Characterizing the molecular pathology of muscle disease

Nemaline Myopathy, the most common non-dystrophic congenital myopathy, encompasses a clinically and genetically heterogeneous group of disorders characterized by nemaline rods and skeletal muscle weakness. Mutations in five sarcomeric thin filament genes have been identified, yet the molecular mechanisms leading to the disease phenotype were until recently unknown. Using whole genome expression profiling we were able to address this question, and to identify significant transcriptional changes in glycolytic pathway, muscle satellite cell and connective tissue related genes, in NM patients' skeletal muscle. Importantly, a novel sub-group of patients with milder prognosis was discovered, and its molecular characteristics were determined. To achieve a better understanding of the observed molecular changes, we proceeded to study the first nemaline myopathy transgenic mouse model. Molecular and histological analyses allowed us to determine the affected molecular pathways and their similarity to our proposed human pathogenesis model. A range of different skeletal muscles were studied in order to evaluate potential inter-muscle variation in disease development/response. We concluded that there is a common process or mechanism that operates in nemaline muscles independently of the variable degrees of pathology. Furthermore, we have evidence to support the presence of a repair process and possibly delayed maturation in the affected muscles. One of the most consistent inter-muscle results was the over-expression of CSRP3 (MLP) and ANKRD2. This led to the hypothesis that these two proteins may play a key role in disease related mechanisms and potentially in response to the disease pathology, with a potentially promising therapeutic role.

Speaker: D. Sanoudou, PhD
Researcher, Molecular Biology Laboratory, Foundation for Biomedical Research of the Academy of Athens
Time: Monday, 26 March 2007, 13:00