If so, an individual might be exposed to a temporary reduction in ACE levels and demonstrate an enhanced, albeit temporary, increase in endurance. The phenotype might be modified further if we consider the possibility that methylation might only occur at a CpG island within the promoter on just one copy of either of the inherited ACE genes. Moreover, as previously mentioned, the observation that circulating ACE levels are not changed by time (11) or certain exercise interventions (14) seems to suggest that epigenetic modifications relevant to endurance will only work through tissue-specific ACE expression.Establishing the methylation status of the ACE gene in participants involved in endurance-related association studies will likely involve a number of technical hurdles. As gene promoter methylation status can vary according to cell type (23) then researchers may need to sample DNA from various tissues to obtain a snapshot of the ACE epigenetic profile at any particular time. Experiments might also extend to longitudinal designs to monitor how the profile changes as a function of climate, season, or environmental setting. This could prove invaluable in the future design of customized training protocols for athletes. Furthermore, this kind of approach may ultimately involve aspects of systems biology. Overcoming the technical aspects of such work should not deter researchers from attempting to plan such studies as the laboratory-based technology needed to characterize gene methylation status is readily available (23).Finally, studies relating to the ACE I/D polymorphism and endurance-related phenotypes have advanced our understanding of how a single genetic locus can influence a complex phenotype such as physical endurance. However, inconsistencies from genetic association studies relating to the ACE gene and it's I/D polymorphism maybe attributable, at least in part, to the epigenetic factors that have been reported to influence ACE activity. It might emerge in the future that epigenetic regulation of the ACE gene is as relevant to human endurance performance as the I/D polymorphism.DISCLOSURESNo conflicts of interest, financial or otherwise, are declared by the author.REFERENCES1. Aguilera O , Fernandez AF , Munoz A , Fraga MF. Epigenetics and environment: a complex relationship. J Appl Physiol 109: 243–251, 2010.Link | ISI | Google Scholar2. Amir O , Amir R , Yamin C , Attias E , Eynon N , Sagiv M , Meckel Y. The ACE deletion allele is associated with Israeli elite endurance athletes. Exp Physiol 92: 881–886, 2007.Crossref | PubMed | ISI | Google Scholar3. Armstrong N , Barker AR. Endurance training and elite young athletes. Med Sport Sci 56: 59–83, 2010.Crossref | Google Scholar4. Arnsdorf EJ , Tummala P , Castillo AB , Zhang F , Jacobs CR. The epigenetic mechanism of mechanically induced osteogenic differentiation. J Biomech 43: 2881–2886, 2010.Crossref | ISI | Google Scholar5. Baldwin KM , Haddad F. 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The I allele of the angiotensin-converting enzyme gene is associated with an increased percentage of slow-twitch type I fibers in human skeletal muscle. Clin Genet 63: 139–144, 2003.Crossref | ISI | Google Scholar33. Zhuo JL , Li XC. New insights and perspectives on intrarenal renin-angiotensin system: focus on intracrine/intracellular angiotensin II. Peptides 32: 1551–1565, 2011.Crossref | PubMed | ISI | Google ScholarAUTHOR NOTESAddress for reprint requests and other correspondence: S. M. Raleigh, Division of Health and Life Science, Univ. of Northampton, Boughton Green Rd., Northampton NN2 7AL (e-mail: stuart.[email protected]ac.uk). Download PDF Previous Back to Top Next FiguresReferencesRelatedInformation Cited ByEpigenetic-related Effects of COVID-19 on Human CellsInfectious Disorders - Drug Targets, Vol. 22, No. 7Future perspectives and concluding remarksMeta-Analysis of association between single nucleotide polymorphisms with sports injuries in soccer31 December 2021 | Revista Médicas UIS, Vol. 34, No. 3The Functional Genome in Physical Exercise1 November 2018Promoter methylation status of the TIMP2 and ADAMTS4 genes and patellar tendinopathyJournal of Science and Medicine in Sport, Vol. 21, No. 4Unknown face of known drugs – what else can we expect from angiotensin converting enzyme inhibitors?European Journal of Pharmacology, Vol. 797The heritable path of human physical performance: from single polymorphisms to the “next generation”6 July 2015 | Scandinavian Journal of Medicine & Science in Sports, Vol. 26, No. 6Conventional and Genetic Talent Identification in Sports: Will Recent Developments Trace Talent?12 July 2014 | Sports Medicine, Vol. 44, No. 11Physical Exercise and Epigenetic Modulation: Elucidating Intricate Mechanisms8 January 2014 | Sports Medicine, Vol. 44, No. 4Exercise: Putting Action into Our Epigenome27 October 2013 | Sports Medicine, Vol. 44, No. 2DNA Methylation Analysis of the Angiotensin Converting Enzyme (ACE) Gene in Major Depression13 July 2012 | PLoS ONE, Vol. 7, No. 7 More from this issue > Volume 112Issue 6March 2012Pages 1082-1083 Copyright & PermissionsCopyright © 2012 the American Physiological Societyhttps://doi.org/10.1152/japplphysiol.00828.2011PubMed22096122History Received 5 July 2011 Accepted 16 November 2011 Published online 15 March 2012 Published in print 15 March 2012 Metrics" @default.
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