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

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-indi...

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Autores principales: Semenova, Ekaterina A., Zempo, Hirofumi, Miyamoto-Mikami, Eri, Kumagai, Hiroshi, Larin, Andrey K., Sultanov, Rinat I., Babalyan, Konstantin A., Zhelankin, Andrey V., Tobina, Takuro, Shiose, Keisuke, Kakigi, Ryo, Tsuzuki, Takamasa, Ichinoseki-Sekine, Noriko, Kobayashi, Hiroyuki, Naito, Hisashi, Burniston, Jatin, Generozov, Edward V., Fuku, Noriyuki, Ahmetov, Ildus I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737696/
https://www.ncbi.nlm.nih.gov/pubmed/36497168
http://dx.doi.org/10.3390/cells11233910
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author Semenova, Ekaterina A.
Zempo, Hirofumi
Miyamoto-Mikami, Eri
Kumagai, Hiroshi
Larin, Andrey K.
Sultanov, Rinat I.
Babalyan, Konstantin A.
Zhelankin, Andrey V.
Tobina, Takuro
Shiose, Keisuke
Kakigi, Ryo
Tsuzuki, Takamasa
Ichinoseki-Sekine, Noriko
Kobayashi, Hiroyuki
Naito, Hisashi
Burniston, Jatin
Generozov, Edward V.
Fuku, Noriyuki
Ahmetov, Ildus I.
author_facet Semenova, Ekaterina A.
Zempo, Hirofumi
Miyamoto-Mikami, Eri
Kumagai, Hiroshi
Larin, Andrey K.
Sultanov, Rinat I.
Babalyan, Konstantin A.
Zhelankin, Andrey V.
Tobina, Takuro
Shiose, Keisuke
Kakigi, Ryo
Tsuzuki, Takamasa
Ichinoseki-Sekine, Noriko
Kobayashi, Hiroyuki
Naito, Hisashi
Burniston, Jatin
Generozov, Edward V.
Fuku, Noriyuki
Ahmetov, Ildus I.
author_sort Semenova, Ekaterina A.
collection PubMed
description 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 < 0.0001) or sprint (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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spelling pubmed-97376962022-12-11 Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition Semenova, Ekaterina A. Zempo, Hirofumi Miyamoto-Mikami, Eri Kumagai, Hiroshi Larin, Andrey K. Sultanov, Rinat I. Babalyan, Konstantin A. Zhelankin, Andrey V. Tobina, Takuro Shiose, Keisuke Kakigi, Ryo Tsuzuki, Takamasa Ichinoseki-Sekine, Noriko Kobayashi, Hiroyuki Naito, Hisashi Burniston, Jatin Generozov, Edward V. Fuku, Noriyuki Ahmetov, Ildus I. Cells Article 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 < 0.0001) or sprint (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. MDPI 2022-12-02 /pmc/articles/PMC9737696/ /pubmed/36497168 http://dx.doi.org/10.3390/cells11233910 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Semenova, Ekaterina A.
Zempo, Hirofumi
Miyamoto-Mikami, Eri
Kumagai, Hiroshi
Larin, Andrey K.
Sultanov, Rinat I.
Babalyan, Konstantin A.
Zhelankin, Andrey V.
Tobina, Takuro
Shiose, Keisuke
Kakigi, Ryo
Tsuzuki, Takamasa
Ichinoseki-Sekine, Noriko
Kobayashi, Hiroyuki
Naito, Hisashi
Burniston, Jatin
Generozov, Edward V.
Fuku, Noriyuki
Ahmetov, Ildus I.
Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title_full Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title_fullStr Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title_full_unstemmed Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title_short Genome-Wide Association Study Identifies CDKN1A as a Novel Locus Associated with Muscle Fiber Composition
title_sort genome-wide association study identifies cdkn1a as a novel locus associated with muscle fiber composition
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9737696/
https://www.ncbi.nlm.nih.gov/pubmed/36497168
http://dx.doi.org/10.3390/cells11233910
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