title: A reporter mouse for optical imaging of inflammation in mdx muscles.
abstract: BACKGROUND
  Duchenne muscular dystrophy (DMD) is due to mutations in the gene coding for human DMD; DMD is characterized by progressive muscle degeneration, inflammation, fat accumulation, and fibrosis. The mdx mouse model of DMD lacks dystrophin protein and undergoes a predictable disease course. While this model has been a valuable resource for pre-clinical studies aiming to test therapeutic compounds, its utility is compromised by a lack of reliable biochemical tools to quantifiably assay muscle disease. Additionally, there are few non-invasive assays available to researchers for measuring early indicators of disease progression in mdx mice.
  
  
  METHODS
  Mdx mice were crossed to knock-in mice expressing luciferase from the Cox2 promoter. These reporter mice (Cox2 (FLuc/+) DMD (-/-) ) were created to serve as a tool for researchers to evaluate muscle inflammation. Luciferase expression was assayed by immunohistochemistry to insure that it correlated with muscle lesions. The luciferase signal was quantified by optical imaging and luciferase assays to verify that the signal correlated with muscle damage. As proof of principle, Cox2 (FLuc/+) DMD (-/-) mice were also treated with prednisolone to validate that a reduction in luciferase signal correlated with prednisone treatment.
  
  
  RESULTS
  In this investigation, a novel reporter mouse (Cox2 (FLuc/+) DMD (-/-) mice) was created and validated for non-invasive quantification of muscle inflammation in vivo. In this dystrophic mouse, luciferase is expressed from cyclooxygenase 2 (Cox2) expressing cells and bioluminescence is detected by optical imaging. Bioluminescence is significantly enhanced in damaged muscle of exercised Cox2 (FLuc/+) DMD (-/-) mice compared to non-exercised Cox2 (FLuc/+) DMD (+/+) mice. Moreover, the Cox2 bioluminescent signal is reduced in Cox2 (FLuc/+) DMD (-/-) mice in response to a course of steroid treatment. Reduction in bioluminescence is detectable prior to measurable therapy-elicited improvements in muscle strength, as assessed by traditional means. Biochemical assay of luciferase provides a second means to quantify muscle inflammation.
  
  
  CONCLUSIONS
  The Cox2 (FLuc/+) DMD (-/-) mouse is a novel tool to evaluate the therapeutic benefits of drugs intended to target inflammatory aspects of dystrophic pathology. This mouse model will be a useful adjunct to traditional outcome measures in assessing potential therapeutic compounds.
authors.affiliation: Department of Neurology and Center for Duchenne Muscular Dystrophy, David Geffen School of Medicine, University of California Los Angeles, 635 Charles Young Dr. South, NRB Room 401, Los Angeles, CA 90095 USA ; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095 USA.
authors.forename: Leonel
authors.initials: L
authors.lastname: Martinez
authors.affiliation: Department of Neurology and Center for Duchenne Muscular Dystrophy, David Geffen School of Medicine, University of California Los Angeles, 635 Charles Young Dr. South, NRB Room 401, Los Angeles, CA 90095 USA ; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095 USA.
authors.forename: Natalia V
authors.initials: NV
authors.lastname: Ermolova
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, 341 Boyer Hall, 611 Charles E Young Dr. So, Los Angeles, CA 90095 USA ; Present address: Genomics Business Department, Trans Genic Inc, Kumamoto, 862-0976 Japan.
authors.forename: Tomo-O
authors.initials: TO
authors.lastname: Ishikawa
authors.affiliation: Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA.
authors.forename: David B
authors.initials: DB
authors.lastname: Stout
authors.affiliation: Department of Biological Chemistry, David Geffen School of Medicine, University of California Los Angeles, 341 Boyer Hall, 611 Charles E Young Dr. So, Los Angeles, CA 90095 USA ; Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095 USA ; Molecular Biology Institute, UCLA, Los Angeles, CA 90095 USA.
authors.forename: Harvey R
authors.initials: HR
authors.lastname: Herschman
authors.affiliation: Department of Neurology and Center for Duchenne Muscular Dystrophy, David Geffen School of Medicine, University of California Los Angeles, 635 Charles Young Dr. South, NRB Room 401, Los Angeles, CA 90095 USA ; Center for Duchenne Muscular Dystrophy at UCLA, Los Angeles, CA 90095 USA ; Molecular Biology Institute, UCLA, Los Angeles, CA 90095 USA.
authors.forename: Melissa J
authors.initials: MJ
authors.lastname: Spencer
keywords: Cox2; Cyclooxygenase 2; Duchenne muscular dystrophy; Imaging; Immune cells; Inflammation; Luciferase; Reporter mouse; mdx