Role of Ca2+/calmodulin kinases in skeletal muscle glucose transport and growth.

Ca2/钙调蛋白激酶在骨骼肌葡萄糖转运和生长中的作用。

• 批准号: 8230213
• 负责人: Carol Ann Witczak
• 金额: $ 24.9万
• 依托单位: EAST CAROLINA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-02-01 至 2014-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8230213
• 关键词: 5' -AMP-activated protein kinase; Acquired Immunodeficiency Syndrome; Address; Affect; Aging; Atrophic; Attenuated; Biochemical; Body Weight decreased; Ca(2+)-Calmodulin Dependent Protein Kinase; Cachexia; Calcium/calmodulin-dependent protein kinase; Chronic lung disease; Complex; Data; Denervation; Development; Diabetes Mellitus; Disease; Equilibrium; Exhibits; Fatty acid glycerol esters; Functional disorder; Gene Transfer; Genetic Transcription; Goals; Growth; Heart Diseases; Hyperglycemia; Hypertrophy; Individual; Instruction; Kidney Diseases; Knockout Mice; Lead; Lipids; Malignant Neoplasms; Mammalian Cell; Metabolic; Metabolism; Modeling; Molecular; Muscle; Muscle Fibers; Muscle Proteins; Muscle Weakness; Muscular Atrophy; Patients; Pharmacologic Substance; Phase; Phosphotransferases; Physiological; Play; Process; Progress Reports; Protein Biosynthesis; Protein-Serine-Threonine Kinases; Proteins; Regulation; Role; Signal Pathway; Signal Transduction; Signaling Protein; Skeletal Muscle; Syndrome; Weight; Work; glucose transport; glucose uptake; in vivo; innovation; mTOR protein; mortality; muscle form; muscle hypertrophy; muscle metabolism; novel; oxidation; protein degradation; protein expression; response; skeletal muscle growth; skeletal muscle wasting; wasting

Skeletal muscle metabolic dysfunction and atrophy are prominent features of cachexia, a complex and devastating syndrome characterized by loss of body weight, loss of skeletal muscle and fat mass, and skeletal muscle weakness. Cachexia occurs as a consequence of a broad range of diseases, including uncontrolled hyperglycemia (i.e. diabetes), cancer, chronic lung, heart and kidney diseases, and AIDS; and in these disease states skeletal muscle wasting significantly contributes to disease mortality via a decrease in mobility and an impaired ability to respirate. Skeletal muscle wasting also occurs in healthy individuals as a normal response to aging, or in response to prolonged bouts of inactivity. Given this wide range of affected patients, and the consequences if muscle wasting is not reversed, determination of the cellular and molecular factors underlying the regulation of skeletal muscle mass is a critical undertaking that could lead to the development of pharmaceutical treatments for muscle wasting disorders. In muscle wasting disorders, dysregulation ofthe balance between protein synthesis and protein degradation shifts towards decreased protein synthesis, and this occurs via a decrease in the activation of the mammalian target of rapamycin (mTOR) signaling cascade. Despite the critical role that mTOR plays in regulating muscle mass, the upstream signaling pathways that regulate mTOR are still largely unknown. In this proposal, we present intriguing new data suggesting that the Ca2+-sensitive, serine/threonine kinase, Ca2+/calmodulin-dependent protein kinase kinase alpha (CaMKKalpha) is a novel regulator of skeletal muscle mass and mTOR signaling. Thus, in this application, we propose to investigate the role of CaMKKalpha in the regulation of growth, protein synthesis and mTOR signaling in skeletal muscle.

骨骼肌代谢功能障碍和萎缩是恶病质的显著特征，恶病质是一种复杂和 以体重减轻、骨骼肌和脂肪减少为特征的破坏性综合征，以及 骨骼肌无力。恶病质是由多种疾病引起的，包括 失控的高血糖(即糖尿病)、癌症、慢性肺、心脏和肾脏疾病以及艾滋病；以及 在这些疾病状态中，骨骼肌萎缩通过减少导致疾病死亡率显著增加。 行动不便，呼吸能力受损。骨骼肌萎缩也发生在健康的人身上，因为 这是对衰老的正常反应，或者是对长时间不活动的反应。考虑到这么大范围的 受影响的患者，以及如果肌肉萎缩不逆转的后果，细胞和 调节骨骼肌质量的分子因素是一项关键任务，它可能导致 为发展治疗肌肉萎缩疾病的药物治疗做出了贡献。 在肌肉萎缩障碍中，蛋白质合成和蛋白质之间的平衡失调 降解转变为蛋白质合成减少，这是通过减少蛋白的激活而发生的 哺乳动物的雷帕霉素靶点(MTOR)信号级联。尽管mTOR在 调节肌肉质量，调节mTOR的上游信号通路在很大程度上仍不清楚。在……里面 这一建议，我们提出了耐人寻味的新数据表明，钙敏感，丝氨酸/苏氨酸激酶， 钙/钙调素依赖的蛋白激酶α(CaMKKalpha)是一种新的骨骼调节因子 肌肉质量和mTOR信号。因此，在本应用程序中，我们建议调查 CaMKKalpha在骨骼肌生长、蛋白质合成和mTOR信号的调节中的作用。