Regulation of Skeletal Muscle LKB1

骨骼肌 LKB1 的调节

• 批准号: 7142762
• 负责人: WILLIAM WINDER
• 金额: $ 33万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7142762
• 关键词: hexokinase; muscle; noninsulin dependent diabetes mellitus; protein kinase; proteins; striated muscles

DESCRIPTION (provided by applicant): LKB1 was reported in September 2003 to be a component of the AMP-activated protein kinase (AMPKK) activity in extracts of liver and of cells in culture. AMPKK phosphorylates and activates AMPK which then phosphorylates proteins involved in stimulation of fatty acid oxidation, stimulation of glucose uptake, increasing insulin sensitivity and in controlling content of hexokinase, GLUT4, and mitochondria! oxidative enzymes in skeletal muscle. AMPKK and AMPK are activated in muscle in response to muscle contraction. Because of the well-demonstrated effects of AMPK activation on glucose uptake, fatty acid oxidation, GLUT4 expression, and insulin sensitivity, this signaling system has been targeted for development of Pharmaceuticals for prevention and treatment of type 2 diabetes. We have recently developed a muscle specific LKB1 knockout mouse in our laboratory that will enable elucidation of roles and mechanisms of activation and actions of the tumor suppressor protein, LKB1, in skeletal muscle. More specifically, these experiments will verify that LKB1 is a component of the AMPKK complex in skeletal muscle and provide new information regarding its regulation. The specific proteins associating with LKB1 in resting and contracting muscle to produce AMPKK activity will be determined. Using recombinant proteins expressed in mammalian cells we will determine which components of the LKB1 complex (postulated to be LKB1, STRAD, MO25 and HSP90) are essential for AMPKK activity. The mechanisms of activation of LKB1 in muscle will be investigated. Finally, the mechanisms of enhancement of GLUT4 transcription by LKB1 and AMPK in skeletal muscle will be studied. This information will be crucial for design of Pharmaceuticals targeting this pathway for treatment of type 2 diabetes. The proposed studies will provide additional rationale for convincing a predominantly sedentary population of the importance of regular exercise in combating inactivity-related diseases.

描述（由申请人提供）：LKB1在2003年9月被报道为肝脏和培养细胞提取物中amp活化蛋白激酶（AMPKK）活性的组成部分。AMPKK磷酸化并激活AMPK， AMPK随后磷酸化参与刺激脂肪酸氧化、刺激葡萄糖摄取、增加胰岛素敏感性和控制己糖激酶、GLUT4和线粒体含量的蛋白质！骨骼肌中的氧化酶。AMPKK和AMPK在肌肉收缩时被激活。由于AMPK激活对葡萄糖摄取、脂肪酸氧化、GLUT4表达和胰岛素敏感性的影响已得到充分证明，该信号系统已成为预防和治疗2型糖尿病的药物开发的目标。我们最近在我们的实验室开发了一种肌肉特异性LKB1敲除小鼠，这将有助于阐明肿瘤抑制蛋白LKB1在骨骼肌中的激活和作用的作用和机制。更具体地说，这些实验将验证LKB1是骨骼肌中AMPKK复合体的一个组成部分，并提供有关其调控的新信息。将确定与LKB1相关的特定蛋白质在静息和收缩肌肉中产生AMPKK活性。利用在哺乳动物细胞中表达的重组蛋白，我们将确定LKB1复合物的哪些成分（假设为LKB1、STRAD、MO25和HSP90）对AMPKK活性至关重要。我们将研究LKB1在肌肉中的激活机制。最后，研究LKB1和AMPK在骨骼肌中增强GLUT4转录的机制。这一信息对于设计针对这一途径治疗2型糖尿病的药物至关重要。拟议的研究将提供额外的理由，让主要久坐不动的人群相信定期锻炼在对抗与不活动有关的疾病方面的重要性。