Role of Potassium Channels in Myogenesis during Myotonic Dystrophy Type 1

Abstract

Myotonic dystrophy type 1 (DM1) is an autosomal dominant neuromuscular disorder affecting 1 in 8000 people worldwide. DM1 is genetically identified as a mutation that contains expansion of CTG repeats in 3' UTR of the DM1 protein kinase gene. It is characterized by muscle wasting and multi-system failure including insulin resistance and major cardiac involvement.We have identified a switch in functional potassium channel expression from KCa1.1 to Kv1 channels when comparing myoblasts from healthy donors and from patients with DM1. Potassium channels are responsible for maintaining resting membrane potential and regulating cell volume, and play a role in cell proliferation. We hypothesize that this switch in potassium channel plays a role in the reduced myogenesis observed in patients with DM1, and that selective inhibition of Kv1 channels will rescue at least some of the pathological features of DM1 in skeletal muscle.We have found that pharmacological inhibition of Kv1 channel decreased proliferation of primary myoblasts from patients with DM1. This blockade also restored production of matrix metalloproteinase-2 (a protease necessary for myotube fusion) in DM1 myoblasts to levels obtained in cells from healthy controls. Blocking KCa1.1 channels induced an increase in the proliferative rate of healthy myoblasts. Our results do support the hypothesis that blocking Kv1 channels will be beneficial in DM1.Ongoing studies focus on the role of KCa1.1 and Kv1 channels in myoblast fusion to form myotubes. We also propose to study the inter-dependency of Kv and KCa1.1 channels by genetically or pharmacologically knocking down one channel and observing compensatory increase in expression of the other.Through this project, our goal is to better understand the roles of potassium channels in DM1 pathogenesis and to establish Kv1 channel as potential targets for therapy.