Role of Monocarboxylate Transporter in Statin-induced Cytotoxicity

被引:2
|
作者
Kobayashi, Masaki [1 ]
机构
[1] Hokkaido Univ, Fac Pharmaceut Sci, Lab Clin Pharmaceut & Therapeut, Kita Ku, Sapporo, Hokkaido 0600812, Japan
关键词
monocarboxylate transporter 4; HMG-CoA reductase inhibitor; cytotoxicity; SKELETAL-MUSCLE; INDUCED APOPTOSIS; LACTIC-ACID; CELLS; EXPRESSION; MECHANISM; ACTIVATION; EXERCISE; MYOPATHY; LACTATE;
D O I
10.1248/yakushi.15-00199
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
Although exercise and drug therapy are important to prevent progression of arteriosclerotic disease, exercise leads to an increase in muscular disorder induced by HMG-CoA reductase inhibitors (statins). Elucidation of this mechanism is needed to prevent the occurrence of muscular disorders. Since exercise induces expression of monocarboxylate transporter (MCT) 4, we focused on the association between MCT4 function and statin-induced muscle injury. First, we examined the transport of L-lactate via MCT4 using MCT4 cRNA-injected Xenopus laevis oocytes. L-lactate uptake by MCT4-expressing oocytes was markedly reduced by alkalizing the buffer pH and saturated at higher L-lactate concentrations. On the other hand, AMP-activated protein kinase (AMPK) and protein kinase C (PKC) are activated by exercise. We next examined whether AMPK and PKC activation affects the expression and function of MCT4 in rat skeletal muscle and RD cells as an in vitro skeletal muscle model. AMPK and PKC activation increased MCT4 expression level and lactate efflux by MCT4. Finally, we examined the association between MCT4 function and statin-induced cytotoxicity. Statins inhibited transport of L-lactate via MCT4 in a concentration-dependent manner. Statin-induced cytotoxicity was associated with intracellular acidification and caspase-3/7 activation. On the other hand, bicarbonate suppressed statin-induced pH alteration, caspase activation, and morphological change. The results suggest that statin-induced muscle injury exacerbated by exercise is associated with intracellular acidification and that the effects of statins on L-lactate transport are mediated by MCT4.
引用
收藏
页码:1227 / 1233
页数:7
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