Holloway Graham P, Bezaire Veronic, Heigenhauser George J F, Tandon Narendra N, Glatz Jan F C, Luiken Joost J F P, Bonen Arend, Spriet Lawrence L
Department of Human Health and Nutritional Sciences, University of Guelph, Guelph, Canada.
J Physiol. 2006 Feb 15;571(Pt 1):201-10. doi: 10.1113/jphysiol.2005.102178. Epub 2005 Dec 15.
Mitochondrial fatty acid transport is a rate-limiting step in long chain fatty acid (LCFA) oxidation. In rat skeletal muscle, the transport of LCFA at the level of mitochondria is regulated by carnitine palmitoyltransferase I (CPTI) activity and the content of malonyl-CoA (M-CoA); however, this relationship is not consistently observed in humans. Recently, fatty acid translocase (FAT)/CD36 was identified on mitochondria isolated from rat and human skeletal muscle and found to be involved in LCFA oxidation. The present study investigated the effects of exercise (120 min of cycling at approximately 60% V(O2peak)) on CPTI palmitoyl-CoA and M-CoA kinetics, and on the presence and functional significance of FAT/CD36 on skeletal muscle mitochondria. Whole body fat oxidation rates progressively increased during exercise (P < 0.05), and concomitantly M-CoA inhibition of CPTI was progressively attenuated. Compared to rest, 120 min of cycling reduced (P < 0.05) the inhibition of 0.7, 2, 5 and 10 microM M-CoA by 16%, 21%, 30% and 34%, respectively. Whole body fat oxidation and palmitate oxidation rates in isolated mitochondria progressively increased (P < 0.05) during exercise, and were positively correlated (r = 0.78). Mitochondrial FAT/CD36 protein increased by 63% (P < 0.05) during exercise and was significantly (P < 0.05) correlated with mitochondrial palmitate oxidation rates at all time points (r= 0.41). However, the strongest (P < 0.05) correlation was observed following 120 min of cycling (r = 0.63). Importantly, the addition of sulfo-N-succimidyloleate, a specific inhibitor of FAT/CD36, reduced mitochondrial palmitate oxidation to approximately 20%, indicating FAT/CD36 is functionally significant with respect to LCFA oxidation. We hypothesize that exercise-induced increases in fatty acid oxidation occur as a result of an increased ability to transport LCFA into mitochondria. We further suggest that decreased CPTI M-CoA sensitivity and increased mitochondrial FAT/CD36 protein are both important for increasing whole body fatty acid oxidation during prolonged exercise.
线粒体脂肪酸转运是长链脂肪酸（LCFA）氧化的限速步骤。在大鼠骨骼肌中，线粒体水平上的LCFA转运受肉碱棕榈酰转移酶I（CPTI）活性和丙二酰辅酶A（M-CoA）含量的调节；然而，这种关系在人类中并不一致。最近，在从大鼠和人类骨骼肌分离出的线粒体上发现了脂肪酸转位酶（FAT）/CD36，并发现其参与LCFA氧化。本研究调查了运动（以约60%的最大摄氧量进行120分钟骑行）对CPTI棕榈酰辅酶A和M-CoA动力学，以及对骨骼肌线粒体上FAT/CD36的存在及其功能意义的影响。运动过程中全身脂肪氧化率逐渐增加（P<0.05），同时M-CoA对CPTI的抑制作用逐渐减弱。与静息状态相比，120分钟的骑行分别使0.7、2、5和10微摩尔M-CoA的抑制作用降低了16%、21%、30%和34%（P<0.05）。运动过程中，分离线粒体中的全身脂肪氧化和棕榈酸氧化率逐渐增加（P<0.05），且呈正相关（r = 0.78）。运动过程中线粒体FAT/CD36蛋白增加了63%（P<0.05），并且在所有时间点均与线粒体棕榈酸氧化率显著相关（P<0.05，r = 0.41）。然而，在120分钟骑行后观察到最强的相关性（P<0.05，r = 0.63）。重要的是，添加FAT/CD36的特异性抑制剂磺基-N-琥珀酰亚胺油酸酯后，线粒体棕榈酸氧化降低至约20%，表明FAT/CD36在LCFA氧化方面具有功能意义。我们假设运动诱导的脂肪酸氧化增加是由于将LCFA转运到线粒体中的能力增强所致。我们进一步认为，CPTI对M-CoA敏感性降低和线粒体FAT/CD36蛋白增加对于长时间运动期间增加全身脂肪酸氧化均很重要。
