Potassium channels in myotonic dystrophy type 1

描述(申请人提供)：强直性肌营养不良1型(DM1)是成人最常见的遗传性神经肌肉疾病。它的特点是成年人进行性肌肉萎缩和虚弱。除了这些特征外，DM1还经常与胰岛素抵抗有关，从而导致2型糖尿病。患有先天性DM1的儿童是DM1最严重的形式，表现为肌肉发育不全和智力低下。一种旨在增加肌肉细胞对胰岛素的敏感性，从而增加肌肉细胞对葡萄糖的摄取，同时促进成肌细胞分化为功能性肌管的策略，将改善先天性DM1儿童的肌肉质量和功能，也可能改善患有DM1的成年人的肌肉质量和功能。人成肌细胞是肌细胞的前体，表达不同的钾通道亚群，包括Kv1.3和Kv1.5通道。我们发现Kv1.3和Kv1.5通道的阻断剂改善了胰岛素对人DM1成肌细胞质膜的GLUT4易位。阻断Kv1.3通道也增加了DM1成肌细胞中基质金属蛋白酶-2(MMP-2)的产量，而在正常成肌细胞中，基质金属蛋白酶-2的产量显著低于正常成肌细胞。我们的数据表明，阻断DM1成肌细胞中的KV1通道具有改善胰岛素敏感性和成肌细胞融合和分化的潜力。基于这些令人兴奋的结果，我们计划研究KV1通道阻滞剂是否能改善DM1成肌细胞对葡萄糖的摄取。我们还将研究这些阻滞剂对蛋白质合成效率和肌管形成的影响。在目标1下，我们将确定阻断KV1通道对DM1成肌细胞葡萄糖摄取和蛋白质合成的影响，并评估参与葡萄糖摄取的激酶在DM1成肌细胞中是否被激活。在目标2下，我们将确定阻断KV1通道对不同MMPs的产生和成肌细胞向肌管分化的影响。钾通道可能是治疗胰岛素抵抗、肌肉发育不良和先天性DM1儿童肌肉萎缩的新靶点，可能也适用于患有DM1和其他营养不良的成年人。 公共卫生相关性：强直性肌营养不良1型是成人最常见的遗传性神经肌肉疾病。我们的目标是开发一种策略，通过靶向成肌细胞的钾通道来治疗这种疾病的两个主要方面-肌肉发育不足和萎缩，以及胰岛素抵抗。这些新的治疗目标将对公众健康产生巨大的好处。

DESCRIPTION (provided by applicant): 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: 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.