Skeletal muscle KATP channels determine bodily energy balance

描述（由申请人提供）：现代世界经历了肥胖症的巨大增长，肥胖症是一种与糖尿病、心血管疾病和癌症的发病率和死亡率增加相关的疾病。即使是5-10%的适度减肥也可以预防肥胖的长期后果。不幸的是，目前肥胖症的治疗选择在其应用和效果方面仍然有限。 我们的初步数据表明，肌膜ATP敏感的K+（KATP）通道限制肌肉能量消耗生理负荷下，而KATP通道赤字引起肌肉性能的额外能量消耗。KATP通道缺乏的肌肉中的燃料代谢效率低下，减少了体内脂肪沉积，促进了瘦型。目前的建议建立在这一发现，以确定KATP通道功能影响骨骼肌性能和脂肪组织动员的机制。 我们假设，膜电位调制，由于KATP通道开放响应生理工作量，限制钙和钠内向电流，从而与离子稳态和收缩持续的能量消耗。在过剩的热量摄入的条件下，这促进了体重增加。相反，KATP通道功能的破坏将导致细胞钙周转过度，导致能量消耗增加和钙/钙调蛋白依赖性蛋白激酶（Ca 2 +/CaMKII）的激活。我们提出，CaMKII的诱导触发Akt依赖性生产和Ca 2+依赖性分泌的信号肽-肌肉蛋白。这种肽以其调节心房利钠肽（ANP）清除的能力而闻名，心房利钠肽是一种潜在的脂解激活剂。通过这种方式，肌肉蛋白信号可以将增加的活动相关的能量消耗转化为脂肪组织动员。本项目的目标是直接研究KATP通道控制活动相关能量消耗的分子机制以及随之而来的脂肪组织动员和体重减轻的机制。 拟议的研究将在多个模型中进行--对细胞和分离器官水平的生化和电生理研究将用于验证分子 在整个身体水平上获得的结果的机制。了解这些机制将为肥胖和相关疾病的靶向管理和预防提供新的途径。

DESCRIPTION (provided by applicant): The modern world has experienced enormous growth in obesity, a disease associated with increased incidence of and mortality from diabetes, cardiovascular disease and cancer. Even moderate weight loss in the range of 5-10% has been shown to prevent the long-term consequences of obesity. Unfortunately, the current treatment options for obesity remain limited in both their application and effect. Our preliminary data indicate that sarcolemmal ATP-sensitive K+ (KATP) channels limit muscle energy expenditure under physiological workload, while KATP channel deficit provokes an extra energy cost of muscle performance. Inefficient fuel metabolism in KATP channel-deficient muscles reduces body fat deposits promoting a lean phenotype. The current proposal builds on this finding to determine the mechanisms by which KATP channel function affects skeletal muscle performance, and adipose tissue mobilization. We hypothesize that membrane potential modulation, due to KATP channel opening in response to a physiological workload, limits calcium and sodium inward currents and thus energy consumption related to ion homeostasis and contraction continuation. Under conditions of surplus calorie intake this promotes weight gain. Conversely, disruption of KATP channel function would result in exaggerated cellular calcium turnover, causing increased energy consumption and activation of calcium/calmodulin dependent protein kinase (Ca2+/CaMKII). We propose, that induction of CaMKII triggers both Akt-dependent production and Ca2+- dependent secretion of a signaling peptide - musclin. This peptide is known for its ability to modulate clearance of atrial natriuretic peptide (ANP) - a potet activator of lipolysis. In this way, musclin signaling could translate increased activity related energy consumption into adipose tissue mobilization. The goal of this project is to directly study the molecular mechanism of KATP channel control of activity- related energy consumption and the mechanism of consequent adipose tissue mobilization and body weight reduction. The proposed investigation will be performed across multiple models - biochemical and electrophysiological studies on cellular and isolated organ levels will be used to verify molecular mechanisms for findings obtained on the whole body level. Understanding these mechanisms will provide novel avenues for targeted management and prevention of obesity and related diseases.