Abstract
eview explores the relationship between genetics and elite endurance ath- letes, summarizes the current literature, highlights some novel findings, and provides a physiological basis for understanding the mechanistic effects of genetics in sport. Key genetic markers include ACTN3R577X (muscle fiber composition),ACEI/D (cardiovascular efficiency), and polymorphisms inPPARA,VEGFA, andADRB2, influencing energy metabolism, angiogenesis, and cardiovascular function. This review underscores the benefits of a multi-omics approach to better understand the complex interactions between genetic polymorphisms and physiological traits. It also addresses long- standing issues such as small sample sizes in studies and the heterogeneity in heritability estimates influenced by factors like sex. Understanding the mechanistic relationship between genetics and endurance performance can lead to personalized training strategies, injury prevention, and improved health outcomes. Future studies should focus on standardized classification of sports, replication studies involving diverse populations, and establishing solid physiological associations between polymorphisms and endurance traits to advance the field of sports genetics. Keywords:VO 2max; exercise; polymorphism; physiology; heredity; multi-omics approach; cardiovascular fitness; energy metabolism; skeletal muscle; angiogenesis 1. Introduction In sports science and especially sports genetics, elite athletes represent a critical population for study. These athletes push the boundaries of human physical performance, allowing researchers to explore fundamental questions such as the interplay between nurture and nature, the effects of specific training modalities, coaching strategies, and the very definition of talent. By
energy metabolism; skeletal muscle; angiogenesis 1. Introduction In sports science and especially sports genetics, elite athletes represent a critical population for study. These athletes push the boundaries of human physical performance, allowing researchers to explore fundamental questions such as the interplay between nurture and nature, the effects of specific training modalities, coaching strategies, and the very definition of talent. By studying elite athletes, researchers can explore the upper limits of human physiological capabilities and the genetic factors that contribute to exceptional performance. This knowledge not only advances the field of sports science but also has broader implications for public health, as cardiorespiratory fitness (CRF) is a key indicator of cardiovascular health and overall mortality risk. Despite the importance of defining elite athlete status, there is no universally established empirical definition [1]. However, the most commonly accepted criterion is competition at the highest national and international levels in a given sport [2–4]. In this review, we define elite athletes as individuals who have achieved top rankings in international competitions, such as world championships or the Olympic Games, and who have dedicated significant time and training to reach the pinnacle of their sport [2–4]. This definition includes athletes who consistently perform at a level significantly above the general athletic population, demonstrating exceptional physiological capacities and skill levels. The lack of a universally accepted definition of ‘elite athlete’ presents challenges in research, particularly regarding the comparability of studies. Different studies may use different criteria to classify athletes as elite, such as performance metrics, competition levels, years of experience, or subjective assessments [5]. This variability can lead to inconsistencies Int. J. Mol. Sci.2024,25, 13041.
Int. J. Mol. Sci.2024,25, 13041 2 of 40 in participant selection and categorization, making it difficult to compare results across studies or to perform meta-analyses [6]. For example, one study may define elite athletes based on national rankings, while another may require international competitive experience, leading to discrepancies that affect the generalizability of findings [6]. To address this issue, researchers need to clearly define their criteria for elite status and, when possible, use standardized definitions or classification systems to improve comparability between studies [1,7]. Establishing a physiological threshold for elite athlete status is very challenging due to the varying physiological demands of different sports [1,7]. Nonetheless, when compared with sedentary individuals or lower-level athletes in their respective sports, elite athletes consistently demonstrate superior physiological and performance capacities [7]. In partic- ular, elite endurance athletes have significantly higher levels of CRF, often measured by maximal oxygen uptake (VO2max), than non-elite athletes and the generalpopulation [7,8]. Investigating the genetic factors that contribute to these superior CRF levels may help elucidate the biological pathways involved in aerobic performance and identify potential genetic markers associated with exceptional endurance performance. Elite athletes can be categorized based on the physiological demands of their sport. Power and speed-oriented athletes specialize in activities requiring explosive strength and anaerobic capacity, such as powerlifting, 100 m sprints, discus throwing, 100 m swimming, and strongman events [3,9]. These sports mainly require bursts of maximal effort over a very short period of time [10]. In contrast, endurance athletes engage in sporting activities that require sustained power production, achieved through repeated isotonic contractions of large skeletal muscle groups over extended periods or distances. By efficiently using oxygen through aerobic metabolism, these muscle contractions enable the body to sustain prolonged physical activity [11]. Endurance sports include activities such as marathon running, cycling, triathlons, long-distance swimming, rowing, pentathlons, cross-country skiing, and ultra- marathons [1,7,12–15]. The exceptional performance of elite endurance athletes suggests that genetic factors play a significant role in their ability to sustain high-intensity exercise over prolonged periods. Understanding these genetic factors, particularly those affecting CRF, is crucial for unravelling the biological basis of
