Distinct Early Signaling Events Resulting From the Expression of the PRKAG2 R302Q Mutant of AMPK Contribute to Increased Myocardial Glycogen
Distinct Early Signaling Events Resulting From the Expression of the PRKAG2 R302Q Mutant of AMPK Contribute to Increased Myocardial Glycogen
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DOI：
10.1161/circgenetics.108.834564
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发表时间：
2009-10-01
影响因子：
--
通讯作者：
Dyck, Jason R. B.
中科院分区：
文献类型：
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作者：
Folmes, Karalyn D.;Chan, Anita Y. M.;Dyck, Jason R. B.
背景-AMPK γ 2（PRKAG 2基因）R302 Q突变的人发生糖原累积性心肌病，其特征为家族性Wolff-Parkinson-白色综合征和心脏肥大。这种表型在心肌细胞限制性表达AMPK γ（2）R302 Q的转基因小鼠中重现。尽管关于携带γ（2）R302 Q突变的后果已知相当多的信息，但是对于导致这种心肌病发展的早期信号传导事件知之甚少。方法和结果-为了区分γ（2）R302 Q表达的直接作用与信号传导中的后期代偿性改变，我们使用表达野生型AMPK γ 2亚基（TG γ 2 WT）或突变形式（TG γ 2 R302 Q）的转基因小鼠，并结合这些蛋白质在新生大鼠心肌细胞中的急性表达。尽管γ（2）R302 Q的急性表达诱导AMPK活化和糖原合酶和AS 160的上调，伴随糖原含量的相关增加，但在TG γ（2）2 R302 Q小鼠的心脏中，AMPK活性、糖原合酶活性和AS 160表达降低，这可能是对糖原增加37倍的响应。有趣的是，gamma 2 WT的表达与gamma（2）R302 Q在心肌细胞和hearts.Conclusions-Using急性和慢性模型的gamma（2）R302 Q表达有相似的，但不太明显的影响，我们已经区分了gamma（2）R302 Q突变的直接影响和最终的代偿性修饰。我们的数据表明，γ（2）R302 Q的表达诱导AMPK激活和糖原含量的最终增加，这一发现在转基因成年小鼠的心脏中被掩盖。这些发现首次强调了PRKAG 2 R302 Q突变对心脏代谢信号事件影响的时间差异。(Circ Genet. 2009;2：457-466）。
Background-Humans with an R302Q mutation in AMPK gamma(2) (the PRKAG2 gene) develop a glycogen storage cardiomyopathy characterized by a familial form of Wolff-Parkinson-White syndrome and cardiac hypertrophy. This phenotype is recapitulated in transgenic mice with cardiomyocyte-restricted expression of AMPK gamma(2)R302Q. Although considerable information is known regarding the consequences of harboring the gamma(2)R302Q mutation, little is known about the early signaling events that contribute to the development of this cardiomyopathy.Methods and Results-To distinguish the direct effects of gamma(2)R302Q expression from later compensatory alterations in signaling, we used transgenic mice expressing either the wild-type AMPK gamma(2) subunit (TG gamma 2WT) or the mutated form (TG gamma(2)R302Q), in combination with acute expression of these proteins in neonatal rat cardiomyocytes. Although acute expression of gamma(2)R302Q induces AMPK activation and upregulation of glycogen synthase and AS160, with an associated increase in glycogen content, AMPK activity, glycogen synthase activity, and AS160 expression are reduced in hearts from TG gamma(2)2R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, gamma 2WT expression has similar, yet less marked effects than gamma(2)R302Q expression in both cardiomyocytes and hearts.Conclusions-Using acute and chronic models of gamma(2)R302Q expression, we have differentiated the direct effects of the gamma(2)R302Q mutation from eventual compensatory modifications. Our data suggest that expression of gamma(2)R302Q induces AMPK activation and the eventual increase in glycogen content, a finding that is masked in hearts from transgenic adult mice. These findings are the first to highlight temporal differences in the effects of the PRKAG2 R302Q mutation on cardiac metabolic signaling events. (Circ Cardiovasc Genet. 2009;2:457-466.)