Skeletal muscle ATP-sensitive potassium channels determine bodily energy balance

骨骼肌 ATP 敏感钾通道决定身体能量平衡

• 批准号: 8597362
• 负责人: Leonid Zingman
• 金额: --
• 依托单位: IOWA CITY VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-04-01 至 2015-09-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8597362
• 关键词: ATP sensitive potassium channel complex; Address; Adipose tissue; Adverse effects; Affect; Area; Arthritis; Atrial Natriuretic Factor; Biochemical; Biology; Body Weight; Body Weight decreased; Body fat; Boxing; Ca(2+)-Calmodulin Dependent Protein Kinase; Calcium; Calcium/calmodulin-dependent protein kinase; Cardiovascular Diseases; Consumption; Data; Deposition; Diabetes Mellitus; Disease; Eating; Energy Metabolism; Equilibrium; Exercise Tolerance; Fatty acid glycerol esters; Food Energy; Functional disorder; Future; Growth; Health; Healthcare; Healthcare Systems; High Prevalence; Homeostasis; Hypertension; Incidence; Injection of therapeutic agent; Insulin; Intake; Investigation; Ions; Life Style; Link; Lipolysis; Malignant Neoplasms; Membrane; Membrane Potentials; Messenger RNA; Metabolism; Modeling; Molecular; Muscle; Myocardial Ischemia; Nuclear; Obesity; Obesity associated disease; Organ; Overweight; Peptide Signal Sequences; Peptides; Performance; Phenotype; Phosphorylation; Physical Endurance; Physiological; Population; Prevention; Production; Proto-Oncogene Proteins c-akt; Regulation; Resistance; Resources; Serum; Signal Transduction; Skeletal Muscle; Sodium; Translating; Translational Research; Veterans; Weight Gain; Weight maintenance regimen; Workload; biochemical model; cost; energy balance; experience; improved; inhibitor/antagonist; mortality; novel; obesity prevention; prevent; response; stress tolerance

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 bodily energy balance. We hypothesize that membrane potential modulation due to KATP channel opening in response to 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. Disruption of KATP channel function results in aggravated cellular calcium turnover, causing increased energy consumption and activation of protein kinase B (Akt) by calcium dependent calmodulin kinase. This insulin independent phosphorylation of Akt triggers a previously unrecognized muscle signaling cascade which could translate increased activity related energy consumption into adipose tissue mobilization. This proposal will directly study (1) the molecular mechanism of KATP channel control of activity-related energy consumption; (2) the mechanism of consequent adipose tissue mobilization and body weight reduction and (3) whether interference with skeletal muscle KATP channel function or downstream signaling cascades can be achieved while minimizing side-effects and disruption of muscle performance. 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 disease and future translational research.

描述（由申请人提供）： 现代世界经历了肥胖症的巨大增长，这种疾病与糖尿病、心血管疾病和癌症的发病率和死亡率增加有关。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的基础上，以确定KATP通道功能影响骨骼肌性能和身体能量平衡的机制。 我们假设，由于KATP通道开放的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的膜电位调制。在过剩的热量摄入的条件下，这促进了体重增加。KATP通道功能的破坏导致细胞钙周转加剧，导致能量消耗增加和钙依赖性钙调蛋白激酶激活蛋白激酶B（Akt）。Akt的这种胰岛素非依赖性磷酸化触发了以前未被认识到的肌肉信号级联，其可以将增加的活动相关的能量消耗转化为脂肪组织动员。该提案将直接研究（1）KATP通道控制活动相关能量消耗的分子机制;（2）随后脂肪组织动员和体重减轻的机制;以及（3）是否可以实现对骨骼肌KATP通道功能或下游信号级联的干扰，同时最大限度地减少副作用和肌肉性能的破坏。 将在多个模型中进行拟议的研究-细胞和离体器官水平的生化和电生理研究将用于验证在全身水平上获得的发现的分子机制。了解这些机制将为肥胖和相关疾病的靶向管理和预防以及未来的转化研究提供新的途径。