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: 2769590
• 负责人: WILLIAM WINDER
• 金额: $ 14万
• 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 2002-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2769590
• 关键词: acetyl coA carboxylase; calmodulin dependent protein kinase; enzyme activity; enzyme mechanism; enzyme structure; exercise; fatty acid metabolism; isolation perfusion; laboratory rat; malonyl coA; mitochondria; muscle contraction; muscle metabolism; oxidation; palmitates; phosphorylation; protein kinase A

DESCRIPTION (Adapted from the applicant's abstract): Malonyl-CoA is a potent inhibitor of mitochondrial carnitine palmitoyltransferase, the rate limiting enzyme for oxidation of fatty acids in skeletal muscle. At submaximal work rates, the rate of fat utilization increases during exercise. Malonyl-CoA, this fat oxidation inhibitor, decreases in the working muscle within minutes after the beginning of exercise. It is increased in muscle of fed rats and isolated muscles exposed to high concentrations of glucose and insulin. A unique isoform (272 kDa) of acetyl-CoA carboxylase (ACC) (the enzyme that synthesizes malonyl-CoA) has been identified in skeletal muscle. The activity of this enzyme has been found to decrease in muscle during exercise concurrent with an increase in the activity of a 5'-AMP-activated protein kinase (AMPK). Purified AMPK has been shown to be effective in phosphorylating and inactivating muscle ACC. In the proposed experiments the short-term mechanisms of regulation of ACC in contracting skeletal muscle will be investigated. These will include studies on correlation between malonyl-CoA and fatty acid oxidation in isolated perfused rat hindlimb, studies on the effect of phosphorylation of ACC by AMPK and calmodulin kinase Ia on activity of ACC in the presence of various concentrations of substrates, activators, and inhibitors, and studies on the effect of different phosphatases on ACC previously inactivated by exercise or muscle stimulation. The mechanisms of activation of AMPK during muscle contraction and exercise will be studied, using precursors of an analogue of AMP and calmodulin antagonists. A putative AMPK kinase will be isolated from skeletal muscle and characterized with respect to activation by calcium/calmodulin and AMP. These studies will provide new information on the basic mechanisms of regulation of malonyl-CoA, the putative modulator of fat oxidation in muscle. These studies will contribute to our understanding of the mechanisms responsible for increasing fat utilization during exercise.

描述（改编自申请人的摘要）：丙二酰辅酶A是一种 线粒体肉毒碱棕榈酰转移酶的有效抑制剂，速率 骨骼肌中脂肪酸氧化的限制酶。 在 次最大工作率时，脂肪利用率会增加 锻炼。 丙二酰辅酶A，这种脂肪氧化抑制剂，会减少 开始运动后几分钟内锻炼肌肉。 这是 喂食大鼠的肌肉和暴露于高浓度的孤立肌肉的肌肉增加 葡萄糖和胰岛素的浓度。 独特的异构体 (272 kDa) 乙酰辅酶A羧化酶（ACC）（合成丙二酰辅酶A的酶）具有 已在骨骼肌中得到鉴定。 该酶的活性为 发现运动过程中肌肉减少，同时肌肉增加 5'-AMP 激活蛋白激酶 (AMPK) 的活性。 纯化的 AMPK 具有 已被证明可有效磷酸化和灭活肌肉 ACC。 在所提出的实验中，ACC 的短期调节机制 将研究收缩骨骼肌的情况。 这些将包括 丙二酰辅酶A与脂肪酸氧化的相关性研究 离体灌注大鼠后肢，磷酸化作用的研究 AMPK 和钙调蛋白激酶 Ia 在存在 ACC 的情况下对 ACC 活性的影响 不同浓度的底物、活化剂和抑制剂，以及 前期不同磷酸酶对ACC影响的研究 通过运动或肌肉刺激而失活。 激活机制 将研究 AMPK 在肌肉收缩和运动过程中的作用，使用 AMP 类似物和钙调蛋白拮抗剂的前体。 一个推定的 AMPK 激酶将从骨骼肌中分离出来并用 关于钙/钙调蛋白和 AMP 的激活。 这些研究将 提供有关基本监管机制的新信息 丙二酰辅酶A，肌肉中脂肪氧化的假定调节剂。 这些 研究将有助于我们了解相关机制 用于增加运动过程中的脂肪利用率。