Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice.
Utrophin has been studied extensively in recent years in an effort to find a cure for Duchenne muscular dystrophy. In this context, we previously showed that mice expressing enhanced muscle calcineurin activity (CnA*) displayed elevated levels of utrophin around their sarcolemma. In the present study, we therefore crossed CnA* mice with mdx mice to determine the suitability of elevating calcineurin activity in preventing the dystrophic pathology. Muscles from mdx/CnA* displayed increased nuclear localization of NFATc1 and a fiber type shift towards a slower phenotype. Measurements of utrophin levels in mdx/CnA* muscles revealed an approximately 2-fold induction in utrophin expression. Consistent with this induction, we also observed that members of the dystrophin-associated protein (DAP) complex were present at the sarcolemma of mdx/CnA* mouse muscle. This restoration of the utrophin-DAP complex was accompanied by significant reductions in the extent of central nucleation and fiber size variability. Importantly, assessment of myofiber sarcolemmal damage, as monitored by the intracellular presence of IgM and albumin as well as by Evans blue uptake in vivo, revealed a net amelioration of membrane integrity. Finally, immunofluorescence experiments using Mac-1 antibodies showed a reduction in the number of infiltrating immune cells in muscles from mdx/CnA* mice. These results show that elevated calcineurin activity attenuates the dystrophic pathology and thus provides an effective target for pharmacological intervention.
Chakkalakal
Joe V
JV
Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, Ontario, Canada.
Harrison
Mary-Ann
MA
Carbonetto
Salvatore
S
Chin
Eva
E
Michel
Robin N
RN
Jasmin
Bernard J
BJ
D000818:Animals; D019703:Calcineurin / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism* / Q000473:pathology; D004268:DNA-Binding Proteins; D016189:Dystrophin / Q000378:metabolism; D005070:Evans Blue / Q000737:chemistry; D016177:Macrophage-1 Antigen / Q000276:immunology; D051379:Mice; D018101:Mice, Inbred mdx; D008822:Mice, Transgenic; D018485:Muscle Fibers, Skeletal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D020388:Muscular Dystrophy, Duchenne / Q000378:metabolism / Q000473:pathology; D050778:NFATC Transcription Factors; D009687:Nuclear Proteins; D012508:Sarcolemma / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014157:Transcription Factors; D049411:Utrophin / Q000378:metabolism
D004268:DNA-Binding Proteins; D016189:Dystrophin; D016177:Macrophage-1 Antigen; D050778:NFATC Transcription Factors; C494005:Nfatc1 protein, mouse; D009687:Nuclear Proteins; D014157:Transcription Factors; C483600:Utrn protein, mouse; D049411:Utrophin; D005070:Evans Blue; D019703:Calcineurin