An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men

Authors

Christopher G. Vann, Auburn University
Robert W. Morton, McMaster University, Faculty of Science
Christopher B. Mobley, University of Kentucky College of Medicine
Ivan J. Vechetti, University of Nebraska–LincolnFollow
Brian K. Ferguson, Auburn University
Cody T. Haun, LLC
Shelby C. Osburn, Auburn University
Casey L. Sexton, Auburn University
Carlton D. Fox, Auburn University
Matthew A. Romero, Auburn University
Paul A. Roberson, Auburn University
Sara Y. Oikawa, McMaster University, Faculty of Science
Chris McGlory, McMaster University, Faculty of Science
Kaelin C. Young, Auburn University
John J. McCarthy, University of Kentucky College of Medicine
Stuart M. Phillips, McMaster University, Faculty of Science
Michael D. Roberts, Auburn University

ORCID IDs

Ivan J. Vechetti https://orcid.org/0000-0003-1024-1011

Stuart M. Phillips https://orcid.org/0000-0002-1956-4098

Michael D. Roberts https://orcid.org/0000-0002-7359-5362

Document Type

Article

Date of this Version

5-1-2021

Citation

The FASEB Journal. 2021;35:e21587.

DOI: 10.1096/fj.202100113RR

Comments

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License,

Abstract

We examined the association between genotype and resistance training-induced changes (12 wk) in dual x-ray energy absorptiometry (DXA)-derived lean soft tissue mass (LSTM) as well as muscle fiber cross-sectional area (fCSA; vastus lateralis; n = 109; age = 22 ± 2 y, BMI = 24.7 ± 3.1 kg/m2). Over 315 000 genetic polymorphisms were interrogated from muscle using DNA microarrays. First, a targeted investigation was performed where single nucleotide polymorphisms (SNP) identified from a systematic literature review were related to changes in LSTM and fCSA. Next, genome-wide association (GWA) studies were performed to reveal associations between novel SNP targets with pre- to post-training change scores in mean fCSA and LSTM. Our targeted investigation revealed no genotype-by-time interactions for 12 common polymorphisms regarding the change in mean fCSA or change in LSTM. Our first GWA study indicated no SNP were associated with the change in LSTM. However, the second GWA study indicated two SNP exceeded the significance level with the change in mean fCSA (P = 6.9 × 10–7 for rs4675569, 1.7 × 10–6 for rs10263647). While the former target is not annotated (chr2:205936846 (GRCh38.p12)), the latter target (chr7:41971865 (GRCh38.p12)) is an intron variant of the GLI Family Zinc Finger 3 (GLI3) gene. Follow-up analyses indicated fCSA increases were greater in the T/C and C/C GLI3 genotypes than the T/T GLI3 genotype (P <.05). Data from the Auburn cohort also revealed participants with the T/C and C/C genotypes exhibited increases in satellite cell number with training (P <.05), whereas T/T participants did not. Additionally, those with the T/C and C/C genotypes achieved myonuclear addition in response to training (P <.05), whereas the T/T participants did not. In summary, this is the first GWA study to examine how polymorphisms associate with the change in hypertrophy measures following resistance training. Future studies are needed to determine if the GLI3 variant differentiates hypertrophic responses to resistance training given the potential link between this gene and satellite cell physiology.