The Functional Swtich in Potassium Channels in Myotonic Dystrophy Type 1 Impairs Proliferation, Migration and Fusion During Myogenesis

Abstract

Voltage-gated K+ channels (Kv) are responsible for myoblasts proliferation and differentiation by triggering changes in membrane potential and cell volume. Since individuals with myotonic dystrophy type 1 (DM1) display reduced myogenesis led by prolonged myoblasts proliferation and delayed myotubes fusion, we investigated the roles of K+ channels in primary human myoblasts obtained from DM1 patients and healthy volunteers. DM1 is an autosomal dominant neuromuscular disorder affecting 1 in 8000 people worldwide. It is the most common adult-onset muscular dystrophy and currently has no treatment. DM1 is characterized by muscle wasting and multi-system disorders.We have identified a switch in functional potassium channel expression from KCa1.1 to Kv1 channels when comparing myoblasts from healthy individuals to myoblasts from patients with DM1. We showed increase in Kv1.2 and Kv1.5 channels, and decrease in KCa1.1 channels in DM1 myoblasts at mRNA level by RT-PCR, at protein level by immunofluorescence, and at channel activity by patch-clamp technique. We hypothesized that this switch in K+ channels plays a role in the reduced myogenesis observed in patients with DM1, and that selective inhibition of Kv1 channels rescues the pathological features of DM1 in skeletal muscle.We show that pharmacological inhibition of Kv1 channels in DM1 myoblasts normalized proliferation, rescued matrix metalloproteinase-2 (MMP-2, a protease necessary for myotube fusion) production, and partially rescued myotube fusion shown as increase in fusion index. On the contrary, selective inhibition of KCa1.1 in normal myoblasts lowered MMP-2 production, impaired wound healing repair, and decreased myotubes formation. Therefore we conclude that loss of KCa1.1 and up-regulation of Kv1 channels in DM1 impairs early stage of myogenesis and can be partially rescued by modulating such K+ channels.