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。

基本信息

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
项目类别：
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&apos -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

项目摘要

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突出特征，恶病质是一种复杂且复杂的疾病。以体重减轻、骨骼肌和脂肪量减少为特征的破坏性综合症，以及骨骼肌无力。恶病质是由多种疾病引起的，包括不受控制的高血糖（即糖尿病）、癌症、慢性肺病、心脏病和肾病以及艾滋病；和在这些疾病状态下，骨骼肌萎缩通过降低死亡率来显着促进疾病死亡率行动不便和呼吸能力受损。骨骼肌消耗也发生在健康个体中，如对衰老的正常反应，或对长时间不活动的反应。鉴于这种广泛的受影响的患者，以及如果肌肉萎缩不逆转的后果，细胞和细胞的测定骨骼肌质量调节背后的分子因素是一项关键任务，可能会导致开发肌肉萎缩症的药物治疗方法。在肌肉消耗性疾病中，蛋白质合成和蛋白质之间的平衡失调降解转向减少蛋白质合成，这是通过减少激活哺乳动物雷帕霉素靶点 (mTOR) 信号级联。尽管 mTOR 在调节肌肉质量，调节 mTOR 的上游信号通路仍然很大程度上未知。在在这个提议中，我们提出了有趣的新数据，表明 Ca2+ 敏感的丝氨酸/苏氨酸激酶， Ca2+/钙调蛋白依赖性蛋白激酶激酶 α (CaMKKα) 是骨骼肌的新型调节剂肌肉质量和 mTOR 信号传导。因此，在本申请中，我们建议研究 CaMKKα 调节骨骼肌生长、蛋白质合成和 mTOR 信号传导。