Genes Whose Gain or Loss-of-Function Increases Endurance Performance in Mice: A Systematic Literature Review.

Fakhreddin Yaghoob Nezhad,Martin Schönfelder,Lore Becker,Sander A J Verbrugge,Henning Wackerhage,Martin Hrabě De Angelis

doi:10.3389/fphys.2019.00262

Abstract

Endurance is not only a key factor in many sports but endurance-related variables are also associated with good health and low mortality. Twin and family studies suggest that several endurance-associated traits are ≈50% inherited. However, we still poorly understand what DNA sequence variants contribute to endurance heritability. To address this issue, we conducted a systematic review to identify genes whose experimental loss or gain-of-function increases endurance capacity in mice. We found 31 genes including two isoforms of Ppargc1a whose manipulation increases running or swimming endurance performance by up to 1800%. Genes whose gain-of-function increases endurance are Adcy5, Adcy8, Hk2, Il15, Mef2c, Nr4a3, Pck1 (Pepck), Ppard, Ppargc1a (both the a and b isoforms of the protein Pgc-1α), Ppargc1b, Ppp3ca (calcineurin), Scd1, Slc5a7, Tfe3, Tfeb, Trib3 & Trpv1. Genes whose loss-of-function increases endurance in mice are Actn3, Adrb2, Bdkrb2, Cd47, Crym, Hif1a, Myoz1, Pappa, Pknox1, Pten, Sirt4, Thbs1, Thra, and Tnfsf12. Of these genes, human DNA sequence variants of ACTN3, ADCY5, ADRB2, BDKRB2, HIF1A, PPARD, PPARGC1A, PPARGC1B, and PPP3CA are also associated with endurance capacity and/or VO2max trainability suggesting evolutionary conservation between mice and humans. Bioinformatical analyses show that there are numerous amino acid or copy number-changing DNA variants of endurance genes in humans, suggesting that genetic variation of endurance genes contributes to the variation of human endurance capacity, too. Moreover, several of these genes/proteins change their expression or phosphorylation in skeletal muscle or the heart after endurance exercise, suggesting a role in the adaptation to endurance exercise.

Highlights

Endurance is a key trait in many sports such as marathon running and triathlon
Human variants of ACTN3, ADRB2, BDKRB2, HIF1A, PPARD, PPARGC1A, PPARGC1B, and PPP3CA are associated with human endurance (Ahmetov et al, 2016) and human variants of ADCY5, PPARD and HIF1A are associated with VO2max trainability (Williams et al, 2017)
The contribution of this study to our understanding of endurance genetics is a list of 31 genes whose gain or loss-of-function increases endurance performance by up to 1800% in mice

Summary

Introduction

Endurance is a key trait in many sports such as marathon running and triathlon. Endurance is associated with health as a high endurance capacity is associated with fewer cardiovascular events and reduced all-cause mortality (Kodama et al, 2009). Endurance capacity is a multi-factorial trait that depends on several sub-traits and organ systems:. In relation to human endurance, two important questions are: How much is endurance inherited? What DNA sequence variants affect endurance capacity? Classical genetic studies suggest that maximal aerobic performance variables (i.e., VO2max, physical working capacity or threshold values) are between 38 and 94% inherited (Peeters et al, 2009). Especially the Heritage study data suggest that the variation of major human endurance-related traits depends probably to ≈50% on DNA sequence variation [i.e., genetics, Simoneau and Bouchard, 1995; Bouchard et al, 1998, 1999)] implying that ≈50% is dependent on environmental factors such as endurance training and nutrition

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