Investigating the fundamental mechanisms underlying the phenotypic diversity observed in RYR1-associated Malignant Hyperthermia.

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Calcium is a crucial regulator of normal function within all cells but in skeletal muscle it has additional roles in allowing the muscle to contract. Therefore, muscle cells (myocytes) have evolved unique structures and pathways to regulate calcium levels within them. The normal functioning of these systems are incompletely understood, as is the detail of how they fail in disease. One of the most dramatic examples of skeletal muscle calcium dysregulation is a potentially lethal reaction to general anaesthetics (GA) called malignant hyperthermia (MH). People with a genetic risk for MH are apparently healthy until exposed to the strong anaesthetic gases which then results in a rapidly progressive and life-threatening (malignant) increase in heat generation (hyperthermia). The MH reaction is due to muscle over-activity from calcium dysregulation. These genetic changes in MH can lead to ongoing calcium dysregulation even without anaesthetic exposure. This then causes long-term adaptations within the myocytes, resulting in muscle pain and damage especially when exposed to stress such as exercise and statin medication. Exercise can also lead to excess heat production and the development of heat illness of which the most severe form known as heat stroke can be fatal. As a result, research into MH has benefits for various people; it can directly help patients at risk of MH (up to 1 in 2,000 people), but also patients with these other disease processes. The studies on MH have provided important discoveries on the mechanisms of normal skeletal muscle function, as well as revealed how such calcium dysregulation can cause problems in other tissues including the heart and brain. A problem with previous research has been the lack of availability of the correct samples to allow a suitable understanding of the mechanisms in humans. I am fortunate to be able to undertake this research in the only MH unit in the UK which has human tissue samples donated by patients undergoing investigations for MH.Recent studies have shown that calcium levels in skeletal myocytes are higher in people who have had MH compared to those who have not. Consequently, this research will address the fundamental need to understand how the genetic differences seen in patients with MH affect the entry and regulation systems of calcium in skeletal myocytes. To understand these mechanisms I will examine how calcium entry into myocytes from patients with MH differs to those without. The initial focus will be to study the most common and serious mutations using various molecular research techniques. One of the techniques I will use is highly specialised, but allows me to directly measure the amount of calcium in myocytes. To learn and import this technique to the UK, I will travel to America for six months. Once I have measured the calcium levels in the different myocyte samples, I can then use several cutting-edge research tools to try and identify the mechanisms of calcium dysregulation and how this can be controlled. After completing these sets of experiments, my research will then examine how the number of mutations affects the amount of calcium that enters and stays in cells. The reason for this is that there are some families with MH where the condition appears to result from the effects of more than one gene interacting with each other. This provides an additional genetic mechanism placing patients at risk of MH. The knowledge gained will allow doctors to better recognize how the genetic changes in patients at risk of MH are likely to affect the patient on exposure to GA, as a result allow patients to receive a safer GA.To summarise, by identifying the structures involved in short and long-term skeletal muscle calcium dysregulation and how they interact, this innovative research could detect potential targets for the development of new drugs. These could be used to prevent and treat MH and various long-term conditions associated with calcium dysregulation.