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Human Molecular Genetics Advance Access originally published online on December 17, 2003
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Human Molecular Genetics, 2004, Vol. 13, No. 4 379-388
DOI: 10.1093/hmg/ddh037

Stimulation of calcineurin signaling attenuates the dystrophic pathology in mdx mice

Joe V. Chakkalakal1, Mary-Ann Harrison2, Salvatore Carbonetto3, Eva Chin4, Robin N. Michel2 and Bernard J. Jasmin1,5,*

1Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, Ottawa, Ontario Canada K1H 8M5, 2Neuromuscular Research Laboratory, Department of Chemistry and Biochemistry, Laurentian University, Sudbury, Ontario, Canada P3E 2C6, 3Centre for Neuroscience Research, Montreal General Hospital, McGill University, Montreal, Quebec, Canada H3G 1A4, 4Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton, CT 06340 and 5Ottawa Health Research Institute, Molecular Medicine Program, Ottawa Hospital, General Campus, Ottawa, Ontario, Canada K1H 8L6

Received September 25, 2003; Revised November 25, 2003; Accepted December 3, 2003

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 ~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.

* To whom correspondence should be addressed at: Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5. Tel: +1 6135625800, ext. 8383; Fax: +1 6135625636; Email: jasmin{at}uottawa.ca


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