Skip Navigation



Human Molecular Genetics Advance Access published online on March 21, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl065
This Article
Right arrow FREE Full Text (PDF) Freely available
Right arrow All Versions of this Article:
15/9/1423    most recent
ddl065v1
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Add to My Personal Archive
Right arrow Download to citation manager
Right arrowRequest Permissions
Google Scholar
Right arrow Articles by Chakkalakal, J. V.
Right arrow Articles by Jasmin, B. J.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Chakkalakal, J. V.
Right arrow Articles by Jasmin, B. J.
Social Bookmarking
Add to CiteULike   Add to Connotea   Add to Del.icio.us  
What's this?

© The Author 2006. Published by Oxford University Press. All rights reserved
Received January 12, 2006
Revised March 14, 2006
Accepted March 14, 2006

Article

Targeted inhibition of Ca+2/calmodulin signaling exacerbates the dystrophic phenotype in mdx mouse muscle

Joe V. Chakkalakal 1, Stephanie A. Michel 2, Eva R. Chin 3, Robin N. Michel 2, and Bernard J. Jasmin 4 *

1 Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5
2 Departments of Chemistry and Biochemistry and Exercise Science, and Centre for Structural and Functional Genomics, Concordia University, The Richard J. Renaud Science Complex, Montreal, QC, Canada H4B 1R6
3 Research Pharmacology, Pfizer Global Research & Development, San Diego, California
4 Department of Cellular and Molecular Medicine and Centre for Neuromuscular Disease, Faculty of Medicine, University of Ottawa, 451 Smyth Road, Ottawa, Ontario, Canada K1H 8M5; Ottawa Health Research Institute, Molecular Medicine Program, Ottawa Hospital, General Campus, Ottawa, Ontario, Canada K1H 8L6

* To whom correspondence should be addressed.
Bernard J. Jasmin, E-mail: jasmin{at}uottawa.ca


  Abstract

In the present study, we crossbred mdx mice with transgenic mice expressing a small peptide inhibitor for calmodulin (CaM), known as the CaM-binding protein (CaMBP), driven by the slow fiber-specific Troponin I slow (TnIs) promoter. This strategy allowed us to determine the impact of interfering with Ca+2/CaM-based signaling in dystrophin-deficient slow myofibers. Consistent with impairments in the Ca+2/CaM-regulated enzymes calcineurin and Ca+2/CaM-dependent kinase (CaMK), the nuclear accumulation of NFATc1 and MEF2C was reduced in slow fibers from mdx/CaMBP mice. We also detected significant reductions in the levels of PGC-1{alpha} and GABP{alpha}? mRNAs in slow fiber-rich soleus muscles of mdx/CaMBP mice. In parallel, we observed significantly lower expression of myosin heavy chain I (MyHC) mRNA in mdx/CaMBP soleus muscles. This correlated with fiber type shifts towards a faster phenotype. Examination of mdx/CaMBP slow muscle fibers revealed significant reductions in A-utrophin, a therapeutically relevant protein that can compensate for the lack of dystrophin in skeletal muscle. In accordance with lower levels of A-utrophin, we noted a clear exacerbation of the dystrophic phenotype in mdx/CaMBP slow fibers as exemplified by several pathological indices. These results firmly establish Ca+2/CaM-based signaling as key to regulating expression of A-utrophin in muscle. Furthermore, this study illustrates the therapeutic potential of using targets of Ca+2/CaM-based signaling as a strategy for treating Duchenne muscular dystrophy (DMD). Finally, our results further support the concept that strategies aimed at promoting the slow oxidative myofiber program in muscle may be effective in altering the relentless progression of DMD.


Add to CiteULike CiteULike   Add to Connotea Connotea   Add to Del.icio.us Del.icio.us    What's this?


This article has been cited by other articles:


Home page
 Hum Mol GenetHome page
P. Miura, J. V. Chakkalakal, L. Boudreault, G. Belanger, R. L. Hebert, J.-M. Renaud, and B. J. Jasmin
Pharmacological activation of PPAR{beta}/{delta} stimulates utrophin A expression in skeletal muscle fibers and restores sarcolemmal integrity in mature mdx mice
Hum. Mol. Genet., December 1, 2009; 18(23): 4640 - 4649.
[Abstract] [Full Text] [PDF]

Home page
 Am. J. Pathol.Home page
R. Xu, S. DeVries, M. Camboni, and P. T. Martin
Overexpression of Galgt2 Reduces Dystrophic Pathology in the Skeletal Muscles of Alpha Sarcoglycan-Deficient Mice
Am. J. Pathol., July 1, 2009; 175(1): 235 - 247.
[Abstract] [Full Text] [PDF]

Home page
 Nucleic Acids ResHome page
J. V. Chakkalakal, P. Miura, G. Belanger, R. N. Michel, and B. J. Jasmin
Modulation of utrophin A mRNA stability in fast versus slow muscles via an AU-rich element and calcineurin signaling
Nucleic Acids Res., February 11, 2008; 36(3): 826 - 838.
[Abstract] [Full Text] [PDF]

Home page
 J. Physiol.Home page
A. J. Rose, C. Frosig, B. Kiens, J. F. P. Wojtaszewski, and E. A. Richter
Effect of endurance exercise training on Ca2+ calmodulin-dependent protein kinase II expression and signalling in skeletal muscle of humans
J. Physiol., September 1, 2007; 583(2): 785 - 795.
[Abstract] [Full Text] [PDF]

Home page
 PhysiologyHome page
S. Schiaffino, M. Sandri, and M. Murgia
Activity-Dependent Signaling Pathways Controlling Muscle Diversity and Plasticity
Physiology, August 1, 2007; 22(4): 269 - 278.
[Abstract] [Full Text] [PDF]

Home page
 Genes Dev.Home page
C. Handschin, Y. M. Kobayashi, S. Chin, P. Seale, K. P. Campbell, and B. M. Spiegelman
PGC-1{alpha} regulates the neuromuscular junction program and ameliorates Duchenne muscular dystrophy
Genes & Dev., April 1, 2007; 21(7): 770 - 783.
[Abstract] [Full Text] [PDF]


Disclaimer: Please note that abstracts for content published before 1996 were created through digital scanning and may therefore not exactly replicate the text of the original print issues. All efforts have been made to ensure accuracy, but the Publisher will not be held responsible for any remaining inaccuracies. If you require any further clarification, please contact our Customer Services Department.