PHYSIOLOGY OF MALONYL COA IN MUSCLE DURING EXERCISE

运动期间肌肉中丙二酰辅酶A的生理学

• 批准号: 2080688
• 负责人: WILLIAM WINDER
• 金额: $ 11.4万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-05-01 至 1997-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2080688
• 关键词: acetyl coA carboxylase; adrenergic agents; affinity chromatography; calmodulin dependent protein kinase; enzyme mechanism; enzyme structure; epinephrine; exercise; insulin; isolation perfusion; laboratory rat; lipid metabolism; malonyl coA; molecular weight; muscle contraction; muscle metabolism; phosphorylation; protein kinase A; striated muscles

In the liver, malonyl-CoA is the first committed intermediate in the pathway for fatty acid synthesis from glucose and other carbohydrate precursors. This compound inhibits carnitine palmitoyl transferase I (the rate limiting enzyme for fatty acid oxidation) in isolated mitochondria from both liver and skeletal muscle. In times of glucose abundance, activation of acetyl-CoA carboxylase (ACC) causes increased malonyl-CoA concentration in the liver. The high concentration of malonyl-CoA inhibits CPT I so that fatty acid oxidation is inhibited at times when glucose is being utilized for fatty acid synthesis. During times of fasting, elevated plasma glucagon inhibits (via cAMP-triggered phosphorylation) ACC resulting in a decline in malonyl-CoA in skeletal muscle (a non-lipogenic tissue). Skeletal muscle malonyl-CoA decreases markedly in response to fasting and exercise. The principal purpose of the proposed experiments is to elucidate the mechanisms of regulation of malonyl-CoA synthesis in muscle by ACC. The skeletal muscle ACC will be isolated and characterized in terms of molecular weight and kinetic properties. The roles of epinephrine, insulin, and muscle contraction in regulation of ACC will be studied using the hindlimb perfusion system. The role of phosphorylation will be studied using cAMP-dependent protein kinase, AMP-dependent protein kinase, and calcium-calmodulin dependent protein kinase II. The effect of acute exercise bouts and of endurance training on ACC will be studied in rat skeletal muscle. These studies will provide new information on regulation of muscle malonyl-CoA, a putative regulator of fat oxidation in muscle. This information will be important for better understanding the metabolic derangements of diabetes mellitus and for understanding regulation of fat utilization during exercise.

在肝脏中，丙二酰辅酶A是肝脏中的第一个确定的中间体。 从葡萄糖和其它碳水化合物合成脂肪酸的途径 前体 该化合物抑制肉毒碱棕榈酰转移酶I（ 脂肪酸氧化的限速酶 从肝脏和骨骼肌中提取 在葡萄糖丰富的时期， 乙酰辅酶A羧化酶（ACC）的激活导致丙二酰辅酶A增加 肝脏中的浓度。 高浓度的丙二酰辅酶A抑制 CPT I，以便在葡萄糖缺乏时抑制脂肪酸氧化。 用于脂肪酸合成。 在禁食期间， 血浆胰高血糖素抑制（通过cAMP触发的磷酸化）ACC， 骨骼肌（一种非脂肪生成组织）中丙二酰辅酶A下降。 骨骼肌丙二酰辅酶A显著降低， 锻炼的 拟议实验的主要目的是 阐明肌肉中丙二酰辅酶A合成的调节机制 骨骼肌ACC将被分离和表征， 分子量和动力学性质。 的作用 肾上腺素、胰岛素和肌肉收缩调节ACC将是 使用后肢灌注系统进行研究。 磷酸化的作用 将使用cAMP依赖性蛋白激酶、AMP依赖性蛋白 激酶和钙-钙调蛋白依赖性蛋白激酶II。 的影响 急性运动和耐力训练对ACC的影响将在 大鼠骨骼肌 这些研究将提供新的信息， 调节肌肉丙二酰辅酶A，一种假定的脂肪氧化调节剂， 肌肉. 这些信息对于更好地了解 糖尿病的代谢紊乱和了解 运动过程中脂肪利用的调节。