Pyruvate suppresses PGC1alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes.
Pyruvate suppresses PGC1alpha expression and substrate utilization despite increased respiratory chain content in C2C12 myotubes.
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DOI：
10.1152/ajpcell.00438.2009
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发表时间：
2010-08
期刊：
影响因子：
--
通讯作者：
Baar K
中科院分区：
文献类型：
--
作者：
Philp A;Perez-Schindler J;Green C;Hamilton DL;Baar K
丙酮酸钠可通过非依赖的方式促进C2C12成肌细胞线粒体的生物合成，这种作用不依赖于过氧化物酶体增殖物激活受体-γ辅活化子-1α(Pgc1α)。本研究以丙酮酸钠(5-50 mM)或氯化钠(50 MM)作为渗透压对照，观察72小时对C2C12肌管线粒体底物代谢和生物发生的调节作用。丙酮酸(50 MM)增加脂肪酸氧化酶(CD36，61%，β氧化酶3-羟基酰辅酶A脱氢酶，54%)的水平，以及细胞色素-c氧化酶I(220%)和细胞色素c(228%)的表达，与先前描述的促进线粒体生物发生的作用一致。相反，丙酮酸处理降低了葡萄糖转运蛋白4(42%)、磷酸果糖激酶(57%)和前列环素α(72%)蛋白含量以及前列环素α(48%)和前列环素β(122%)。Pgc1α的减少被Pgc1α相关辅活化子(PRC；187%)的增加所抵消。丙酮酸治疗降低了基础和胰岛素刺激的葡萄糖摄取(分别为41%和31%)以及棕榈酸酯的摄取和氧化(分别为24%和31%)。加入丙酮酸脱氢酶激动剂二氯乙酸酯和三氯乙酸谷氨酰胺后，Pgc1α的表达增加(368%)，Pc1的表达恢复到基础水平。添加DCA和谷氨酰胺，葡萄糖摄取量增加4.2倍，棕榈酸摄取量增加18%。伴随着这种适应，耗氧量增加了80%。这些数据表明，尽管生物发生有限，超生理剂量的丙酮酸会降低线粒体的功能，而抗性剂可以逆转这种影响。
Sodium pyruvate can increase mitochondrial biogenesis in C2C12 myoblasts in a peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α)-independent manner. The present study examined the effect of 72-h treatment with sodium pyruvate (5–50 mM) or sodium chloride (50 mM) as an osmotic control on the regulation of mitochondrial substrate metabolism and biogenesis in C2C12 myotubes. Pyruvate (50 mM) increased the levels of fatty acid oxidation enzymes (CD36, 61%, and β-oxidative enzyme 3-hydroxyacyl-CoA dehydrogenase, 54%) and the expression of cytochrome-c oxidase subunit I (220%) and cytochrome c (228%), consistent with its previous described role as a promoter of mitochondrial biogenesis. However, in contrast, pyruvate treatment reduced glucose transporter 4 (42%), phosphofructokinase (57%), and PGC1α (72%) protein content as well as PGC1α (48%) and PGC1β (122%) mRNA. The decrease in PGC1α was compensated for by an increase in the PGC1α-related coactivator (PRC; 187%). Pyruvate treatment reduced basal and insulin-stimulated glucose uptake (41% and 31%, respectively) and palmitate uptake and oxidation (24% and 31%, respectively). The addition of the pyruvate dehydrogenase activator dichloroacetate (DCA) and the TCA precursor glutamine increased PGC1α expression (368%) and returned PRC expression to basal. Glucose uptake increased by 4.2-fold with DCA and glutamine and palmitate uptake increased by 18%. Coupled to this adaptation was an 80% increase in oxygen consumption. The data suggest that supraphysiological doses of pyruvate decrease mitochondrial function despite limited biogenesis and that anaplerotic agents can reverse this effect.
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DOI：
10.1042/bj20091372
发表时间：
2010-01-27
期刊：
The Biochemical journal
影响因子：
--
作者：
Fogarty S;Hawley SA;Green KA;Saner N;Mustard KJ;Hardie DG
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