Bergersen L H, Thomas M, Jóhannsson E, Waerhaug O, Halestrap A, Andersen K, Sejersted O M, Ottersen O P
Centre for Molecular Biology and Neuroscience, and Department of Anatomy, IMB, University of Oslo, POB 1105 Blindern, N-0317 Oslo, Norway.
Neuroscience. 2006;138(4):1105-13. doi: 10.1016/j.neuroscience.2005.12.014. Epub 2006 Jan 30.
The monocarboxylate transporters 1 and 4 are expressed in brain as well as in skeletal muscle and play important roles in the energy metabolism of both tissues. In brain, monocarboxylate transporter 1 occurs in astrocytes, ependymocytes, and endothelial cells while monocarboxylate transporter 4 appears to be restricted to astrocytes. In muscle, monocarboxylate transporter 1 is enriched in oxidative muscle fibers whereas monocarboxylate transporter 4 is expressed in all fibers, with the lowest levels in oxidative fiber types. The mechanisms regulating monocarboxylate transporter 1 and monocarboxylate transporter 4 expression are not known. We hypothesized that the expression of these transporters would be sensitive to long term changes in metabolic activity level. This hypothesis can be tested in rat skeletal muscle, where permanent changes in activity level can be induced by cross-reinnervation. We transplanted motor axons originally innervating the fast-twitch extensor digitorum longus muscle to the slow-twitch soleus muscle and vice versa. Four months later, microscopic analysis revealed transformation of muscle fiber types in the cross-reinnervated muscles. Western blot analysis showed that monocarboxylate transporter 1 was increased by 140% in extensor digitorum longus muscle and decreased by 30% in soleus muscle after cross-reinnervation. In contrast, cross-reinnervation induced a 62% decrease of monocarboxylate transporter 4 in extensor digitorum longus muscle and a 1300% increase in soleus muscle. Our findings show that cross-reinnervation causes pronounced changes in the expression levels of monocarboxylate transporter 1 and monocarboxylate transporter 4, probably as a direct consequence of the new pattern of nerve impulses. The data indicate that the mode of innervation dictates the expression of monocarboxylate transporter proteins in the target cells and that the change in monocarboxylate transporter isoform profile is an integral part of the muscle fiber transformation that occurs after cross-reinnervation. Our findings support the hypothesis that the expression of monocarboxylate transporter 1 and monocarboxylate transporter 4 in excitable tissues is regulated by activity.
单羧酸转运蛋白1和4在大脑以及骨骼肌中均有表达，且在这两种组织的能量代谢中发挥重要作用。在大脑中，单羧酸转运蛋白1存在于星形胶质细胞、室管膜细胞和内皮细胞中，而单羧酸转运蛋白4似乎仅限于星形胶质细胞。在肌肉中，单羧酸转运蛋白1在氧化型肌纤维中富集，而单羧酸转运蛋白4在所有纤维中均有表达，在氧化型纤维类型中表达水平最低。调节单羧酸转运蛋白1和单羧酸转运蛋白4表达的机制尚不清楚。我们推测这些转运蛋白的表达会对代谢活动水平的长期变化敏感。这一假设可在大鼠骨骼肌中进行验证，在那里可通过交叉神经支配诱导活动水平的永久性变化。我们将原本支配快肌趾长伸肌的运动轴突移植到慢肌比目鱼肌，反之亦然。四个月后，显微镜分析显示交叉神经支配的肌肉中肌纤维类型发生了转变。蛋白质印迹分析表明，交叉神经支配后，趾长伸肌中的单羧酸转运蛋白1增加了140%，比目鱼肌中的单羧酸转运蛋白1减少了30%。相比之下，交叉神经支配导致趾长伸肌中的单羧酸转运蛋白4减少了62%，比目鱼肌中的单羧酸转运蛋白4增加了1300%。我们的研究结果表明，交叉神经支配会导致单羧酸转运蛋白1和单羧酸转运蛋白4的表达水平发生显著变化，这可能是新神经冲动模式的直接结果。数据表明，神经支配模式决定了靶细胞中单羧酸转运蛋白的表达，且单羧酸转运蛋白异构体谱的变化是交叉神经支配后发生的肌纤维转变的一个组成部分。我们的研究结果支持这样的假设，即可兴奋组织中单羧酸转运蛋白1和单羧酸转运蛋白4的表达受活动调节。
