Genes and Epigenetics Together Shape the Biology of Elite Endurance

Endurance performance has long been treated as the product of relentless training and psychological grit, but a sweeping new review published in Frontiers in Systems Biology argues that the molecular machinery beneath elite aerobic capacity is far more intricate than any single

The review’s central argument rests on a distinction that has often been blurred in popular coverage of sports genetics: the difference between identifying a genetic variant and demonstrating that the variant reliably predicts athletic outcomes. As the authors note, more than 200 polymorphisms have been linked to athlete status across the literature, yet only a small fraction shows consistent, replicated associations with endurance performance. This gap between discovery and replication is not unique to sports science, but it is particularly pronounced here because elite endurance athletes are rare, samples tend to be small, and the phenotype itself is shaped by years of training, nutrition, and environment. A variant that appears significant in one cohort of runners may vanish in another cohort of cyclists or rowers, where the physiological demands and training histories differ substantially.

Among the variants that have held up across studies, the iron-regulating polymorphism HFE rs1799945 stands out as a strong predictor of endurance ability in the review’s synthesis. This finding is intriguing because HFE is best known in the context of iron metabolism and hemochromatosis rather than muscle physiology. Its association with endurance capacity underscores how systemic factors, such as oxygen transport capacity and iron availability for hemoglobin synthesis, can be as decisive for aerobic performance as properties of the muscle fibers themselves. Endurance performance depends on an entire chain of oxygen delivery and utilization, from pulmonary uptake through cardiovascular transport to mitochondrial oxidation, and genetic influence can enter at any link in that chain.

The other highlighted variants map onto this chain in instructive ways. ACE rs1799752, one of the most extensively studied polymorphisms in exercise science, influences the renin-angiotensin system and has been associated with cardiovascular efficiency and training response. PPARGC1A rs8192678 affects the gene encoding PGC-1α, a master regulator of mitochondrial biogenesis that coordinates the production of new mitochondria in response to exercise stimuli. PPARA rs4253778 participates in fatty acid oxidation, shaping how muscle tissue prioritizes lipid metabolism during prolonged effort. CDKN1A rs236448, tied to cell cycle regulation, adds a further dimension related to tissue remodeling and recovery. None of these variants acts alone, and the review emphasizes that their effects are cumulative and pathway-dependent rather than deterministic.

This polygenic framing helps explain one of the most persistent puzzles in the field: the existence of elite athletes who lack the so-called favorable genotypes identified in earlier candidate gene studies. If dozens of variants each contribute a small effect, then many different combinations of alleles can produce a similar overall capacity, much as many different routes can lead to the same destination. Conversely, an individual carrying several favorable variants may never reach elite level without the training exposure, nutritional support, and environmental conditions required to express that potential. The review is explicit that no single variant is sufficient to explain elite endurance status, a conclusion that should temper expectations for simple genetic talent tests.

The methodological challenges facing the field deserve particular attention. Genome-wide association studies, which scan hundreds of thousands of genetic markers across the genome without preselecting candidates, have the advantage of hypothesis-free discovery but require very large sample sizes to detect the small effect sizes typical of complex traits. Recruiting thousands of elite endurance athletes is inherently difficult, and most GWAS in sports science have relied on comparisons between elite athletes and sedentary or recreational controls, which conflates genetic influence on performance with genetic influence on the propensity to train competitively in the first place. Meta-analyses attempt to overcome sample size limitations by pooling studies, but heterogeneity in phenotype definitions, ancestry, and sport disciplines can obscure genuine signals.

The review also draws attention to a population problem that extends beyond sample size. Most genomic studies in sports science have been conducted in relatively homogeneous populations, typically of European descent, which limits the generalizability of findings and may overlook population-specific genetic and epigenetic signatures. Allele frequencies differ across ancestries, and gene-environment interactions shaped by altitude, diet, and historical selection pressures may produce distinct adaptive architectures in underrepresented populations. The high endurance performance of certain high-altitude populations, for example, likely reflects variants and physiological adaptations that would not be captured by association studies conducted in lowland European cohorts. Building a genuinely inclusive understanding of endurance biology requires deliberate investment in diverse study populations.

Perhaps the most forward-looking portion of the review concerns epigenetics, the layer of molecular regulation that sits above the DNA sequence and modulates gene activity without altering the underlying genetic code. Three principal mechanisms are discussed. DNA methylation, the addition of methyl groups to cytosine bases, typically suppresses gene expression and can change in response to exercise in a manner that is both tissue-specific and sometimes long-lasting. Histone modifications, which alter how tightly DNA is wound around protein spools, control the accessibility of genes to the transcriptional machinery. Non-coding RNAs, particularly microRNAs, fine-tune gene expression after transcription by targeting messenger RNAs for degradation or translational repression.

