Myotonic dystrophy type 1 (DM1) is the most common inherited neuromuscular disorder in adults. It is characterized by progressive muscle wasting and weakness in adults. In addition to these features, DM1 is often associated with insulin resistance, leading to type-2 diabetes. Children with congenital DM1, the most severe form of DM1, present with muscle underdevelopment and mental retardation. A strategy designed to increase insulin sensitivity, and therefore glucose uptake, by muscular cells while improving the differentiation of myoblasts into functional myotubes would improve muscle mass and function in children with congenital DM1, and also possibly in adults with DM1. Human myoblasts, the precursors of muscle cells, express different subsets of potassium channels, including Kv1.3 and Kv1.5 channels. We have found that a blocker of both Kv1.3 and Kv1.5 channels improved GLUT4 translocation to the plasma membrane of human DM1 myoblasts in response to insulin. Blocking Kv1.3 channels also increased production of matrix metalloproteinase-2 (MMP-2) in DM1 myoblasts where it is significantly lower than in normal myoblasts. Our data suggest that blocking Kv1 channels in DM1 myoblats has the potential of improving insulin sensitivity and myoblasts fusion and differentiation. Based on these exciting results, we plan on examining if Kv1 channel blockers improve glucose uptake in DM1 myoblasts. We will also examine the effect of these blockers on the efficiency of protein synthesis and on the formation of myotubes.
Under Aim 1 we will determine the effects of blocking Kv1 channels on glucose uptake and protein synthesis by DM1 myoblasts and assess whether kinases involved in glucose uptake are activated in DM1 myoblasts.
Under aim 2 we will determine the effects of blocking Kv1 channels on the production of different MMPs and on the differentiation of myoblasts in to myotubes. Potassium channels may represent new targets for the treatment of insulin resistance, muscle underdevelopment, and muscle wasting in children with congenital DM1, and possibly in adults with DM1 and other dystrophies.
Public Health Relevance Myotonic dystrophy type 1 is the most common inherited neuromuscular disorder in adults. Our goal is to develop a strategy for treating two major aspects of this disease - muscle underdevelopment and wasting, and insulin resistance - by targeting potassium channels on myoblasts. Such new therapeutic targets would have tremendous benefits for public health.
