Grant: Operating Grant

Muscle contraction is triggered by the release of calcium into muscle cells from a storage compartment inside the cells, referred to as the sarcoplasmic reticulum; relaxation is initiated by return of calcium to the storage compartment. Thus every bodily movement and every heartbeat is dependent on calcium fluxes. Calcium release channels are responsible for releasing calcium from the storage compartment to bring about muscle contraction. Two human diseases, malignant hyperthermia, a toxic response to anesthetics, and central core disease, causing muscle weakness, are caused by mutations in the skeletal muscle form of the calcium release channel. In recent work, Dr. MacLennan and his group have developed a mouse line in which the calcium release channel is mutated to an inactive form. When both copies of the mutant gene are present, the embryonic mouse displays a block in development; when only one copy is present, the mouse lives, but displays symptoms of muscle disease that are consistent with central core disease. Both of these mouse models of disease are interesting. The block in development is caused by the lack of calcium signals that direct proper development in mice, but these signals are not defined. Dr. Maclennan's group propose to identify these signals. The mouse with central core disease offers the opportunity for understanding how this and other muscle diseases develop and how intervention might ameliorate the effects of muscle diseases.