title: Alterations in osteopontin modify muscle size in females in both humans and mice.
abstract: OBJECTIVE
  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), 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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Integrative Systems Biology, Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC 20010, USA. ehoffman@cnmcresearch.org
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.forename: Virginia D
authors.initials: VD
authors.lastname: McLane
authors.forename: Joseph M
authors.initials: JM
authors.lastname: Devaney
authors.forename: Paul D
authors.initials: PD
authors.lastname: Thompson
authors.forename: Paul
authors.initials: P
authors.lastname: Visich
authors.forename: Paul M
authors.initials: PM
authors.lastname: Gordon
authors.forename: Linda S
authors.initials: LS
authors.lastname: Pescatello
authors.forename: Robert F
authors.initials: RF
authors.lastname: Zoeller
authors.forename: Niall M
authors.initials: NM
authors.lastname: Moyna
authors.forename: Theodore J
authors.initials: TJ
authors.lastname: Angelopoulos
authors.forename: Elena
authors.initials: E
authors.lastname: Pegoraro
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Cox
authors.forename: Priscilla M
authors.initials: PM
authors.lastname: Clarkson
mesh_terms: D000328:Adult; D000704:Analysis of Variance; D000818:Animals; D015415:Biomarkers / Q000097:blood; D005260:Female; D056726:Genetic Association Studies; D005819:Genetic Markers; D060005:Genotyping Techniques; D064368:Healthy Volunteers; D006801:Humans; D016014:Linear Models; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D053580:Muscle Strength / Q000235:genetics; D018482:Muscle, Skeletal / Q000033:anatomy & histology* / Q000502:physiology; D009211:Myoglobin / Q000097:blood; D053495:Osteopontin / Q000235:genetics*; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D055070:Resistance Training; D012737:Sex Factors
chemical_list: D015415:Biomarkers; D005819:Genetic Markers; D009211:Myoglobin; C506896:Spp1 protein, mouse; D053495:Osteopontin