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: 7978133
• 负责人: Christine Beeton
• 金额: $ 7.68万
• 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/7978133
• 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; 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）：1型肌发育症（DM1）是成​​人最常见的遗传神经肌肉疾病。它的特征是成人进行性肌肉浪费和无力。除这些特征外，DM1通常与胰岛素抵抗有关，导致2型糖尿病。先天性DM1的儿童，是DM1最严重的形式，肌肉不发育和智力低下。一种旨在通过肌肉细胞来提高胰岛素敏感性并因此增加葡萄糖摄取的策略，同时改善成肌细胞分化为功能性肌管，可以改善先天性DM1儿童的肌肉质量和功能，并且可能在成年DM1的成年人中。 人肌细胞（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通道的阻断剂改善了GLUT4易位，以响应胰岛素，将人DM1成肌细胞的质膜转移到质膜上。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，在DM1成肌细胞中它的产生明显低于正常成肌细胞。我们的数据表明，阻断DM1肌间的KV1通道具有提高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，我们计划检查KV1通道阻滞剂是否改善了DM1成肌细胞中的葡萄糖摄取。我们还将检查这些阻滞剂对蛋白质合成效率和肌管形成的影响。 在AIM 1下，我们将确定通过DM1成肌细胞阻断KV1通道对葡萄糖摄取和蛋白质合成的影响，并评估在DM1成肌细胞中激活参与葡萄糖摄取的激酶。在AIM 2下，我们将确定阻止KV1通道对不同MMP的产生以及对肌管中的成肌分化的影响。 钾通道可能代表了先天性DM1儿童的胰岛素抵抗，肌肉欠发育和肌肉浪费的新目标，可能是患有DM1和其他营养不良的成年人。 公共卫生相关性：公共卫生相关性肌发育症1型是成年人最常见的遗传神经肌肉疾病。我们的目标是制定一种治疗该疾病的两个主要方面的策略 - 肌肉不发育和浪费以及胰岛素抵抗 - 通过靶向肌细胞上的钾通道。这种新的治疗靶标将对公共卫生带来巨大的好处。