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: 3161881
• 负责人: WILLIAM WINDER
• 金额: $ 11.09万
• 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/3161881
• 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是第一个参与的中间体。 从葡萄糖和其他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（ 分离线粒体中的脂肪酸氧化限速酶） 来自肝脏和骨骼肌。 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 使得当葡萄糖存在时脂肪酸氧化被抑制 用于脂肪酸合成。 禁食期间，升高 血浆胰高血糖素抑制（通过 cAMP 触发的磷酸化）ACC 骨骼肌（非脂肪生成组织）中丙二酰辅酶 A 的下降。 骨骼肌丙二酰辅酶 A 因禁食和 锻炼。 所提出的实验的主要目的是 阐明肌肉中丙二酰辅酶A合成的调节机制 由 ACC 提供。 骨骼肌 ACC 将被分离并表征为 分子量和动力学性质。 的角色 肾上腺素、胰岛素和肌肉收缩对 ACC 的调节作用 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 依赖性蛋白进行研究 激酶和钙钙调蛋白依赖性蛋白激酶 II。 的效果 ACC 的急性运动和耐力训练将在 大鼠骨骼肌。 这些研究将提供新的信息 肌肉丙二酰辅酶A的调节，一种假定的脂肪氧化调节剂 肌肉。 这些信息对于更好地理解非常重要 糖尿病的代谢紊乱及其理解 运动过程中脂肪利用的调节。