sports include activities such as marathon running, cycling, triathlons, long-distance swimming, rowing, pentathlons, cross-country skiing, and ultra- marathons [1,7,12–15]. The exceptional performance of elite endurance athletes suggests that genetic factors play a significant role in their ability to sustain high-intensity exercise over prolonged periods. Understanding these genetic factors, particularly those affecting CRF, is crucial for unravelling the biological basis of endurance performance. For an elite endurance athlete, a high level of CRF is essential [16]. CRF is defined as the capacity of the cardiorespiratory system to deliver oxygen and substrates to muscles during exercise [8,17]. While a high CRF is a key indicator of athletic performance, it also plays a key role in general human health by serving as a protective factor against cardiovascular disease, a leading cause of all-cause mortality [17–19]. For endurance athletes, however, a high CRF is a requirement for competing at an elite level [7]. The interplay between genetic predisposition and environmental factors such as training and nutrition contributes to the development of high CRF levels in elite athletes. Investigating the genetic determinants of CRF may provide insight into individual variability in endurance performance and the potential for personalized training programs tailored to an athlete’s genetic profile. Given its importance, the measurement and quantification of CRF is essential for monitoring both exercise performance and health outcomes. Maximal oxygen uptake (VO2max) is the gold standard for assessing CRF and endurance performance [8,20]. VO2max is defined as the maximum rate at which an individual can consume oxygen during intense or maximal exercise [8]. It reflects a person’s aerobic fitness and is an important determinant of endurance capacity. VO2maxis typically measured in milliliters of oxygen consumed per kilogram of body weight per minute (mL/kg/min) [21]. A higher VO2maxindicates a greater ability of the heart and lungs to deliver oxygen to the working muscles and the muscles’ efficiency in using that oxygen to produce energy (ATP) through aerobic metabolism [8,22]. VO 2maxcan be assessed using incremental exercise tests on a treadmill or cycle ergometer, where the intensity is gradually increased until exhaustion [8]. For elite endurance athletes, VO2maxis used as
greater ability of the heart and lungs to deliver oxygen to the working muscles and the muscles’ efficiency in using that oxygen to produce energy (ATP) through aerobic metabolism [8,22]. VO 2maxcan be assessed using incremental exercise tests on a treadmill or cycle ergometer, where the intensity is gradually increased until exhaustion [8]. For elite endurance athletes, VO2maxis used as both an indicator of endurance performance capacity and a developmental tool for optimizing training or exercise modalities [8,23].
Int. J. Mol. Sci.2024,25, 13041 3 of 40 Although contemporary sports science incorporates additional markers, such as blood lactate thresholds to supplement both research and performance enhancement [24], VO2max remains central to endurance sports [25–28]. VO2maxis a complex trait influenced by both genetic and environmental factors, with limitations imposed by physiological factors such as cardiac output and pulmonary diffusing capacity [8,20,29]. Genetic factors account for approximately 44% to 68% of the interindividual variation in VO2maxand VO2maxresponse to training [20,29,30]. Thus, the role of genetics in the observed variation is undeniable. However, VO2maxis a polygenic trait influenced by multiple genes as well as single nucleotide polymorphisms (SNPs), including interactions between different SNPs (SNP–SNP interactions) [31]. SNPs are genetic variations that occur when a single nucleotide (adenine [A], thymine [T], cytosine [C], or guanine [G]) in the DNA sequence is altered [32]. If such a variation is present in at least 1% of the population, it is classified as a SNP [32,33]. SNPs are the most common type of genetic variation among people and form the basis of many genetic studies because they can influence how genes function and how individuals respond to environmental factors, including exercise. Understanding these genetic and physiological factors may be important in developing personalized training interventions. The polygenic nature of VO2maxis closely linked to various physiological systems (e.g., cardiorespiratory and neuromuscular). By mapping an athlete’s SNP profile, researchers may gain insights into their current physiological status and their potential for adaptation through training. Although this field is still in its infancy and not yet widely used in sports practice, future advances could allow coaches and trainers to use genetic information to design personalized training programs tailored to the athlete’s genetic predispositions. For example, if genetic analysis indicates that an athlete has a predisposition for strong cardiorespiratory fitness but weaker muscular endurance, training could be adjusted to focus more on improving muscle fatigue resistance rather than just increasing VO2max. This personalized approach has the potential to make training strategies more efficient, potentially leading to faster improvements and optimized performance outcomes [34,35]. Gene–environment interactions also play a critical role
