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

骨骼肌代谢功能障碍和萎缩是恶病质的突出特征， 以体重减轻、骨骼肌和脂肪量减少为特征的破坏性综合征，以及 骨骼肌无力恶病质的发生是多种疾病的结果，包括 不受控制的高血糖症（即糖尿病）、癌症、慢性肺、心脏和肾脏疾病以及艾滋病;以及 在这些疾病状态下，骨骼肌萎缩通过降低 活动能力和活动能力受损骨骼肌萎缩也发生在健康个体中， 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，确定细胞和 调节骨骼肌质量的分子因素是一项重要的任务， 涉及肌肉萎缩症的药物治疗的发展。 在肌肉萎缩性疾病中，蛋白质合成和蛋白质合成之间的平衡失调， 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蛋白（mTOR）信号级联。尽管mTOR在 尽管mTOR的上游信号通路调节肌肉质量，但调节mTOR的上游信号通路仍在很大程度上未知。在 这个建议，我们提出了有趣的新数据表明，钙敏感，丝氨酸/苏氨酸激酶， Ca 2 +/钙调蛋白依赖性蛋白激酶激酶α（CaMKKa）是一种新型的骨骼肌细胞生长调节因子， 肌肉质量和mTOR信号。因此，在本申请中，我们提出研究 CaMKKa在骨骼肌生长、蛋白质合成和mTOR信号传导中的调节。

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.