Luckey Stephen W, Haines Chris D, Konhilas John P, Luczak Elizabeth D, Messmer-Kratzsch Antke, Leinwand Leslie A
1 Department of Molecular, Cellular and Developmental Biology and BioFrontiers Institute University of Colorado at Boulder, Boulder, CO 80309, USA.
2 Biology Department, Seattle University, Seattle, WA 98122, USA.
Exp Biol Med (Maywood). 2017 Dec;242(18):1820-1830. doi: 10.1177/1535370217731503. Epub 2017 Sep 13.
A number of signaling pathways underlying pathological cardiac hypertrophy have been identified. However, few studies have probed the functional significance of these signaling pathways in the context of exercise or physiological pathways. Exercise studies were performed on females from six different genetic mouse models that have been shown to exhibit alterations in pathological cardiac adaptation and hypertrophy. These include mice expressing constitutively active glycogen synthase kinase-3β (GSK-3βS9A), an inhibitor of CaMK II (AC3-I), both GSK-3βS9A and AC3-I (GSK-3βS9A/AC3-I), constitutively active Akt (myrAkt), mice deficient in MAPK/ERK kinase kinase-1 (MEKK1), and mice deficient in cyclin D2 (cyclin D2). Voluntary wheel running performance was similar to NTG littermates for five of the mouse lines. Exercise induced significant cardiac growth in all mouse models except the cyclin D2 mice. Cardiac function was not impacted in the cyclin D2 mice and studies using a phospho-antibody array identified six proteins with increased phosphorylation (greater than 150%) and nine proteins with decreased phosphorylation (greater than 33% decrease) in the hearts of exercised cyclin D2 mice compared to exercised NTG littermate controls. Our results demonstrate that unlike the other hypertrophic signaling molecules tested here, cyclin D2 is an important regulator of both pathologic and physiological hypertrophy. Impact statement This research is relevant as the hypertrophic signaling pathways tested here have only been characterized for their role in pathological hypertrophy, and not in the context of exercise or physiological hypertrophy. By using the same transgenic mouse lines utilized in previous studies, our findings provide a novel and important understanding for the role of these signaling pathways in physiological hypertrophy. We found that alterations in the signaling pathways tested here had no impact on exercise performance. Exercise induced cardiac growth in all of the transgenic mice except for the mice deficient in cyclin D2. In the cyclin D2 null mice, cardiac function was not impacted even though the hypertrophic response was blunted and a number of signaling pathways are differentially regulated by exercise. These data provide the field with an understanding that cyclin D2 is a key mediator of physiological hypertrophy.
已经确定了一些病理性心脏肥大背后的信号通路。然而，很少有研究在运动或生理通路的背景下探究这些信号通路的功能意义。对来自六种不同基因小鼠模型的雌性小鼠进行了运动研究，这些模型已被证明在病理性心脏适应和肥大方面表现出改变。其中包括组成型活性糖原合酶激酶-3β（GSK-3βS9A）的表达小鼠、CaMK II抑制剂（AC3-I）、GSK-3βS9A和AC3-I（GSK-3βS9A/AC3-I）、组成型活性Akt（myrAkt）、缺乏丝裂原活化蛋白激酶/细胞外信号调节激酶激酶激酶-1（MEKK1）的小鼠以及缺乏细胞周期蛋白D2（细胞周期蛋白D2）的小鼠。对于其中五个小鼠品系，自愿轮转跑步表现与野生型同窝小鼠相似。除细胞周期蛋白D2小鼠外，运动在所有小鼠模型中均诱导了显著的心脏生长。细胞周期蛋白D2小鼠的心脏功能未受影响，并且使用磷酸化抗体阵列的研究发现，与运动的野生型同窝对照相比，运动的细胞周期蛋白D2小鼠心脏中有六种蛋白磷酸化增加（大于150%），九种蛋白磷酸化减少（大于33%）。我们的结果表明，与这里测试的其他肥大信号分子不同，细胞周期蛋白D2是病理性和生理性肥大的重要调节因子。影响声明 本研究具有相关性，因为这里测试的肥大信号通路仅因其在病理性肥大中的作用而被表征，而非在运动或生理性肥大的背景下。通过使用先前研究中使用的相同转基因小鼠品系，我们的发现为这些信号通路在生理性肥大中的作用提供了新的重要理解。我们发现这里测试的信号通路改变对运动表现没有影响。除缺乏细胞周期蛋白D2的小鼠外，运动在所有转基因小鼠中均诱导了心脏生长。在细胞周期蛋白D2基因敲除小鼠中，尽管肥大反应减弱且许多信号通路受运动的差异调节，但心脏功能未受影响。这些数据使该领域了解到细胞周期蛋白D2是生理性肥大的关键介质。
