Paul H S, Adibi S A
J Clin Invest. 1980 Jun;65(6):1285-93. doi: 10.1172/JCI109791.
Treatment of hyperlipidemia with clofibrate may result in development of a muscular syndrome. Our previous investigation (1979. J. Clin. Invest.64: 405.) showed that chronic administration of clofibrate to rats causes myotonia and decreases glucose and fatty acid oxidation and total protein of skeletal muscle. In the present experiments we have investigated amino acid and protein metabolism in these rats. Clofibrate administration decreased the concentration of all three branched-chain amino acids without affecting those of others in muscle. Studies to examine the mechanism of decreases in muscle concentrations of branched-chain amino acids showed the following: (a) Plasma concentration of leucine was decreased, whereas there was no significant change in the concentration of isoleucine and valine. (b) Liver concentrations of all three branched-chain amino acids remained unaltered. (c) The uptake of cycloleucine (a nonmetabolizable analogue of leucine) by both muscle and liver was unaffected. (d) The percentage of a trace amount of injected [1-(14)C]leucine expired as (14)CO(2) in 1 h was significantly increased. (e) The capacity of muscle homogenate for alpha-decarboxylation of leucine was enhanced, whereas that of liver was unaffected. (f) The activity of leucine transaminase was unaffected, whereas that of alpha-ketoisocaproate dehydrogenase was increased in muscle. Studies of protein synthesis, carried out as incorporation of leucine into protein and corrected for differences in specific activity, showed no alteration in liver but enhanced synthesis in muscle of clofibrate-fed rats. Clofibrate stimulated muscle protein degradation, which was demonstrated by increased tyrosine release from gastrocnemius muscle slices and by increased urinary excretion of 3-methylhistidine. We conclude that (a) clofibrate treatment increased branched-chain amino acid oxidation by increasing the activity of branched-chain alpha-ketoacid dehydrogenase in the muscle, (b) increased oxidation results in selective decreases in the concentration of these amino acids in muscle, and (c) decreases in branched-chain amino acid concentration may be responsible for increased protein degradation in muscle.
用氯贝丁酯治疗高脂血症可能会导致一种肌肉综合征的发生。我们之前的研究（1979年。《临床研究杂志》64: 405.）表明，给大鼠长期服用氯贝丁酯会导致肌强直，并降低骨骼肌的葡萄糖和脂肪酸氧化以及总蛋白含量。在本实验中，我们研究了这些大鼠的氨基酸和蛋白质代谢。服用氯贝丁酯会降低所有三种支链氨基酸的浓度，而不影响肌肉中其他氨基酸的浓度。研究支链氨基酸在肌肉中浓度降低的机制显示如下：(a) 亮氨酸的血浆浓度降低，而异亮氨酸和缬氨酸的浓度没有显著变化。(b) 肝脏中所有三种支链氨基酸的浓度保持不变。(c) 肌肉和肝脏对环亮氨酸（亮氨酸的一种不可代谢类似物）的摄取不受影响。(d) 注射的微量[1-(14)C]亮氨酸在1小时内以(14)CO(2)形式呼出的百分比显著增加。(e) 肌肉匀浆对亮氨酸的α-脱羧作用能力增强，而肝脏的不受影响。(f) 亮氨酸转氨酶的活性不受影响，而肌肉中α-酮异己酸脱氢酶的活性增加。以亮氨酸掺入蛋白质并校正比活性差异进行的蛋白质合成研究表明，服用氯贝丁酯的大鼠肝脏中没有变化，但肌肉中的合成增加。氯贝丁酯刺激肌肉蛋白质降解，这通过腓肠肌切片中酪氨酸释放增加以及3-甲基组氨酸尿排泄增加得到证明。我们得出结论：(a) 氯贝丁酯治疗通过增加肌肉中支链α-酮酸脱氢酶的活性来增加支链氨基酸氧化，(b) 氧化增加导致这些氨基酸在肌肉中的浓度选择性降低，并且(c) 支链氨基酸浓度降低可能是肌肉中蛋白质降解增加的原因。
