CALSEQUESTRINS IN CALCIUM HOMEOSTASIS AND POTENTIAL ROLE IN INHERITED HUMAN SKELETAL MUSCLE DISEASES

Several pathological conditions in muscle have been associated with mutations of proteins involved in the control of calcium (Ca) levels. Calsequestrin (CASQ) is a key protein that modulates Ca release/uptake from intracellular stores called sarcoplasmic reticulum (SR). Myopathies such as malignant hyperthermia (MH, an extremely dangerous and possibly lethal reaction to anesthetics characterized by muscle contractures and uncontrolled increase in body temperature) and core myopathies (CCD and MmD, characterized by muscle weakness and degeneration of fiber architecture) result from altered Ca levels. Most cases of MH/CCD have been linked with mutations in the RYR gene, encoding for the SR Ca release channel. However, not all patients diagnosed as MH and or CCD carry mutations in that gene. Interestingly, MH bears many similarities (hyper-metabolic state, increase in body temperature, etc) with overheating episodes known as heat-strokes (HS), triggered by strenuous exercise performed in challenging environmental conditions (hot temperatures, high humidity). Our project is based on the following: a – a novel finding: disruption of the CASQ1 gene in mice increases the susceptibility of the animals to lethal episode in response to heat-stress and anesthetics, which are strikingly similar to human MH crises, and also to HS. b – an hypothesis: since CASQ interact with RYR and is crucial for controlling Ca levels, it is possible that CASQ mutations are involved in MH, HS, and core myopathies; The project aims to collect conclusive evidence to support the hypothesis from a) animal experiments; and b) screening DNA from humans diagnosed as MH and CCD. In addition, we will try to develop either pharmacological/dietary approaches aiming to prevent the acute episodes and/or to revert the pathological phenotype. The results may be of great importance for prevention and treatment of these types of myopathies.