Suetterlin, Karen Joan; (2021) Understanding the Pathophysiology of Skeletal Muscle Channelopathies. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

Skeletal muscle channelopathies are rare inherited neuromuscular conditions caused by ion channel gene mutations. They are grouped into the non-dystrophic myotonias and the periodic paralyses (PP). An intriguing but as yet unexplained phenomenon is that phenotype severity varies significantly with species, gender and age. The first part of my thesis explores my hypothesis that this phenotype variability in skeletal muscle channelopathies reflects physiological differences in skeletal muscle excitability. To do this, I reverse translated Muscle Velocity Recovery Cycles (MVRCs), an in vivo technique for assessing ion channel function, from humans to mice. My data suggest that murine skeletal muscle has increased chloride conductance compared to human skeletal muscle. This could explain the species difference seen between mouse models of Myotonia Congenita and humans with clinical disease. I also found gender differences in healthy murine muscle excitability that vary by muscle and are associated with gender difference in the skeletal muscle channelome. On the background of these physiological gender differences in murine muscle excitability, the effect of gain-of-function sodium channel mutation is more severe in male mice. Finally, I found that the phenotype change with age seen in patients with PP also occurs in a mouse model. Surprisingly, an increased resistance to potassium-induced weakness was most pronounced in old wild-type mice, suggesting it is a phenomenon of normal aging. In contrast, the onset of permanent progressive weakness was specific to PP mouse muscle. My experiments suggest this may be due to acquired ryanodine receptor dysfunction resulting in sarcoplasmic reticulum calcium leak and impaired mitochondrial oxidative capacity. The aim of the second part of my thesis was to extend our knowledge of ClC-1 structure-function and improve genetic counselling for patients with Myotonia Congenita (MC). I identified a novel molecular pathomechanism for MC and found that dominant mutations cluster in the first half of the channel sequence. Combining variant location with functional characterisation significantly improves the accuracy of genetic counselling we can provide patients.

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