Dynamine, a therapeutic target for different myopathies
Cutting of muscle fibers of wild mice (left) and mice without amphiphysin with reduced level of dynamine (right). While animals without amphiphysin are not viable, the reduction of dynamin in these animals leads to normal muscle fiber structure and activity.
J Clin Invest Dec. 1, 2017
Nov. 14, 2017
The regulation of muscular development is a complex process that is not fully understood and in which among others two proteins, amphiphysin and dynamin, are involved. In this study, Jocelyn Laporte's team at IGBMC show that amphiphysin negatively regulates dynamin activity for normal muscle development and, on the other hand, that a reduction in dynamin levels prevents several types of myopathies. These results were published on November 13, 2017, in the Journal of Clinical Investigation.
Many human myopathies result from protein mutations involved in the proper development of muscles. Amphiphysins and dynamins are thus mutated into rare congenital myopathies called centronuclear myopathies. Despite numerous in vitro studies, the interaction between amphiphysins and dynamins remains poorly understood.
To understand the mechanisms of regulation between amphiphysins and dynamins, Belinda Cowling and Ivana Prokic in Jocelyn Laporte's team have generated mouse lines for which genes coding for these proteins have been invalidated. Researchers have observed that while amphiphysin-deficient mice develop myopathy and die at birth, the decrease in dynamin in these mice restores normal life expectancy. This in vivo result, which shows that amphiphysin regulates dynamin negatively, calling into question the basic concept that amphiphysin was a dynamin activator.
In collaboration with the University of Geneva, and Sylvie Friant, University of Strasbourg, IGBMC researchers then characterized specific forms of amphiphysin and dynamin in muscle cells. Although amphiphysin inhibits dynamin activity during muscle development, it has no effect on dynamin in the adult muscle. These observations thus reveal the major role of dynamin in muscle development and organization and make it possible to envisage dynamin as a target in the treatment of several types of myopathies. These promising results will be used by a start-up company, Dynacure, to develop clinical trials for the treatment of myopathies.
Since amphiphysin is known to be involved in myopathies but also cancer, arrhythmia and late onset Alzheimer's disease, this study also opens up new therapeutic perspectives for these common diseases.
This study is financed by the program Investissements d’Avenir Labex, ANR, SATT Connectus Alsace, the Association Française contre les Myopathies and the Myotubular Trust (UK).