Association analysis of indel variants and gene expression identifies MDM4 as a novel locus for skeletal muscle hypertrophy and power athlete status.

Autor: Kazan HH; Department of Medical Biology, Gulhane Faculty of Medicine, University of Health Sciences, Ankara, Türkiye., Kasakolu A; Graduate School of Natural and Applied Sciences, Ankara University, Ankara, Türkiye., Koncagul S; Graduate School of Natural and Applied Sciences, Ankara University, Ankara, Türkiye., Ergun MA; Department of Medical Genetics, Faculty of Medicine, Gazi University, Ankara, Türkiye., John G; Transform Specialist Medical Centre, Dubai, UAE., Sultanov RI; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Zhelankin AV; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Semenova EA; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.; Research Institute of Physical Culture and Sport, Volga Region State University of Physical Culture, Sport and Tourism, Kazan, Russia., Yusupov RA; Department of Physical Culture and Sport, Kazan National Research Technical University Named after A.N. Tupolev-KAI, Kazan, Russia., Kulemin NA; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Larin AK; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Generozov EV; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia., Bulgay C; Sports Science Faculty, Bingol University, Bingol, Türkiye., Ahmetov II; Department of Molecular Biology and Genetics, Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine of Federal Medical Biological Agency, Moscow, Russia.; Sports Genetics Laboratory, St Petersburg Research Institute of Physical Culture, St Petersburg, Russia.; Laboratory of Genetics of Aging and Longevity, Kazan State Medical University, Kazan, Russia.; Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, Liverpool, UK.
Jazyk: angličtina
Zdroj: Experimental physiology [Exp Physiol] 2024 Jul 23. Date of Electronic Publication: 2024 Jul 23.
DOI: 10.1113/EP091992
Abstrakt: Insertions and deletions (indels) are the second most common type of variation in the human genome. However, limited data on their associations with exercise-related phenotypes have been documented. The aim of the present study was to examine the association between 18,370 indel variants and power athlete status, followed by additional studies in 357,246 individuals. In the discovery phase, the D allele of the MDM4 gene rs35493922 I/D polymorphism was over-represented in power athletes compared with control subjects (P = 7.8 × 10 -9 ) and endurance athletes (P = 0.0012). These findings were replicated in independent cohorts, showing a higher D allele frequency in power athletes compared with control subjects (P = 0.016) and endurance athletes (P = 0.031). Furthermore, the D allele was positively associated (P = 0.0013) with greater fat-free mass in the UK Biobank. MDM4 encodes a protein that inhibits the activity of p53, which induces muscle fibre atrophy. Accordingly, we found that MDM4 expression was significantly higher in the vastus lateralis of power athletes compared with endurance athletes (P = 0.0009) and was positively correlated with the percentage of fast-twitch muscle fibres (P = 0.0062) and the relative area occupied by fast-twitch muscle fibres (P = 0.0086). The association between MDM4 gene expression and an increased proportion of fast-twitch muscle fibres was confirmed in two additional cohorts. Finally, we found that the MDM4 DD genotype was associated with increased MDM4 gene expression in vastus lateralis and greater cross-sectional area of fast-twitch muscle fibres. In conclusion, MDM4 is suggested to be a potential regulator of muscle fibre specification and size, with its indel variant being associated with power athlete status. HIGHLIGHTS: What is the central question of this study? Which indel variants are functional and associated with sport- and exercise-related traits? What is the main finding and its importance? Out of 18,370 tested indels, the MDM4 gene rs35493922 I/D polymorphism was found to be the functional variant (affecting gene expression) and the most significant, with the deletion allele showing associations with power athlete status, fat-free mass and cross-sectional area of fast-twitch muscle fibres. Furthermore, the expression of MDM4 was positively correlated with the percentage of fast-twitch muscle fibres and the relative area occupied by fast-twitch muscle fibres.
(© 2024 The Author(s). Experimental Physiology published by John Wiley & Sons Ltd on behalf of The Physiological Society.)
Databáze: MEDLINE
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