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

Christopher G. Vann; Robert W. Morton; Christopher B. Mobley; Ivan J. Vechetti; Brian K. Ferguson; Cody T. Haun; Shelby C. Osburn; Casey L. Sexton; Carlton D. Fox; Matthew A. Romero; Paul A. Roberson; Sara Y. Oikawa; Chris McGlory; Kaelin C. Young; John J. McCarthy; Stuart M. Phillips; Michael D. Roberts

doi:10.1096/fj.202100113RR

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

Christopher G. Vann, Robert W. Morton, Christopher B. Mobley, Ivan J. Vechetti, Brian K. Ferguson, Cody T. Haun, Shelby C. Osburn, Casey L. Sexton, Carlton D. Fox, Matthew A. Romero, Paul A. Roberson, Sara Y. Oikawa, Chris McGlory, Kaelin C. Young, John J. McCarthy, Stuart M. Phillips, Michael D. Roberts

Research output: Contribution to journal › Article › peer-review

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.

Original language	English
Article number	e21587
Journal	FASEB Journal
Volume	35
Issue number	5
DOIs	https://doi.org/10.1096/fj.202100113RR
State	Published - May 2021

Bibliographical note

Funding Information:
We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann’s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts.

Funding Information:
We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann?s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts.

Publisher Copyright:
© 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology

Keywords

GLI3
hypertrophy
polymorphisms
skeletal muscle

ASJC Scopus subject areas

Biotechnology
Biochemistry
Molecular Biology
Genetics

Access to Document

10.1096/fj.202100113RR

Cite this

Vann, C. G., Morton, R. W., Mobley, C. B., Vechetti, I. J., Ferguson, B. K., Haun, C. T., Osburn, S. C., Sexton, C. L., Fox, C. D., Romero, M. A., Roberson, P. A., Oikawa, S. Y., McGlory, C., Young, K. C., McCarthy, J. J., Phillips, S. M., & Roberts, M. D. (2021). An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men. FASEB Journal, 35(5), Article e21587. https://doi.org/10.1096/fj.202100113RR

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

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.",

keywords = "GLI3, hypertrophy, polymorphisms, skeletal muscle",

author = "Vann, {Christopher G.} and Morton, {Robert W.} and Mobley, {Christopher B.} and Vechetti, {Ivan J.} and Ferguson, {Brian K.} and Haun, {Cody T.} and Osburn, {Shelby C.} and Sexton, {Casey L.} and Fox, {Carlton D.} and Romero, {Matthew A.} and Roberson, {Paul A.} and Oikawa, {Sara Y.} and Chris McGlory and Young, {Kaelin C.} and McCarthy, {John J.} and Phillips, {Stuart M.} and Roberts, {Michael D.}",

note = "Funding Information: We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann{\textquoteright}s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts. Funding Information: We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann?s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts. Publisher Copyright: {\textcopyright} 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology",

year = "2021",

month = may,

doi = "10.1096/fj.202100113RR",

language = "English",

volume = "35",

number = "5",

}

Vann, CG, Morton, RW, Mobley, CB, Vechetti, IJ, Ferguson, BK, Haun, CT, Osburn, SC, Sexton, CL, Fox, CD, Romero, MA, Roberson, PA, Oikawa, SY, McGlory, C, Young, KC, McCarthy, JJ, Phillips, SM & Roberts, MD 2021, 'An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men', FASEB Journal, vol. 35, no. 5, e21587. https://doi.org/10.1096/fj.202100113RR

TY - JOUR

T1 - An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men

AU - Vann, Christopher G.

AU - Morton, Robert W.

AU - Mobley, Christopher B.

AU - Vechetti, Ivan J.

AU - Ferguson, Brian K.

AU - Haun, Cody T.

AU - Osburn, Shelby C.

AU - Sexton, Casey L.

AU - Fox, Carlton D.

AU - Romero, Matthew A.

AU - Roberson, Paul A.

AU - Oikawa, Sara Y.

AU - McGlory, Chris

AU - Young, Kaelin C.

AU - McCarthy, John J.

AU - Phillips, Stuart M.

AU - Roberts, Michael D.

N1 - Funding Information: We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann’s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts. Funding Information: We thank the participants who volunteered to take part in both studies. We also acknowledge the technical assistance of Todd Prior and Joshua Nederveen (McMaster University) as well as Petey Mumford and Wes Kephart (Auburn University). We thank Rob Schleifer (Thermo Fisher Scientific) for providing tremendous insight into our genome analyses. Funding for participant compensation and fCSA analyses for the Auburn University Study were provided to M.D. Roberts by Hilmar Ingredients (Hilmar, CA, USA) and Bionutritional Research Group (Irvine, CA, USA), and said funds were solicited by Dr. Christopher Lockwood (Lockwood, LLC; Belton, TX, USA). Additionally, a portion of C. G. Vann?s effort was funded through the National Institute of Health (R01AG054840), and P.A.R. is currently supported through the National Institute of Health (F32DK126312). The project at McMaster University was supported by an operating grant to S. M. Phillips from the Natural Science and Engineering Research Council of Canada. Funding for genotyping and publication costs were provided through discretionary laboratory funds from M. D. Roberts. Publisher Copyright: © 2021 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology

PY - 2021/5

Y1 - 2021/5

N2 - 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.

AB - 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.

KW - GLI3

KW - hypertrophy

KW - polymorphisms

KW - skeletal muscle

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

Abstract

Bibliographical note

Keywords

ASJC Scopus subject areas

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