Human Molecular Genetics, 2003, Vol. 12, No. 15 1813-1821
DOI: 10.1093/hmg/ddg197
© 2003 Oxford University Press
Dissection of temporal gene expression signatures of affected and spared muscle groups in dystrophin-deficient (mdx) mice
1Department of Ophthalmology, 2Department of Neurology and 3Department of Neurosciences and 4The Comprehensive Cancer Center, Case Western Reserve University and University Hospitals of Cleveland, Cleveland, OH 44106, USA
Received April 3, 2003; Accepted June 1, 2003
Although dystrophin mutations are the proximate cause of Duchenne muscular dystrophy (DMD), interactions among heterogeneous downstream mechanisms may be key phenotypic determinants. Temporal gene expression profiling was used to identify and correlate diverse transcriptional patterns to one another and to the disease course, for both affected and spared muscle groups, in postnatal day 7–112 dystrophin-deficient (mdx) mice. While 719 transcripts were differentially expressed at one or more ages in leg muscle, only 56 genes were altered in the spared extraocular muscles (EOM). Contrasting molecular signatures of affected versus spared muscles provide compelling evidence that the absence of dystrophin alone is necessary but not sufficient to cause the patterned fibrosis, inflammation and failure of muscle regeneration characteristic of dystrophinopathy. Dystrophic and adaptive changes in the microarray profiles were further quantified using an aggregate disease load index (DLI) to measure stage-dependent transcriptional impact in both muscles. DLI analysis highlighted the divergent responses of EOM and leg muscle groups. Cellular process-specific DLIs in leg muscle identified positively correlated temporal expression profiles for some gene classes, and the independence of others, that are linked to major disease components. Data also showed a previously unrecognized transient and selective developmental delay in pre-necrotic mdx skeletal muscle that was confirmed by qPCR. Taken together, validation and targeting of signaling pathways responsible for the coordination of the fibrotic, proteolytic and inflammatory mechanisms shown here for mdx muscle may yield new therapeutic means of mitigating the devastating consequences of DMD.
* To whom correspondence should be addressed at: Department of Ophthalmology, Case Western Reserve University, 11100 Euclid Avenue, Cleveland, OH 44106-5068, USA. Tel: +1 2168447053; Fax: +1 2168444792; Email: jdp7{at}po.cwru.edu
CiteULike 
Connotea 
Del.icio.us What's this?
This article has been cited by other articles:
|
|
 |
|
  P. A. C. 't Hoen, E. J. de Meijer, J. M. Boer, R. H. A. M. Vossen, R. Turk, R. G. H. J. Maatman, K. E. Davies, G.-J. B. van Ommen, J. C. T. van Deutekom, and J. T. den Dunnen Generation and Characterization of Transgenic Mice with the Full-length Human DMD Gene J. Biol. Chem., February 29, 2008; 283(9): 5899 - 5907. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. J. McCarthy, K. A. Esser, and F. H. Andrade MicroRNA-206 is overexpressed in the diaphragm but not the hindlimb muscle of mdx mouse Am J Physiol Cell Physiol, July 1, 2007; 293(1): C451 - C457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Pescatori, A. Broccolini, C. Minetti, E. Bertini, C. Bruno, A. D'amico, C. Bernardini, M. Mirabella, G. Silvestri, V. Giglio, et al. Gene expression profiling in the early phases of DMD: a constant molecular signature characterizes DMD muscle from early postnatal life throughout disease progression FASEB J, April 1, 2007; 21(4): 1210 - 1226. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 I Strickland and S Ghosh Use of cell permeable NBD peptides for suppression of inflammation Ann Rheum Dis, November 1, 2006; 65(suppl_3): iii75 - iii82. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 X. Shi and D. J. Garry Muscle stem cells in development, regeneration, and disease. Genes & Dev., July 1, 2006; 20(13): 1692 - 1708. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Khanna, G. Cheng, B. Gong, M. J. Mustari, and J. D. Porter Genome-Wide Transcriptional Profiles Are Consistent with Functional Specialization of the Extraocular Muscle Layers Invest. Ophthalmol. Vis. Sci., September 1, 2004; 45(9): 3055 - 3066. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Matecki, R. W. R. Dudley, M. Divangahi, R. Gilbert, J. Nalbantoglu, G. Karpati, and B. J. Petrof Therapeutic gene transfer to dystrophic diaphragm by an adenoviral vector deleted of all viral genes Am J Physiol Lung Cell Mol Physiol, September 1, 2004; 287(3): L569 - L576. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. Cheng, A. P. Merriam, B. Gong, P. Leahy, S. Khanna, and J. D. Porter Conserved and muscle-group-specific gene expression patterns shape postnatal development of the novel extraocular muscle phenotype Physiol Genomics, July 8, 2004; 18(2): 184 - 195. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. A. Lapidos, R. Kakkar, and E. M. McNally The Dystrophin Glycoprotein Complex: Signaling Strength and Integrity for the Sarcolemma Circ. Res., April 30, 2004; 94(8): 1023 - 1031. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. D. Porter, A. P. Merriam, P. Leahy, B. Gong, J. Feuerman, G. Cheng, and S. Khanna Temporal gene expression profiling of dystrophin-deficient (mdx) mouse diaphragm identifies conserved and muscle group-specific mechanisms in the pathogenesis of muscular dystrophy Hum. Mol. Genet., February 1, 2004; 13(3): 257 - 269. [Abstract] [Full Text] [PDF]
|
|