Potassium channels in myotonic dystrophy type 1

1 型强直性肌营养不良中的钾通道

• 批准号: 8101904
• 负责人: Christine Beeton
• 金额: $ 7.37万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8101904
• 关键词: Adult; Binding; Cell membrane; Cells; Child; Cytoplasm; Data; Differentiation Antigens; Dose; GLUT4 gene; Gelatinase A; Glucose; Glucose Transporter; Goals; Human; Impairment; Inherited; Insulin; Insulin Receptor; Insulin Resistance; Matrix Metalloproteinases; Measures; Mental Retardation; Mus; Muscle; Muscle Cells; Muscle Development; Muscle Fibers; Muscle function; Myoblasts; Myopathy; Myotonic Dystrophy; Neuromuscular Diseases; Non-Insulin-Dependent Diabetes Mellitus; Phosphorylation; Phosphorylation Inhibition; Phosphotransferases; Physiological; Play; Potassium Channel; Potassium Channel Blockers; Production; Protein Biosynthesis; Proteins; Public Health; Regulation; Role; Signal Transduction; base; channel blockers; design; glucose uptake; improved; insulin sensitivity; muscle form; myogenesis; new therapeutic target; olfactory bulb; public health relevance; receptor; response; wasting

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.

描述（由申请人提供）：强直性肌营养不良1型（DM 1）是成人中最常见的遗传性神经肌肉疾病。它的特点是进行性肌肉萎缩和无力的成年人。除了这些特征，DM 1通常与胰岛素抵抗有关，导致2型糖尿病。患有先天性DM 1的儿童，DM 1的最严重形式，表现为肌肉发育不全和智力迟钝。一种旨在增加胰岛素敏感性的策略，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，将改善先天性DM 1儿童的肌肉质量和功能，也可能改善DM 1成人的肌肉质量和功能。 人类成肌细胞是肌肉细胞的前体，表达不同的钾通道子集，包括Kv1.3和Kv1.5通道。我们已经发现，Kv1.3和Kv1.5通道的阻断剂改善了GLUT 4转位到人DM 1成肌细胞的质膜以响应胰岛素。阻断Kv1.3通道也增加了DM 1成肌细胞中基质金属蛋白酶-2（MMP-2）的产生，其显著低于正常成肌细胞。我们的数据表明，阻断DM 1成肌细胞中的Kv 1通道具有改善胰岛素敏感性和成肌细胞融合与分化的潜力。基于这些令人兴奋的结果，我们计划研究Kv 1通道阻滞剂是否能改善DM 1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Kv 1通道对DM 1成肌细胞葡萄糖摄取和蛋白质合成的影响，并评估DM 1成肌细胞中参与葡萄糖摄取的激酶是否被激活。在目标2下，我们将确定阻断Kv 1通道对不同MMP的产生以及对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、肌肉发育不全和先天性DM 1儿童肌肉萎缩的新靶点，也可能是治疗DM 1和其他营养不良成人的新靶点。 公共卫生相关性：公共卫生相关性1型强直性肌营养不良症是成人中最常见的遗传性神经肌肉疾病。我们的目标是通过靶向成肌细胞上的钾通道，开发一种治疗这种疾病的两个主要方面的策略-肌肉发育不全和萎缩，以及胰岛素抵抗。这些新的治疗靶点将对公共卫生产生巨大的好处。