title: Eccentric muscle challenge shows osteopontin polymorphism modulation of muscle damage.
abstract: A promoter polymorphism of the osteopontin (OPN) gene (rs28357094) has been associated with multiple inflammatory states, severity of Duchenne muscular dystrophy (DMD) and muscle size in healthy young adults. We sought to define the mechanism of action of the polymorphism, using allele-specific in vitro reporter assays in muscle cells, and a genotype-stratified intervention in healthy controls. In vitro reporter constructs showed the G allele to respond to estrogen treatment, whereas the T allele showed no transcriptional response. Young adult volunteers (n = 187) were enrolled into a baseline study, and subjects with specific rs28357094 genotypes enrolled into an eccentric muscle challenge intervention [n = 3 TT; n = 3 GG/GT (dominant inheritance model)]. Female volunteers carrying the G allele showed significantly greater inflammation and increased muscle volume change as determined by magnetic resonance imaging T1- and T2-weighted images after eccentric challenge, as well as greater decrement in biceps muscle force. Our data suggest a model where the G allele enables enhanced activities of upstream enhancer elements due to loss of Sp1 binding at the polymorphic site. This results in significantly greater expression of the pro-inflammatory OPN cytokine during tissue remodeling in response to challenge in G allele carriers, promoting muscle hypertrophy in normal females, but increased damage in DMD patients.
authors.affiliation: Department of Microbiology and vbond@howard.edu ehoffman@cnmcresearch.org.
authors.forename: Whitney L
authors.initials: WL
authors.lastname: Barfield
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
authors.forename: Kitipong
authors.initials: K
authors.lastname: Uaesoontrachoon
authors.affiliation: Department of Radiology, Howard University School of Medicine, Washington, DC, USA.
authors.forename: Chung-Sheih
authors.initials: CS
authors.lastname: Wu
authors.affiliation: Department of Radiology, Howard University School of Medicine, Washington, DC, USA.
authors.forename: Stephen
authors.initials: S
authors.lastname: Lin
authors.affiliation: Department of Radiology, Howard University School of Medicine, Washington, DC, USA.
authors.forename: Yue
authors.initials: Y
authors.lastname: Chen
authors.affiliation: Department of Radiology, Howard University School of Medicine, Washington, DC, USA.
authors.forename: Paul C
authors.initials: PC
authors.lastname: Wang
authors.affiliation: Department of Microbiology and.
authors.forename: Yasmine
authors.initials: Y
authors.lastname: Kanaan
authors.affiliation: Department of Health, Human Performance and Leisure Studies, Howard University, Washington, DC, USA.
authors.forename: Vernon
authors.initials: V
authors.lastname: Bond
authors.affiliation: Center for Genetic Medicine Research, Children's National Medical Center, Washington, DC, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
mesh_terms: D000483:Alleles; D002460:Cell Line; D004967:Estrogens / Q000494:pharmacology; D015444:Exercise; D005260:Female; D015870:Gene Expression; D005838:Genotype; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000503:physiopathology; D007537:Isometric Contraction; D008279:Magnetic Resonance Imaging; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D032446:Myoblasts / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D053495:Osteopontin / Q000235:genetics* / Q000378:metabolism; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D014158:Transcription, Genetic; D055815:Young Adult
chemical_list: D004967:Estrogens; D053495:Osteopontin