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Human Molecular Genetics Advance Access published online on July 28, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl186
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© 2006 The Author(s). This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/2.0/uk/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.
Received May 12, 2006
Revised July 20, 2006
Accepted July 20, 2006

Article

Skeletal muscle repair in a mouse model of nemaline myopathy

Despina Sanoudou 1, Mark A. Corbett 2, Mei Han 3, Majid Ghoddusi 2, Mai-Anh T. Nguyen 2, Nicole Vlahovich 2, Edna C. Hardeman 2, and Alan H. Beggs 4 *

1 Program in Genomics and Genetics Division, Children's Hospital, and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA; Molecular Biology Division, Foundation for Biomedical Research, Academy of Athens, Soranou Efesiou 4, Athens 115-27, Greece
2 Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Westmead, New South Wales 2145, Australia
3 Program in Genomics and Genetics Division, Children's Hospital, and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA
4 Enders-5, Program in Genomics and Genetics Division, Children's Hospital, and Harvard Medical School, 300 Longwood Avenue, Boston, MA, 02115, USA

* To whom correspondence should be addressed.
Alan H. Beggs, E-mail: beggs{at}enders.tch.harvard.edu


  Abstract

Nemaline myopathy, the most common non-dystrophic congenital myopathy, is a variably severe neuromuscular disorder for which no effective treatment is available. Although a number of genes have been identified in which mutations can cause nemaline myopathy, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in a nemaline myopathy mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed 5 different skeletal muscles from affected mice that are representative of muscles with differing fiber type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in nonaffected mice showed marked variation in patterns of gene expression, with diaphragm being the most dissimilar, the presence of the mutant protein in nemaline muscles resulted in a more similar pattern of gene expression amongst the muscles. This result suggests a common process or mechanism operating in nemaline muscles independent of the variable degrees of pathology. Transcriptional and protein expression data indicate the presence of a repair process and possibly delayed maturation in nemaline muscles. Markers indicative of satellite cell number, activated satellite cells and immature fibers including M-Cadherin, MyoD, desmin, Pax7 and Myf6 were elevated by Western blot analysis or immunohistochemistry. Evidence suggesting elevated focal repair was observed in nemaline muscle in electron micrographs. This analysis reveals that nemaline myopathy is characterized by a novel repair feature operating in multiple different muscles.


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