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

• Published in: Medicine and science in sports and exercise Vol. 45; no. 6; pp. 1060 - 1068
• Main Authors: HOFFMAN, ERIC P, GORDISH-DRESSMAN, HEATHER, MCLANE, VIRGINIA D, DEVANEY, JOSEPH M, THOMPSON, PAUL D, VISICH, PAUL, GORDON, PAUL M, PESCATELLO, LINDA S, ZOELLER, ROBERT F, MOYNA, NIALL M, ANGELOPOULOS, THEODORE J, PEGORARO, ELENA, COX, GREGORY A, CLARKSON, PRISCILLA M
• Format: Journal Article
• Language: English
• Published: Hagerstown, MD The American College of Sports Medicine 01-06-2013; Lippincott Williams & Wilkins
• Subjects: Adult; Analysis of Variance; Animals; Biological and medical sciences; Biomarkers - blood; Female; Fundamental and applied biological sciences. Psychology; Genetic Association Studies; Genetic Markers; Genotyping Techniques; Healthy Volunteers; Human physiology applied to population studies and life conditions. Human ecophysiology; Humans; Linear Models; Magnetic Resonance Imaging; Male; Medical sciences; Mice; Mice, Knockout; Muscle Strength - genetics; Muscle, Skeletal - anatomy & histology; Muscle, Skeletal - physiology; Myoglobin - blood; Osteopontin - genetics; Phenotype; Polymorphism, Single Nucleotide; Resistance Training; Sex Factors; Space life sciences; Vertebrates: body movement. Posture. Locomotion. Flight. Swimming. Physical exercise. Rest. Sports; Human; Secretion; MRI; SECRETED PHOSPHOPROTEIN 1 (SPP1); Estrogen; Osteopontin; Striated muscle; Nuclear magnetic resonance imaging; OSTEOPONTIN (OPN); Animal; Female; Genetics; Mouse (computer peripheral); Secrecy; Hypertrophy; Polymorphism; GENETIC POLYMORPHISM
• ISSN: 0195-9131; 1530-0315
• DOI: 10.1249/MSS.0b013e31828093c1

PURPOSEAn 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.
METHODSGene 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.
RESULTSIn 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), 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.
CONCLUSIONOPN 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.