that an athlete has a predisposition for strong cardiorespiratory fitness but weaker muscular endurance, training could be adjusted to focus more on improving muscle fatigue resistance rather than just increasing VO2max. This personalized approach has the potential to make training strategies more efficient, potentially leading to faster improvements and optimized performance outcomes [34,35]. Gene–environment interactions also play a critical role in shaping VO2max, as en- vironmental factors such as training intensity, altitude exposure, and nutritional status can modulate the expression of genetic potential. Understanding the complexity of these genetic influences and interactions is essential to fully elucidate the determinants of elite endurance performance. Despite advances in sports genetics, the genetic determinants of elite endurance athlete status remain only partially understood, with inconsistent findings and a lack of clarity regarding the polygenic nature of endurance traits. This gap in knowledge is partly due to methodological challenges such as small sample sizes, population stratification, and the complex interplay of multiple genetic and environmental factors. Inconsistencies in findings across studies do highlight the need for more comprehensive research that integrates genetic data with physiological and environmental variables. Addressing these gaps is crucial for advancing our understanding of the genetic architecture underlying elite endurance performance and for translating this knowledge into practical applications in sports and health sciences. Bray et al. [31] contributed one of the earliest compilations of sports-related genes and polymorphisms. In the seventh edition of the Human Gene Map for Performance and Health-Related Fitness Phenotypes, they added over 20 new genes to the map, bringing the total to 221 autosomal and X-linked genes, along with 18 mitochondrial markers. In later years, with the introduction and spread of new research strategies and methods, more focused and detailed genetic compilation studies in sports science have been published. One of the most up-to-date works is the review by Semenova et al. [27]. These authors examined literature on sports genetics and provided extensive detail on genes and poly- morphisms that affect sports. According to Semenova et al. [36], as of May 2023, the total
science have been published. One of the most up-to-date works is the review by Semenova et al. [27]. These authors examined literature on sports genetics and provided extensive detail on genes and poly- morphisms that affect sports. According to Semenova et al. [36], as of May 2023, the total
Int. J. Mol. Sci.2024,25, 13041 4 of 40 number of DNA polymorphisms associated with athletic performance is 128; of those 128 markers, 41 are endurance-related, 45 are power-related, and 42 are strength-related. While the review by Semenova et al. [36] provides a comprehensive overview of genetic polymorphisms associated with athletic performance, our review aims to build on this foundation by focusing specifically on the integration of genetic findings with physiological data to understand the mechanistic effects of genetics in endurance sports. We concentrate on recent studies from the last five years that have examined not only known polymorphisms but also less-studied genes and new discoveries that have emerged since the publication of Semenova et al. [36]. In addition, we emphasize a bottom–up approach using multi-omics in the hypothesis generation phase by examining product– product interactions in candidate gene selection, which differs from traditional top–down methods. In this way, we aim to provide new insights into the polygenic complexity of endurance traits and highlight potential areas for future research. This review aims to fill the aforementioned gaps in the literature by addressing the fol- lowing research questions: (1) What are the key genetic factors influencing VO2maxand en- durance performance in elite athletes, and how do these factors contribute to the polygenic complexity of endurance traits? (2) How do these genetic factors interact with physiological systems to influence endurance performance? (3) What are the methodological challenges in current genetic studies of endurance athletes or performance, particularly with regard to study design and sample size, and how can these challenges be overcome? (4) What future research directions are needed to advance our understanding of the genetic basis of endurance performance? By focusing on these questions, this review aims to synthesize current knowledge on the genetic factors influencing VO2maxand endurance performance by assessing and highlighting how these genes interact with physiological systems. By examining the sports genetics literature relevant to elite athlete status, this review also aims to highlight the potential benefits of integrating genetic and physiological data to better understand the molecular mechanisms underlying endurance performance and development. Furthermore, by focusing attention on
