Potassium channels in myotonic dystrophy type 1

描述（由申请人提供）：1 型强直性肌营养不良 (DM1) 是成人中最常见的遗传性神经肌肉疾病。其特点是成人进行性肌肉萎缩和无力。除了这些特征之外，DM1 通常与胰岛素抵抗相关，从而导致 2 型糖尿病。患有先天性 DM1（最严重的 DM1 形式）的儿童会出现肌肉发育不良和智力低下。旨在增加胰岛素敏感性，从而增加肌肉细胞对葡萄糖的摄取，同时改善成肌细胞分化为功能性肌管的策略，将改善患有先天性 DM1 的儿童以及患有 DM1 的成人的肌肉质量和功能。 人类成肌细胞（肌肉细胞的前体）表达不同的钾通道子集，包括 Kv1.3 和 Kv1.5 通道。我们发现 Kv1.3 和 Kv1.5 通道阻断剂可改善 GLUT4 易位至人 DM1 成肌细胞质膜对胰岛素的反应。阻断 Kv1.3 通道还增加了 DM1 成肌细胞中基质金属蛋白酶 2 (MMP-2) 的产生，但其显着低于正常成肌细胞。我们的数据表明，阻断 DM1 成肌细胞中的 Kv1 通道有可能改善胰岛素敏感性以及成肌细胞融合和分化。基于这些令人兴奋的结果，我们计划检查 Kv1 通道阻滞剂是否可以改善 DM1 成肌细胞的葡萄糖摄取。我们还将研究这些阻断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是否在 DM1 成肌细胞中被激活。在目标 2 下，我们将确定阻断 Kv1 通道对不同 MMP 的产生以及成肌细胞分化为肌管的影响。 钾通道可能是治疗患有先天性 DM1 的儿童以及患有 DM1 和其他营养不良的成人的胰岛素抵抗、肌肉发育不良和肌肉萎缩的新靶点。 公共卫生相关性： 公共卫生相关性 1 型强直性肌营养不良是成人中最常见的遗传性神经肌肉疾病。我们的目标是制定一种策略，通过针对成肌细胞上的钾通道来治疗这种疾病的两个主要方面——肌肉发育不良和消耗以及胰岛素抵抗。这些新的治疗靶点将为公众健康带来巨大的好处。

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.