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MedUni Vienna: Milestone in muscle research

(Vienna, 15 April 2011) Muscle researchers at MedUni Vienna are showing that genes which were previously associated with muscular dystrophies are also tumour genes. For the first time they are therefore bridging the gap between muscular dystrophies and cancers, and are thus opening up new ways of carrying out research and treating patients.

Picture: In a muscle biopsy of a Duchenne patient aged just 9 months DNA damage response can be seen in nearly all cell nuclei (arrows): gamma-H2Ax immunohistochemistry

Muscular dystrophies are characterised by progressive muscle weakness and lead to reduced life expectancy. Although the genetic causes of most muscular dystrophies have been discovered in the last two and a half decades, the molecular mechanism has remained unexplained so far.  For the affected patients there is still no prospect of being cured. In Austria there are several thousand patients – mostly children and youths – affected by these rare hereditary diseases which usually develop dramatically.

Genomic instability as a key mechanism
In “PLoS Genetics”, one of the leading genetics journals, Wolfgang Schmidt from the Neuromuscular Research Centre at MedUni Vienna (headed by Reginald Bittner) describes the mechanism of the pathological processes occurring in muscular dystrophies. He explains that one thing all muscular dystrophies have in common is a change at the DNA level which we already know about mainly from tumour biology: genomic instability. The pathological changes to the chromatin, in particular the DNA damage, are already present in the earliest stages when, in patients with muscular dystrophy, there are still no visible pathological tissue changes or clinical symptoms. The number of defective chromosomes increases as the disease progresses.


Two myoblast nuclei of a patient with dysferlinopathy (limb-girdle muscular dystrophy 2B) with trisomy 8 (green in situ hybridisation signal) while there are 2 copies for chromosome 18 (red).

In mouse models for various forms of human muscular dystrophy the authors show that spontaneous malignant muscle tumours, so-called sarcomas, develop in old age. The combination of two different muscular dystrophy genetic defects also leads to much more frequent and clearly earlier sarcoma development. Here muscular dystrophy genes therefore behave in exactly the same way as “established” tumour suppressor genes.

From dystrophy to the tumour
With major importance for further studies the researchers managed to show that there is a biological continuum from muscular dystrophy to rapidly growing malignant sarcomas. In dystrophic muscles of mice which had still not developed any visible tumours they found that there were repeatedly “microsarcomas” between the muscle fibres: “To date these cell nests have always been considered as accumulations of macrophages or histiocytes – so cells which have been attributed immunological functions as well as the capacity to remove dead muscle fibres. Based on our findings we are now assessing the proliferation of connective tissue cells and fat cells in dystrophic muscles differently,” says the head of the study Reginald Bittner. The researchers hope that muscular dystrophy patients will, in the future, benefit from the huge efforts and progress made in the field of tumour therapy.

High-tech microscope as a boost for muscle research
The now published scientific breakthrough is based on several years of research and was ultimately possible because of the interdisciplinary cooperation of many contributors at the interface between the research and diagnosis of muscular diseases at the Neuromuscular Research Centre and its cooperation partners. To continue the research the Neuromuscular Research Centre was recently equipped with a laser microdissection microscope thanks to a joint sponsorship from Nikon Instruments, the Harley Davidson Charity Fund and Molecular Machines & Industries AG. With this “Harley Charity Scope” it is possible to use a laser to cut out individual cells or areas of interest from histological preparations and to use these for further detailed biochemical and molecular biological tests.

Publication: 
Schmidt WM, Uddin MH, Dysek S, Moser-Thier K, Pirker C, et al. (2011) DNA Damage, Somatic Aneuploidy, and Malignant Sarcoma Susceptibility in Muscular Dystrophies. PLoS Genet 7(4): e1002042. doi:10.1371/journal.pgen.1002042