Alterations in Osteopontin Modify Muscle Size in Females in Both Humans and Mice

HOFFMAN, ERIC P.1; GORDISH-DRESSMAN, HEATHER1; MCLANE, VIRGINIA D.2; DEVANEY, JOSEPH M.1; THOMPSON, PAUL D.3; VISICH, PAUL4; GORDON, PAUL M.5; PESCATELLO, LINDA S.6; ZOELLER, ROBERT F.7; MOYNA, NIALL M.8; ANGELOPOULOS, THEODORE J.9; PEGORARO, ELENA10; COX, GREGORY A.11; CLARKSON, PRISCILLA M.12

Medicine & Science in Sports & Exercise:
doi: 10.1249/MSS.0b013e31828093c1
Basic Sciences
Abstract

Purpose: An osteopontin (OPN; SPP1) gene promoter polymorphism modifies disease severity in Duchenne muscular dystrophy, and we hypothesized that it might also modify muscle phenotypes in healthy volunteers.

Methods: Gene association studies were carried out for OPN (rs28357094) in the FAMuSS cohort (n = 752; mean ± SD age = 23.7 ± 5.7 yr). The phenotypes studied included muscle size (MRI), strength, and response to supervised resistance training. We also studied 147 young adults that had carried out a bout of eccentric elbow exercise (age = 24.0 ± 5.2 yr). Phenotypes analyzed included strength, soreness, and serum muscle enzymes.

Results: In the FAMuSS cohort, the G allele was associated with 17% increase in baseline upper arm muscle volume only in women (F = 26.32; P = 5.32 × 10−7), explaining 5% of population variance. In the eccentric damage cohort, weak associations of the G allele were seen in women with both baseline myoglobin and elevated creatine kinase. The sexually dimorphic effects of OPN on muscle were also seen in OPN-null mice. Five of seven muscle groups examined showed smaller size in OPN-null female mice, whereas two were smaller in male mice. The query of OPN gene transcription after experimental muscle damage in mice showed rapid induction within 12 h (100-fold increase from baseline), followed by sustained high-level expression through 16 d of regeneration before falling to back to baseline.

Conclusion: OPN is a sexually dimorphic modifier of muscle size in normal humans and mice and responds to muscle damage. The OPN gene is known to be estrogen responsive, and this may explain the female-specific genotype effects in adult volunteers.

Author Information

1Children’s National Medical Center, Washington, DC; 2Graduate School of Biomedical Sciences, University of Maine, Orono, ME; 3Hartford Hospital, Hartford, CT; 4University of New England, Biddeford, ME; 5University of Michigan, Ann Arbor, MI; 6University of Connecticut, Storrs, CT; 7Florida Atlantic University, Boca Raton, FL; 8Dublin City University, Dublin, IRELAND; 9University of Central Florida, Orlando, FL; 10University of Padova, Padova, ITALY; 11The Jackson Laboratory, Bar Harbor, ME; and 12University of Massachusetts Amherst, Amherst, MA

Address for correspondence: Eric P. Hoffman, Ph.D., Department of Integrative Systems Biology, Center for Genetic Medicine Research, Children’s National Medical Center, George Washington University School of Medicine 111 Michigan Avenue, NW, Washington, DC 20010; E-mail: ehoffman@cnmcresearch.org.

Submitted for publication August 2012.

Accepted for publication November 2012.

©2013The American College of Sports Medicine