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. 2024 Dec 5;14(12):684.
doi: 10.3390/metabo14120684.

The ARK2N (C18ORF25) Genetic Variant Is Associated with Muscle Fiber Size and Strength Athlete Status

Rukiye Çığırtaş  1 , Celal Bulgay  1 , Hasan Hüseyin Kazan  2 , Onur Akman  3 , Goran Sporiš  4 , George John  5 , Rinat A Yusupov  6 , Rinat I Sultanov  7 , Andrey V Zhelankin  7 , Ekaterina A Semenova  7   8 , Andrey K Larin  7 , Nikolay A Kulemin  7 , Edward V Generozov  7 , Damir Jurko  4 , Ildus I Ahmetov  7   9   10   11
Affiliations

The ARK2N (C18ORF25) Genetic Variant Is Associated with Muscle Fiber Size and Strength Athlete Status

Rukiye Çığırtaş et al. Metabolites. .

Abstract

Background: Data on the genetic factors contributing to inter-individual variability in muscle fiber size are limited. Recent research has demonstrated that mice lacking the Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (Ark2n; also known as C18orf25) gene exhibit reduced muscle fiber size, contraction force, and exercise capacity, along with defects in calcium handling within fast-twitch muscle fibers. However, the role of the ARK2N gene in human muscle physiology, and particularly in athletic populations, remains poorly understood. The aim of this study was threefold: (a) to compare ARK2N gene expression between power and endurance athletes; (b) to analyze the relationship between ARK2N gene expression and muscle fiber composition; and (c) to investigate the association between the functional variant of the ARK2N gene, muscle fiber size, and sport-related phenotypes.

Results: We found that ARK2N gene expression was significantly higher in power athletes compared to endurance athletes (p = 0.042) and was positively associated with the proportion of oxidative fast-twitch (type IIA) muscle fibers in untrained subjects (p = 0.017, adjusted for age and sex). Additionally, we observed that the ARK2N rs6507691 T allele, which predicts high ARK2N gene expression (p = 3.8 × 10-12), was associated with a greater cross-sectional area of fast-twitch muscle fibers in strength athletes (p = 0.015) and was over-represented in world-class strength athletes (38.6%; OR = 2.2, p = 0.023) and wrestlers (33.8%; OR = 1.8, p = 0.044) compared to controls (22.0%).

Conclusions: In conclusion, ARK2N appears to be a gene specific to oxidative fast-twitch myofibers, with its functional variant being associated with muscle fiber size and strength-athlete status.

Keywords: SNP; athlete status; gene expression; genotype; molecular physiology; muscle hypertrophy; polymorphism; skeletal muscle; sport; weightlifting.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Comparison of Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (ARK2N) gene expression between power and endurance athletes.
Figure 2
Figure 2
Relationship between Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (ARK2N) gene expression and the proportion of type IIA muscle fibers in the FUSION cohort (p = 0.017; adjusted for age and sex).
Figure 3
Figure 3
Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (ARK2N) rs6507691 T allele frequency (%) in Russian athletic cohorts (22 world-class strength athletes, 34 world-class wrestlers, 91 elite wrestlers, 68 elite strength athletes) and controls (n = 182). * p = 0.023, ** p = 0.044, and *** p = 0.016 indicate statistically significant differences between athletic cohorts and controls.
Figure 4
Figure 4
Comparison of cross-sectional area of (a) fast-twitch, (b) slow-twitch, and (c) combined muscle fibers between strength athletes with different Arkadia (RNF111) N-terminal-like PKA signaling regulator 2N (ARK2N) rs6507691 genotypes (n = 24). Abbreviations: CSA, cross-sectional area; FT MF, fast-twitch muscle fibers; ST MF, slow-twitch muscle fibers; all MF, combined fast-twitch + slow-twitch muscle fibers.
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