title: Complement 3 deficiency and oral prednisolone improve strength and prolong survival of laminin alpha2-deficient mice.
abstract: Complement deposition and macrophages are common in biopsies of children with muscular dystrophy. While the presumed roles of complement and macrophages have been those of scavenger to remove and clear necrotic fibers, there is some evidence that they play a primary role in the pathogenesis of these diseases. Here, we explore the role of complement in the pathogenesis of the most severe animal model of congenital dystrophy, the dy-/- mouse, which is laminin alpha2-deficient. We generated animals deficient in both C3 and laminin alpha2. C3 is the third component of the complement cascade and is required for activation of either the classical or alternative pathways. Thirty-three percent of the dy-/-:C3+ mice (n=59) died before 24 weeks while only 14% of the dy-/-:C3-/- (n=29) mice died (p=0.04). Absolute forepaw strength was 25-30% greater for the dy-/-:C3-/- mice up to 20 weeks of age (p<0.05 compared to complement-sufficient). Forepaw strength adjusted for weight also showed significant differences with C3-/- mice being stronger up to 20 weeks (p<0.05). However, by 24 weeks, the two groups did not differ for strength. Next, we treated 20 mice with twice weekly oral prednisolone. Survival at 24 weeks for the prednisolone treated dy-/- mice (C3-/- or C3+) was 90% (p=0.04). This work shows that complement insufficiency and weekly prednisone prolong survival and improve strength of the laminin alpha2-deficient mouse. This work suggests that the complement system may contribute directly to the pathogenesis of this form of dystrophy. Because complement activity may be modified pharmacologically, this work may have implications for treatment of children with congenital muscular dystrophy secondary to laminin alpha2 deficiency.
authors.affiliation: Department of Neurology, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110, USA. Connolly@kids.wustl.edu
authors.forename: Anne M
authors.initials: AM
authors.lastname: Connolly
authors.forename: Richard M
authors.initials: RM
authors.lastname: Keeling
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Streif
authors.forename: Alan
authors.initials: A
authors.lastname: Pestronk
authors.forename: Shobhna
authors.initials: S
authors.lastname: Mehta
mesh_terms: D000284:Administration, Oral; D000818:Animals; D000893:Anti-Inflammatory Agents / Q000494:pharmacology*; D001835:Body Weight; D003176:Complement C3 / Q000032:analysis / Q000235:genetics* / Q000276:immunology; D005260:Female; D005552:Forelimb / Q000502:physiology; D007150:Immunohistochemistry; D007797:Laminin / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D018482:Muscle, Skeletal / Q000737:chemistry / Q000473:pathology / Q000502:physiology; D009137:Muscular Dystrophy, Animal / Q000188:drug therapy* / Q000235:genetics / Q000401:mortality; D011239:Prednisolone / Q000494:pharmacology*; D015996:Survival Rate
chemical_list: D000893:Anti-Inflammatory Agents; D003176:Complement C3; D007797:Laminin; C102645:laminin alpha 2; D011239:Prednisolone