Mechanical control of energy metabolism in cardiomyocytes

跳动的心脏通过对血液动力学变化做出反应来维持持续的循环，例如改变血压和心率。例如，为了适应高血压，心肌细胞必须产生更多的ATP来收缩，即使在高机械过载下也是如此。为了探索机械刺激和能量补偿之间的功能联系，我们搜索了对机械力做出反应的因素，并找到了一种转录辅助激活因子，它可以在物理力的作用下从细胞质穿梭到细胞核。这种共激活剂有力地激活核受体，在跳动的心肌细胞中调节脂质代谢。因此，这种共激活剂通过增强线粒体中的氧化磷酸化(OxPhos)来增加ATP的产生。我们的发现为能量适应机制提供了重要和新颖的见解，在这种机制中，可以找到治疗心脏疾病的药物靶点，如心力衰竭。

Beating heart maintains constant circulation by responding to hemodynamics changes, such as altering blood pressure and heart rate. To adapt to high blood pressure, for example, cardiomyocytes must produce more ATP to contract even under the high mechanical overload. To explore a functional link between mechanical stimuli and energetic compensation, we searched for factors that respond to mechanical forces, and found a transcriptional co-activator that shuttles from cytoplasm to nucleus in response to physical force. This co-activator robustly activates nuclear receptors that regulate lipid metabolism in beating cardiomyocytes. As a result, this co-activator increases ATP production by enhancing oxidative phosphorylation (OxPhos) in mitochondria. Our finding provides an essential and novel insight on the energetic adaptation mechanism, in which drug targets can be found for therapy of heart diseases, such as heart failure.