Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the ACTN3 R577X Polymorphism

Carmen Fiuza-Luces1, Jonatan R. Ruiz2,3, Gabriel Rodrı´guez-Romo4, Catalina Santiago1, Fe´lix Go´ mez- Gallego1, Thomas Yvert1, Amalia Cano-Nieto5, Nuria Garatachea6, Marı´a Mora´n7. , Alejandro Lucia1*.

1Universidad Europea de Madrid, Madrid, Spain, 2Department of Physical Education, School of Physical Activity and Sport Sciences, University of Granada, Granada, Spain, 3Department of Biosciences and Nutrition at NOVUM, Unit for Preventive Nutrition, Karolinska Institutet, Stockholm, Sweden, 4INEF, Universidad Polite´cnica de Madrid, Madrid, Spain, 5SUAP Archena, Hospital Morales Meseguer, Murcia, Spain, 6Faculty of Health and Sport Science, Department of Physiotherapy and Nursing, University of Zaragoza, Zaragoza, Spain, 7Centro de Investigacio´n Hospital 12 de Octubre and CIBERER, Madrid, Spain

Abstract

Exercise phenotypes have played a key role for ensuring survival over human evolution. We speculated that some genetic variants that influence exercise phenotypes could be associated with exceptional survival (i.e. reaching $100years of age). Owing to its effects on muscle structure/function, a potential candidate is the Arg(R)577Ter(X) polymorphism (rs1815739) in ACTN3, the structural gene encoding the skeletal muscle protein a-actinin-3. We compared the ACTN3 R577X genotype/ allele frequencies between the following groups of ethnically-matched (Spanish) individuals: centenarians (cases, n =64; 57 female; age range: 100–108 years), young healthy controls (n= 283, 67 females, 216 males; 2162 years), and humans who are at the two end-points of exercise capacity phenotypes, i.e. muscle endurance (50 male professional road cyclists) and muscle power (63 male jumpers/sprinters). Although there were no differences in genotype/allele frequencies between centenarians (RR:28.8%; RX:47.5%; XX:23.7%), and controls (RR:31.8%; RX:49.8%; XX:18.4%) or endurance athletes (RR:28.0%; RX:46%; XX:26.0%), we observed a significantly higher frequency of the X allele (P =0.019) and XX genotype (P =0.011) in centenarians compared with power athletes (RR:47.6%; RX:36.5%;XX:15.9%). Notably, the frequency of the null XX (a-actinin- 3 deficient) genotype in centenarians was the highest ever reported in non-athletic Caucasian populations. In conclusion, despite there were no significant differences with the younger, control population, overall the ACTN3 genotype of centenarians resembles that of world-class elite endurance athletes and differs from that of elite power athletes. Our preliminary data would suggest a certain ‘survival’ advantage brought about by a-actinin-3 deficiency and the ‘endurance’/ oxidative muscle phenotype that is commonly associated with this condition.

Citation: Fiuza-Luces C, Ruiz JR, Rodr´ıguez-Romo G, Santiago C, Go´mez-Gallego F, et al. (2011) Are ‘Endurance’ Alleles ‘Survival’ Alleles? Insights from the R577X Polymorphism. PLoS ONE 6(3): e17558. doi:10.1371/journal.pone.0017558 Editor: Conrad Earnest, Pennington Biomedical Research Center, United States of America Received December 10, 2010; Accepted January 26, 2011; Published March 3, 2011 Copyright:   2011 Fiuza-Luces et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This study was funded by the Fondo de Investigaciones Sanitarias (FIS, ref. # PS09/00194), and Swedish Council for Working Life and Social (FAS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: Alejandro Lucia and Jonatan R. Ruiz are involved with PLoS ONE as Section Editor and Academic Editor, respectively. * E-mail: alejandro.lucia@uem.es

. These authors contributed equally to this work.

Introduction

(,40.000–60.000 years ago) can affect exercise phenotypes [8]. The a-actinin-3 deficient XX genotype (with a frequency of ,18% among European Caucasians) is believed to preclude top-level athletic performance in ‘pure’ power and sprint sports (e.g. sprinting, jumping events), especially in women [9]. In contrast, compared with the general population, the X allele tends to be overrepresented in those humans with an ‘extreme endurance phenotype’, i.e. elite endurance athletes [9,10]. Mechanistic explanation for the latter finding might be found in the a-actinin-3 knockout (KO) mouse developed by Prof. North’s group. Compared with wild-type mice, the muscles of the KO mouse exhibit 33% higher endurance and a shift towards increased activity of mitochondrial oxidative metabo- lism [8,11]. With regards to this, improved oxidative pathways in mitochondria may be a common factor linking physical fitness and decreased disease risk [12,13]. For the abovementioned reasons, it could be speculated that the shift towards more efficient aerobic metabolism associated with the XX genotype might confer a ‘survival advantage’.

Identifying candidate gene variants associated with ‘longevity assurance’ is possible by studying the genotype of centenarians [1]. This group of people are the survival tail of population; indeed, they escaped diseases of the pre-antibiotic era, and have postponed/avoided several ageing-related diseases as well as their fatal consequences [2]. Genetically we are still citizens of the Paleolithic era living in the 21st century [3,4]. In the Paleolitithic societies survival was essentially linked to exercise (e.g. ‘long time tracking persistence’ for successful hunting) [5,6]. Therefore, it would be plausible to speculate that some identified genetic variants associated with exercise phenotypes could also be associated with exceptional survival.