The Role of Inositol 1,4,5-trisphosphate Mediated Nuclear Ca2+ Signals In Core Myopathies

The optimal strength and timing of muscle contraction is controlled by the precise regulation of the amount of Ca2+ ions inside the muscle fibers. Thus genetic defects of the molecules regulating the movement of these ions result in muscle weakness, the main symptom of diseases called myopathies. In certain cases, such as a particular group of myopathies, called Central Core Disease, these genetic defects also lead to alterations of structure of the fibers. Remarkably, many disparate genetic defects lead to similar alterations in structure in this disease group. Therefore, understanding how these structural abnormalities are caused is key for finding a cure. Intriguingly, according to recent research, in normal muscle the same Ca2+ ions that cause contraction are also responsible for the regulation of genes determining the structure and size of the muscle. Whether Ca2+ will cause contraction or growth depends on exactly where in the cell it is located. We propose that in myopathies the localization of Ca2+ ions in the cells can be altered and consequently it can lead to deregulation of genes. This process ultimately can cause the structural alteration of the muscle fiber and other symptoms of the Central Core Disease. In this project we will compare the localization of Ca2+ inside normal and diseased muscle fibers to test this hypothesis. If the localization is different we will further ask the question whether these differences can be responsible for the development of the symptoms and which are the genes involved in the process. Identifying those genes will help to develop therapies to the disease.