Folmes Karalyn D, Chan Anita Y M, Koonen Debby P Y, Pulinilkunnil Thomas C, Baczkó István, Hunter Beth E, Thorn Stephanie, Allard Michael F, Roberts Robert, Gollob Michael H, Light Peter E, Dyck Jason R B
Cardiovascular Research Centre, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, Alberta, Canada.
Circ Cardiovasc Genet. 2009 Oct;2(5):457-66. doi: 10.1161/CIRCGENETICS.108.834564. Epub 2009 Jul 15.
Humans with an R302Q mutation in AMPKgamma(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 AMPKgamma(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.
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 AMPKgamma(2) subunit (TGgamma(2)WT) or the mutated form (TGgamma(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 TGgamma(2)R302Q mice, likely in response to the existing 37-fold increase in glycogen. Interestingly, gamma(2)WT expression has similar, yet less marked effects than gamma(2)R302Q expression in both cardiomyocytes and hearts.
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.
携带AMPKγ(2)（PRKAG2基因）R302Q突变的人类会患糖原贮积性心肌病，其特征为家族性预激综合征和心脏肥大。在心肌细胞特异性表达AMPKγ(2)R302Q的转基因小鼠中也出现了这种表型。尽管关于γ(2)R302Q突变的后果已有相当多的信息，但对于导致这种心肌病发生的早期信号事件却知之甚少。
为了区分γ(2)R302Q表达的直接作用与信号传导后期的代偿性改变，我们使用了表达野生型AMPKγ(2)亚基（TGγ(2)WT）或突变形式（TGγ(2)R302Q）的转基因小鼠，并在新生大鼠心肌细胞中急性表达这些蛋白。尽管γ(2)R302Q的急性表达会诱导AMPK激活以及糖原合酶和AS160上调，同时糖原含量增加，但TGγ(2)R302Q小鼠心脏中的AMPK活性、糖原合酶活性和AS160表达降低，这可能是对已存在的糖原增加37倍的反应。有趣的是，γ(2)WT表达在心肌细胞和心脏中具有与γ(2)R302Q表达相似但不太明显的作用。
通过使用γ(2)R302Q表达的急性和慢性模型，我们区分了γ(2)R302Q突变的直接作用与最终的代偿性改变。我们的数据表明，γ(2)R302Q的表达诱导AMPK激活以及糖原含量最终增加，这一发现在转基因成年小鼠的心脏中被掩盖。这些发现首次突出了PRKAG2 R302Q突变对心脏代谢信号事件影响的时间差异。
