Human Molecular Genetics Advance Access originally published online on July 28, 2006
Human Molecular Genetics 2006 15(17):2603-2612; doi:10.1093/hmg/ddl186
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Skeletal muscle repair in a mouse model of nemaline myopathy
1 Program in Genomics and Genetics Division, Children's Hospital Boston, Harvard Medical School, 300 Longwood Avenue, Boston, MA 02115, USA, 2 Molecular Biology Division, Foundation for Biomedical Research, Academy of Athens, Soranou Efesiou 4, Athens 115-27, Greece and 3 Muscle Development Unit, Children's Medical Research Institute, Locked Bag 23, Westmead, NSW 2145, Australia
* To whom correspondence should be addressed. Tel: +1 6179192170; Fax: +1 6177300253; Email: beggs{at}enders.tch.harvard.edu
Received May 12, 2006; Accepted June 20, 2006
Nemaline myopathy (NM), 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 NM, the pathogenetic mechanisms leading to the phenotypes are poorly understood. To address this question, we examined gene expression patterns in an NM mouse model carrying the human Met9Arg mutation of alpha-tropomyosin slow (Tpm3). We assessed five different skeletal muscles from affected mice, which are representative of muscles with differing fiber-type compositions, different physiological specializations and variable degrees of pathology. Although these same muscles in non-affected 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 among 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 NM is characterized by a novel repair feature operating in multiple different muscles.
These laboratories contributed equally to this study.
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  B. M. Miller and K. M. Trybus Functional Effects of Nemaline Myopathy Mutations on Human Skeletal {alpha}-Actin J. Biol. Chem., July 11, 2008; 283(28): 19379 - 19388. [Abstract] [Full Text] [PDF]
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