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：
8436134
负责人：
Carol Ann Witczak
金额：
$ 23.66万
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 2015-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8436134
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卡赫西亚的突出特征毁灭性综合征的特征是体重减轻，骨骼肌和脂肪质量的损失，以及骨骼肌无力。恶病质是由于广泛的疾病而发生的不受控制的高血糖（即糖尿病），癌症，慢性肺，心脏和肾脏疾病以及艾滋病；和在这些疾病中，骨骼肌浪费显着导致疾病死亡率通过降低在移动性和呼吸能力受损中。骨骼肌浪费也发生在健康个体中对衰老的正常反应，或者对长期不活动的响应。考虑到这一广泛的受影响的患者，以及如果不逆转肌肉的后果，确定细胞和骨骼肌质量调节的分子因素是一项关键的事业，可能导致开发肌肉浪费障碍的药物治疗方法。在肌肉浪费障碍中，蛋白质合成与蛋白质之间的平衡失调降解转向蛋白质合成的降低，这是通过降低激活而发生的雷帕霉素（MTOR）信号级联的哺乳动物靶标。尽管MTOR在调节肌肉质量，调节MTOR的上游信号通路仍然很大未知。在这项建议，我们提供了有趣的新数据，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（Camkkalpha）是骨骼的新调节剂肌肉质量和MTOR信号传导。因此，在此应用中，我们建议研究 Camkkalpha在骨骼肌中调节生长，蛋白质合成和MTOR信号传导方面。