Targeting mitochondria in myopathies with RyR1 and MICU1 mutations

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, called ion channels, result in loss of muscle function and strength, the main symptoms of diseases called myopathies. We will study the basic pathogenic mechanisms of two particular myopathies, caused by mutations in two genes. In “central core” disease, characterised by muscle weakness around the trunk, a channel called ryanodine receptor is defective. In contrast, the lack of a channel gauge protein, called MICU1, affect the nervous system, causing problems to control voluntary movements in addition to loss of muscle performance (disease called myopathy with extrapyramidal signs). An important clue to understand how these mutations cause the disease comes from our previous observation that demonstrated in both cases the mitochondrion, the organelle that is the main source of energy for muscle movement, is defective. Altogether the lack of healthy energy source leads to reduced muscle force, pain and eventually muscle wasting, together with eventual nerve cell loss. The principal aim of this project is to understand the mechanism by which the defect of the energy-producing organelles is caused by altered spreading of Ca2+ inside muscle fibers. If we understand the precise molecular mechanism we will be able to apply pharmacological treatment or genetic modification to combat the disease. In the experimental work we will take advantage of the vast resources available in the laboratory and institution to apply state-of-the art techniques. This will allow us to study a wide range of aspects of the disease, from the mechanism by which cells adapt to damage, how they eventually degenerate and dye. We will use genetically modified animal models and patient derived cellular models for our experiments. On these models we can apply advanced techniques of microscopy and biochemistry to identify the basic mechanism of the disease. Exploring these pathogenic mechanisms will help us to apply and test drugs and drug targets to ameliorate and possibly cure the disease.