Regulation of Skeletal Muscle LKB1

骨骼肌 LKB1 的调节

• 批准号: 7858297
• 负责人: WILLIAM WINDER
• 金额: $ 31.09万
• 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 2012-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7858297
• 关键词: 5' -AMP-activated protein kinase; AMP-activated protein kinase kinase; Alcar; Calcium; Complex; Contracts; Cyclic AMP-Dependent Protein Kinases; Data; Development; Disease; Enzymes; Exercise; GLUT4 gene; Genetic Transcription; Heat-Shock Proteins 90; Hepatocyte; Hexokinase 2; Knockout Mice; Laboratories; Mammalian Cell; Mitochondria; Mus; Muscle; Muscle Contraction; Non-Insulin-Dependent Diabetes Mellitus; Pathway interactions; Pharmacologic Substance; Phosphorylation; Population; Prevention; Proteins; Recombinant Proteins; Regulation; Reporting; Rest; Role; STK11 gene; Signal Transduction; Skeletal Muscle; System; Tumor Suppressor Proteins; combat; design; fatty acid oxidation; glucose uptake; hexokinase; insulin sensitivity; research study; response; sedentary

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）：2003年9月报道，LKB 1是肝脏和培养细胞提取物中AMP活化蛋白激酶（AMPKK）活性的组分。AMPKK磷酸化并激活AMPK，AMPK然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、GLUT 4和线粒体含量的蛋白质！骨骼肌中的氧化酶。AMPKK和AMPK在肌肉中响应于肌肉收缩而被激活。由于AMPK激活对葡萄糖摄取、脂肪酸氧化、GLUT 4表达和胰岛素敏感性的充分证明的作用，该信号传导系统已被靶向用于开发用于预防和治疗2型糖尿病的药物。我们最近在我们的实验室开发了一种肌肉特异性LKB 1基因敲除小鼠，这将能够阐明骨骼肌中肿瘤抑制蛋白LKB 1的激活和作用的作用和机制。更具体地说，这些实验将验证LKB 1是骨骼肌中AMPKK复合物的一种成分，并提供有关其调节的新信息。将确定在静息和收缩肌肉中与LKB 1相关以产生AMPKK活性的特异性蛋白。使用在哺乳动物细胞中表达的重组蛋白，我们将确定LKB 1复合物的哪些组分（假定为LKB 1、STRAD、MO 25和HSP 90）对AMPKK活性是必需的。将研究肌肉中LKB 1的激活机制。最后，我们将研究LKB 1和AMPK增强骨骼肌中GLUT 4转录的机制。这些信息对于设计靶向这一途径治疗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，说服主要是久坐不动的人口的重要性，定期运动，以打击与不活动有关的疾病。

项目成果

The effects of age and muscle contraction on AMPK activity and heterotrimer composition.

• DOI: 10.1016/j.exger.2014.04.007
• 发表时间: 2014-07
• 期刊: EXPERIMENTAL GERONTOLOGY
• 影响因子: 3.9
• 作者: Hardman, Shalene E.;Hall, Derrick E.;Cabrera, Alyssa J.;Hancock, Chad R.;Thomson, David M.
• 通讯作者: Thomson, David M.

Effects of excess corticosterone on LKB1 and AMPK signaling in rat skeletal muscle.

过量皮质酮对大鼠骨骼肌 LKB1 和 AMPK 信号传导的影响。

• DOI: 10.1152/japplphysiol.00906.2009
• 发表时间: 2010
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Nakken,GNathan;Jacobs,DanielL;Thomson,DavidM;Fillmore,Natasha;Winder,WilliamW
• 通讯作者: Winder,WilliamW

Characterization of the liver kinase B1-mouse protein-25 -Ste-20-related adaptor protein complex in adult mouse skeletal muscle.

成年小鼠骨骼肌中肝激酶 B1-小鼠蛋白 25 -Ste-20 相关接头蛋白复合物的表征。

• DOI: 10.1152/japplphysiol.00160.2011
• 发表时间: 2011
• 期刊: Journal of applied physiology (Bethesda, Md. : 1985)
• 作者: Smith,CodyD;Compton,RichardA;Bowler,JoshuaS;Kemp,JonathanT;Sudweeks,SterlingN;Thomson,DavidM;Winder,WilliamW
• 通讯作者: Winder,WilliamW

Skeletal muscle dysfunction in muscle-specific LKB1 knockout mice.

• DOI: 10.1152/japplphysiol.01293.2009
• 发表时间: 2010-06
• 期刊: Journal of applied physiology
• 影响因子: 3.3
• 作者: D. Thomson;C. Hancock;Bradley Evanson;Steven G Kenney;Brandon B. Malan;A. Mongillo;Jacob D Brown;Squire D Hepworth;N. Fillmore;A. C. Parcell;D. Kooyman;W. Winder

Chronic AICAR treatment enhances anabolic signaling in sarcopenic skeletal muscle.

长期 AICAR 治疗可增强少肌骨骼肌的合成代谢信号。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Calixto,Jouber;Johnson,Connor;Smith,Andrew;Brodowski,Kole;Wilcox,ShaleneH;Hill,JonathonT;Thomson,DavidM
• 通讯作者: Thomson,DavidM