the genetic factors influencing VO2maxand endurance performance by assessing and highlighting how these genes interact with physiological systems. By examining the sports genetics literature relevant to elite athlete status, this review also aims to highlight the potential benefits of integrating genetic and physiological data to better understand the molecular mechanisms underlying endurance performance and development. Furthermore, by focusing attention on some of the less studied genes and recent discoveries, we aim to provide innovative directions for future research. We hypothesize that integrating genetic findings with physiological data will improve our understanding of the complex interactions between genetic polymorphisms and physio- logical traits that influence endurance performance. In addition, we propose that addressing methodological challenges such as small sample sizes and population homogeneity will improve the reliability and replicability of genetic associations in endurance studies. While the use of multi-omics approaches is not entirely novel in genetics research, we propose that applying multi-omics at the hypothesis generation stage represents an innovative approach in sports genetics. By adopting a bottom–up methodology, we suggest that integrating genomics, transcriptomics, proteomics, and metabolomics can help identify candidate genes based on physiological pathways and product–product interactions. This contrasts with traditional top–down approaches that start with known genes and look for associations. A better understanding of physiology, including how it is affected by epigenetic factors, might play a pivotal role in identifying which genes to examine. By using multi-omics data in this way, researchers can uncover new genetic factors that contribute to endurance performance, leading to a more comprehensive understanding of the underlying mechanisms. This approach could be achieved by examining product–product interactions in the candidate gene selection process, providing a novel perspective in the field. We discuss the current understanding of the genetic basis of VO2maxand endurance performance, including key genes and genetic variants identified in recent studies. We examine how these genetic factors interact with physiological systems to influence en- durance performance. We also critically review the methodological challenges in genetic studies of endurance, emphasizing the need for robust study designs and larger, more diverse cohorts. Finally, we identify gaps in current research and suggest
endurance performance, including key genes and genetic variants identified in recent studies. We examine how these genetic factors interact with physiological systems to influence en- durance performance. We also critically review the methodological challenges in genetic studies of endurance, emphasizing the need for robust study designs and larger, more diverse cohorts. Finally, we identify gaps in current research and suggest future directions, emphasizing the importance of integrating genetic findings with physiological and training data to improve our understanding of elite endurance performance. By addressing these
Int. J. Mol. Sci.2024,25, 13041 5 of 40 questions and highlighting the current limitations of sports genetics research, this review aims to provide a comprehensive understanding of the genetic factors that influence elite endurance performance. This knowledge has the potential to inform the development of personalized training strategies, improve talent identification processes, and contribute to the broader field of precision medicine. 2. Genes and Polymorphisms and Their Association with Endurance Performance 2.1. Materials and Methods A comprehensive literature search was conducted across four databases—PubMed, Science Direct, Cochrane, and Google Scholar—from 14 April 2024 to 6 May 2024. The aim was to identify polymorphisms and their combinations that require further investigation in the context of endurance performance. Polymorphisms were considered for investigation if: (1) they had shown inconsistent or conflicting results in previous studies regarding their association with endurance performance or VO2max; (2) they were identified in recent studies but lacked extensive research or replication; (3) they were located in genes with known physiological relevance to endurance performance but had not been extensively studied in elite endurance athletes; (4) they were novel or understudied polymorphisms emerging from recent genetic studies, such as genome-wide association studies (GWAS), suggesting potential associations with endurance performance. Studies were also considered for inclusion if they met additional criteria: published in the last 5 years (from 1 January 2019 to 30 April 2024), compared elite endurance athletes with sedentary controls or other athlete groups if they had a dedicated endurance subject group, examined mixed-sport athletes, and studies with only athlete groups. Articles written in English only were considered. Exceptions were made if the articles had abstracts in another language, but the full text was written in English, as long as the content met our inclusion criteria. In such cases, abstracts were translated using well-established online translation tools, such as Deepl, to ensure accuracy and consistency in the selection pro- cess. Studies focusing on genes and their effect on VO2maxand VO2maxtrainability were sought using Boolean operators AND/OR, and the following keywords to guide this search: “single nucleotide polymorphisms”, “SNPs”, “cardiorespiratory fitness”, “cardiovascular fitness”, “polymorphism”, “endurance”, “elite athletes”, “VO2max,
Description
A review on genetic factors influencing endurance performance in elite athletes.