Mechanisms controlling calcium dyshomeostasis in malignant hyperthermia susceptible mice

Rationale

The overall rationale behind this project is to determine the mechanisms by which mutations in proteins that are responsible for maintaining normal intracellular calcium ion concentrations at rest cause the symptoms of malignant hyperthermia (MH), a rare disorder that occurs when patients are exposed to volatile anaesthesia agents during surgery.

Symptoms of MH include fast heart rate, raised temperature, elevated carbon dioxide in their expired air, and muscle rigidity. If not treated immediately with dantrolene it can lead to multiple organ failure and death. Additional non anaesthesia MH stressors are heat and vigorous exercise, such as exertional heat illness which can also be fatal and has some clinical overlap with MH.

Plan of work and impact of our studies

The plan of the work proposed is to determine what the mechanisms are that cause MH, and to determine if the syndrome can be prevented by pre-treating patients with drugs that have different protein functions as their target. Experiments will include measuring intracellular calcium and sodium levels, and RNA and protein expression, and will include some in vitro and in vivo assays. In addition to determining the mechanisms that cause MH, we hope that the research performed will also provide insight as to what causes exertional heat stroke and how it can be treated. In addition, because many inherited muscle diseases such as muscular dystrophy share dysregulation of intracellular calcium as one of their findings, what is learned here could be applied to treatment of these diseases as well.

Animal welfare

The investigators performing this research have created mouse models of human MH and are well versed on their proper care and minimization of the number of animals that will be needed for these studies. All animals will be treated humanely and every precaution will be taken to prevent or minimize any pain or distress. This includes sedation with anaesthetics to render the animal unconscious so that they will not experience any pain during the subsequent exposure to the MH triggering agent. Where anaesthetic sedation is not possible animals will be closely monitored following exposure to MH-like triggers, and when initial symptoms are detected intervention will counteract the effects of the trigger and reduce animal pain or distress.

Non-technical summary 

Read mechanisms controlling calcium dyshomeostasis in malignant hyperthermia susceptible mice non-technical summary (PDF).

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