Cells (Dec 2022)

Genome-Wide Association Study Identifies <i>CDKN1A</i> as a Novel Locus Associated with Muscle Fiber Composition

  • Ekaterina A. Semenova,
  • Hirofumi Zempo,
  • Eri Miyamoto-Mikami,
  • Hiroshi Kumagai,
  • Andrey K. Larin,
  • Rinat I. Sultanov,
  • Konstantin A. Babalyan,
  • Andrey V. Zhelankin,
  • Takuro Tobina,
  • Keisuke Shiose,
  • Ryo Kakigi,
  • Takamasa Tsuzuki,
  • Noriko Ichinoseki-Sekine,
  • Hiroyuki Kobayashi,
  • Hisashi Naito,
  • Jatin Burniston,
  • Edward V. Generozov,
  • Noriyuki Fuku,
  • Ildus I. Ahmetov

DOI
https://doi.org/10.3390/cells11233910
Journal volume & issue
Vol. 11, no. 23
p. 3910

Abstract

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Muscle fiber composition is associated with physical performance, with endurance athletes having a high proportion of slow-twitch muscle fibers compared to power athletes. Approximately 45% of muscle fiber composition is heritable, however, single nucleotide polymorphisms (SNP) underlying inter-individual differences in muscle fiber types remain largely unknown. Based on three whole genome SNP datasets, we have shown that the rs236448 A allele located near the cyclin-dependent kinase inhibitor 1A (CDKN1A) gene was associated with an increased proportion of slow-twitch muscle fibers in Russian (n = 151; p = 0.039), Finnish (n = 287; p = 0.03), and Japanese (n = 207; p = 0.008) cohorts (meta-analysis: p = 7.9 × 10−5. Furthermore, the frequency of the rs236448 A allele was significantly higher in Russian (p = 0.045) and Japanese (p = 0.038) elite endurance athletes compared to ethnically matched power athletes. On the contrary, the C allele was associated with a greater proportion of fast-twitch muscle fibers and a predisposition to power sports. CDKN1A participates in cell cycle regulation and is suppressed by the miR-208b, which has a prominent role in the activation of the slow myofiber gene program. Bioinformatic analysis revealed that the rs236448 C allele was associated with increased CDKN1A expression in whole blood (p = 8.5 × 10−15) and with greater appendicular lean mass (p = 1.2 × 10−5), whereas the A allele was associated with longer durations of exercise (p = 0.044) reported amongst the UK Biobank cohort. Furthermore, the expression of CDKN1A increased in response to strength (p p = 0.00035) training. Accordingly, we found that CDKN1A expression is significantly (p = 0.002) higher in the m. vastus lateralis of strength athletes compared to endurance athletes and is positively correlated with the percentage of fast-twitch muscle fibers (p = 0.018). In conclusion, our data suggest that the CDKN1A rs236448 SNP may be implicated in the determination of muscle fiber composition and may affect athletic performance.

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