What makes these mechanisms especially relevant to endurance training is their dynamism. Unlike static genetic variants, which are fixed at conception, epigenetic marks respond to physiological stress within hours to weeks, providing a flexible interface between environment and genome. Acute exercise sessions have been shown to provoke rapid demethylation at promoters of metabolic genes in skeletal muscle, effectively priming the tissue for the mitochondrial biogenesis that follows. This plasticity offers a compelling explanation for the marked inter-individual variability in training responsiveness, the phenomenon in which some individuals, the high responders, show dramatic gains in aerobic capacity while others, the low responders, improve minimally despite identical training programs. Classic heritability studies of trainability have long suggested that the response to exercise is itself substantially inherited, and epigenetic regulation is a plausible mechanistic bridge between that observation and molecular biology.

The exercise-responsive microRNAs highlighted in the review each carry functional significance for endurance adaptation. miR-1 and miR-206 are enriched in skeletal muscle and participate in muscle differentiation and remodeling. miR-21 is implicated in inflammation and fibrosis pathways, influencing how muscle tissue recovers from the repeated micro-damage of endurance training. miR-146 participates in inflammatory signaling regulation, potentially modulating the chronic low-grade inflammation that can accompany heavy training loads. miR-208 is largely cardiac-specific and involved in cardiac muscle remodeling, while miR-222 has been linked to cardiac growth and, intriguingly, to exercise-induced angiogenesis, the formation of new capillaries that improves oxygen delivery to working muscle. Circulating levels of several of these microRNAs change measurably after acute exercise bouts and shift with chronic training, raising the possibility that they could serve as molecular biomarkers of training status and adaptation.

The review’s call for multi-omics integration reflects a broader shift in the life sciences. Genomics alone describes potential; epigenomics describes regulation; transcriptomics describes what genes are actually being expressed at a given moment. Layering these data types, alongside proteomics and metabolomics, allows researchers to construct dynamic models of how an athlete’s physiology responds to a training block, rather than static snapshots of genetic risk. Systems biology approaches can then model the interactions among oxygen transport, mitochondrial biogenesis, angiogenesis, muscle remodeling, and anti-inflammatory responses as a network, identifying which nodes are most influential and which combinations of molecular states correspond to high responsiveness.

The practical implications, if handled carefully, could be significant. Personalized training interventions informed by an athlete’s genomic and epigenomic profile might eventually allow coaches to tailor training loads, recovery protocols, and nutritional strategies to individual molecular signatures, optimizing adaptation while reducing injury and overtraining risk. Talent identification programs might incorporate molecular information, though the review’s emphasis on the limits of single-marker approaches argues strongly against simplistic genetic screening. The authors also flag the ethical dimension: genetic and epigenetic data are sensitive personal information, and their use in sport raises questions about privacy, discrimination, fairness, and the potential for misuse in selection decisions. Any translation into practice would require robust governance frameworks.

It is worth noting what the review does not claim. It does not suggest that genetics and epigenetics replace training, motivation, or technique as determinants of performance. Environmental modulators, including training itself, nutrition, recovery and sleep, environmental stressors, and altitude exposure, remain central to the integrated model the authors present. The molecular layers they describe are best understood as modulators of how an individual responds to those environmental inputs, not as substitutes for them. Endurance performance emerges from the continuous interaction of inherited architecture and lived experience, and the review’s contribution is to map, with unusual comprehensiveness, the molecular terrain on which that interaction unfolds.

For researchers, the immediate priorities are clear: larger and more diverse cohorts, standardized phenotype definitions, longitudinal designs that track epigenetic change across training cycles, and replication of the small set of variants that have shown consistent associations. For athletes and practitioners, the message is one of measured expectation. The molecular basis of endurance is real, increasingly well characterized, and scientifically fascinating, but it operates through many small effects distributed across interconnected pathways. Understanding that architecture, rather than searching for a single endurance gene, is the path the review charts toward precision sports medicine.

Subject of Research: Genetic and epigenetic determinants of endurance performance and training adaptation

Article Title: Decoding endurance performance: integrative genomic and epigenetic insights into the molecular basis of athletic adaptation

Article References: Decoding endurance performance: integrative genomic and epigenetic insights into the molecular basis of athletic adaptation. (n.d.). https://doi.org/10.3389/fsysb.2026.1858520

Image Credits: AI Generated

DOI: 10.3389/fsysb.2026.1858520

Keywords: endurance performance, sports genomics, GWAS, epigenetics, DNA methylation, microRNAs, mitochondrial biogenesis, polygenic scores, ACE, PPARGC1A, training response, athlete genetics