title: Discovery of serum protein biomarkers in the mdx mouse model and cross-species comparison to Duchenne muscular dystrophy patients.
abstract: It is expected that serum protein biomarkers in Duchenne muscular dystrophy (DMD) will reflect disease pathogenesis, progression and aid future therapy developments. Here, we describe use of quantitative in vivo stable isotope labeling in mammals to accurately compare serum proteomes of wild-type and dystrophin-deficient mdx mice. Biomarkers identified in serum from two independent dystrophin-deficient mouse models (mdx-Δ52 and mdx-23) were concordant with those identified in sera samples of DMD patients. Of the 355 mouse sera proteins, 23 were significantly elevated and 4 significantly lower in mdx relative to wild-type mice (P-value < 0.001). Elevated proteins were mostly of muscle origin: including myofibrillar proteins (titin, myosin light chain 1/3, myomesin 3 and filamin-C), glycolytic enzymes (aldolase, phosphoglycerate mutase 2, beta enolase and glycogen phosphorylase), transport proteins (fatty acid-binding protein, myoglobin and somatic cytochrome-C) and others (creatine kinase M, malate dehydrogenase cytosolic, fibrinogen and parvalbumin). Decreased proteins, mostly of extracellular origin, included adiponectin, lumican, plasminogen and leukemia inhibitory factor receptor. Analysis of sera from 1 week to 7 months old mdx mice revealed age-dependent changes in the level of these biomarkers with most biomarkers acutely elevated at 3 weeks of age. Serum analysis of DMD patients, with ages ranging from 4 to 15 years old, confirmed elevation of 20 of the murine biomarkers in DMD, with similar age-related changes. This study provides a panel of biomarkers that reflect muscle activity and pathogenesis and should prove valuable tool to complement natural history studies and to monitor treatment efficacy in future clinical trials.
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA, yhathout@childrensnational.org.
authors.forename: Yetrib
authors.initials: Y
authors.lastname: Hathout
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Ramya L
authors.initials: RL
authors.lastname: Marathi
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Sree
authors.initials: S
authors.lastname: Rayavarapu
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Aiping
authors.initials: A
authors.lastname: Zhang
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Kristy J
authors.initials: KJ
authors.lastname: Brown
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Haeri
authors.initials: H
authors.lastname: Seol
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Heather
authors.initials: H
authors.lastname: Gordish-Dressman
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Sebahattin
authors.initials: S
authors.lastname: Cirak
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Luca
authors.initials: L
authors.lastname: Bello
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Kanneboyina
authors.initials: K
authors.lastname: Nagaraju
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Terry
authors.initials: T
authors.lastname: Partridge
authors.affiliation: Research Center for Genetic Medicine, Children's National Medical Center, Washington, DC 20010, USA.
authors.forename: Eric P
authors.initials: EP
authors.lastname: Hoffman
authors.affiliation: Department of Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Ogawa-higashi, Kodaira Tokyo 187-0031, Japan.
authors.forename: Shin'ichi
authors.initials: S
authors.lastname: Takeda
authors.affiliation: Department of Pediatrics, Alberta Children's Hospital, Calgary, AB, Canada T3B 6A8 and.
authors.forename: Jean K
authors.initials: JK
authors.lastname: Mah
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA.
authors.forename: Erik
authors.initials: E
authors.lastname: Henricson
authors.affiliation: Department of Physical Medicine and Rehabilitation, University of California, Davis School of Medicine, Davis, CA 95618, USA.
authors.forename: Craig
authors.initials: C
authors.lastname: McDonald
mesh_terms: D000293:Adolescent; D000375:Aging / Q000097:blood* / Q000235:genetics / Q000473:pathology; D000818:Animals; D015415:Biomarkers / Q000097:blood; D001798:Blood Proteins / Q000235:genetics / Q000378:metabolism*; D002648:Child; D002675:Child, Preschool; D016000:Cluster Analysis; D016189:Dystrophin / Q000172:deficiency* / Q000235:genetics; D005260:Female; D015870:Gene Expression; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D058977:Molecular Sequence Annotation; D009137:Muscular Dystrophy, Animal / Q000097:blood* / Q000235:genetics / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000097:blood* / Q000235:genetics / Q000473:pathology; D013045:Species Specificity
chemical_list: D015415:Biomarkers; D001798:Blood Proteins; D016189:Dystrophin; C085339:apo-dystrophin 1