title: Thrombospondin-1 levels correlate with macrophage activity and disease progression in dysferlin deficient mice.
abstract: Dysferlinopathy is associated with accumulation of thrombospondin (TSP)-1 and macrophages, both of which may contribute to the pathogenesis of the disease. The purpose of this study was to determine whether TSP-1 levels can predict macrophage activity and disease progression in dysferlin deficient BlaJ mice, focusing on the early disease process. In 3 month-old BlaJ mice, muscle TSP-1 levels exhibited strong positive correlations with both accumulation of F4/80hi macrophages and with their in vivo phagocytic activity in psoas muscles as measured by magnetic resonance imaging and flow cytometry. Muscle TSP-1 levels also exhibited a strong negative correlation with muscle mass and strong positive correlations with histological measurements of muscle fiber infiltration and regeneration. Over the course of disease progression from 3 to 12 months of age, muscle TSP-1 levels showed more complicated relationships with macrophage activity and an inverse relationship with muscle mass. Importantly, blood TSP-1 levels showed strong correlations with macrophage activity and muscle degeneration, particularly early in disease progression in BlaJ mice. These data indicate that TSP-1 may contribute to a destructive macrophage response in dysferlinopathy and pose the intriguing possibility that TSP-1 levels may serve as a biomarker for disease progression.
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA; Center for Tissue Repair and Regeneration, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Norifumi
authors.initials: N
authors.lastname: Urao
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Rita E
authors.initials: RE
authors.lastname: Mirza
authors.affiliation: Department of Physiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Ahlke
authors.initials: A
authors.lastname: Heydemann
authors.affiliation: Department of Physiology, University of Illinois at Chicago, Chicago, IL 60612, USA.
authors.forename: Jesus
authors.initials: J
authors.lastname: Garcia
authors.affiliation: Department of Kinesiology and Nutrition, University of Illinois at Chicago, Chicago, IL 60612, USA; Center for Tissue Repair and Regeneration, University of Illinois at Chicago, Chicago, IL 60612, USA. Electronic address: tjkoh@uic.edu.
authors.forename: Timothy J
authors.initials: TJ
authors.lastname: Koh
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood / Q000378:metabolism; D004195:Disease Models, Animal; D018450:Disease Progression; D000073939:Dysferlin; D008264:Macrophages / Q000502:physiology*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D049288:Muscular Dystrophies, Limb-Girdle / Q000235:genetics / Q000378:metabolism* / Q000473:pathology* / Q000503:physiopathology; D010587:Phagocytosis; D016658:Psoas Muscles / Q000378:metabolism / Q000473:pathology; D019700:Thrombospondin 1 / Q000097:blood / Q000378:metabolism*
chemical_list: D015415:Biomarkers; C497505:Dysf protein, mouse; D000073939:Dysferlin; D008565:Membrane Proteins; D019700:Thrombospondin 1
keywords: Dysferlinopathy; Inflammation; Macrophage; Skeletal muscle; Thrombospondin