In mice reprogramming of energy metabolism restores cardiac function after infarction
重新編碼小鼠中的能量代謝指令序列，於梗塞後恢了復心臟功能。
After birth, the human heart loses its regenerative capacity almost completely. Damage to the heart muscle, e.g. due to a heart attack, therefore usually leads to a permanent loss of function in adults.
於出生後，人類心臟幾乎完全喪失再生能力。譬如，由於心臟病發作，對心肌造成損傷。因此，通常於諸多成人中，導致永久性功能喪失。
Scientists from the Max Planck Institute for Heart and Lung Research have now shown for the first time in mice that a change in the energy metabolism of heart muscle cells enables heart regeneration. In the animals, heart function could thus be restored to a large extent after a heart attack. The study is groundbreaking and could enable completely new therapeutic approaches.
目前，來自德國馬克斯普朗克心肺研究所的科學家們，在小鼠中，已經首度證實，於心肌細胞能量代謝上的改變，能使心臟再生。在動物中，心臟病發作後，因此心臟功能，可能大程度被恢復。該項研究具開創性，因此可能完全實現，新的治療方法。
圖1. 在具有Cpt1b基因不活躍的小鼠中，在梗塞後，心臟能再生。
In mice with an inactive Cpt1b gene, the heart can regenerate after an infarction.
Shortly after birth, the human heart largely loses its ability to repair itself in the event of damage. Injuries or diseases of the heart muscle therefore lead to permanent damage and a reduction in heart function. The loss of regenerative capacity is due, among other things, to the loss of the ability of heart muscle cells to divide after birth.
出生後不久，在受損事件進程中，人類的心臟大部分喪失自行修復能力。因此，心肌損傷或疾病會導致，永久性損傷及心臟功能下降。喪失再生能力的其他問題中，是由於在出生後，喪失心肌細胞分裂能力。
This is accompanied by a fundamental change in the energy metabolism of the heart cells: Instead of obtaining energy from sugars, which is known as glycolysis, the heart muscle cells now obtain their energy largely from fats. This form of energy production is known as fatty acid oxidation.
這伴隨著，心臟細胞能量代謝的一種根本改變：現在心肌細胞大部分，從脂肪獲取能量，而不是從被通稱為糖解的糖獲取能量。這種能量產生的方式，被通稱為脂肪酸氧化。
The research group led by Thomas Braun, Director at the Max Planck Institute for Heart and Lung Research in Bad Nauheim, Germany, started looking for new methods to promote heart regeneration:
該由德國馬克斯普朗克心肺研究所(位於徳國巴特瑙海姆市鎮)所長，Thomas Braun領導的研究團隊開始找尋了，促進心臟再生的新方法：
"It is known that animal species capable of regenerating their hearts primarily use sugars and glycolysis as fuel for heart muscle cells. The human heart also primarily uses glycolysis in early stages of development, but then switches to fatty acid oxidation because it can produce more energy," explain Xiang Li and Xuejun Yuan, authors of the study. "With the switch in energy production after birth, the activity of many genes changes and cell division activity is lost.
該項研究撰文人，Xiang Li及Xuejun Yuan解釋：「眾所周知，能再生心臟的動物物種，主要使用糖及糖解，作為心肌細胞的養料。在發育初期階段中，人類心臟主要也使用糖解。不過，之後轉向脂肪酸氧化。因為，它可以產生更多能量。於出生後，隨著能量產生上的轉變，許多基因的活性發生改變，結果喪失細胞分裂活力。
Individual metabolites from energy production also have important functions for the activity of enzymes that regulate gene activities. We therefore hoped to trigger changes in gene activities by reprogramming energy metabolism to turn cell division ability back on in cardiac muscle cells."
來自能量生產的各個代謝產物，對於調節基因活性的酵素活性，也具有諸多重要功能。因此我們期盼，藉由重新編碼能量新陳代謝指令序列，以觸發在基因活性上的改變，來重新開啟心肌細胞的細胞分裂能力。」
To do this, the Max Planck researchers first inactivated a gene called Cpt1b, which is essential for fatty acid oxidation, in mice. "We then observed that hearts in these mice started to grow again," Li explains. Over the course of the experiment, cell numbers in the hearts of these mice nearly doubled.
為此，馬克斯普朗克的研究人員們首先鈍化了，於小鼠中一種，對於脂肪酸氧化至關重要，被稱為Cpt1b的基因。Li解釋：「之後，我們觀察到，於此些老鼠中的心臟，再次開始生長。」在此實驗過程中，於此些小鼠的心臟中，細胞數量幾乎倍增。
In the next step, the Bad Nauheim researchers triggered heart attacks in mice in which Cpt1b was switched off. In the chosen approach, a phase of lack of blood flow to the heart is followed by a reperfusion phase, in which the heart is flushed again with oxygenated blood.
在接下一來的步驟中，於徳國巴特瑙海姆市鎮(Bad Nauheim)的研究人員們，在Cpt1b被關閉的小鼠中，誘發了心臟病發作。在該被選擇的方法中，心臟血流不足階段，之後是再灌注階段。在此階段，心臟再次湧流充氧的血液。
"This model is comparable to a cardiac patient whose heart is treated with the insertion of a stent due to an occlusion of the coronary arteries," Yuan explains. The effect was impressive: otherwise common scars in the heart muscle were barely noticeable after weeks, and contractility in animals without Cpt1b almost returned to pre-infarction levels.
Yuan解釋：「該模型類似心臟病患者，由於冠狀動脈阻塞，其心臟經由使用插入支架的治療。」此效果令人印象深刻：除此之外，於幾週後，在心肌中常見的疤痕幾乎不明顯，且在沒有Cpt1b 之動物中的收縮力，幾乎恢復到梗塞前的水平。
In further studies, the scientists were able to decipher the underlying mechanism: "In heart muscle cells of the mice with the inactivated gene, we found a twenty-fold increased level of alpha-ketoglutarate. The high level of this metabolite leads to a significant increase in the activity of the enzyme KDM5," Braun explains.
在諸多進一步的研究中，此些科學家能破解潛在的機制：Braun解釋：「在此些具上述鈍化之基因小鼠的心肌細胞中，我們發現了，α-酮戊二酸的含量增加二十倍。這種代謝產物的高水平，導致了在KDM5酶的活性上，顯著增加。」
This enzyme is a so-called histone demethylase, which removes methyl groups from histones and thus reduces the activity of various genes. The change in gene activity causes cardiac muscle cells to become immature and thus regain the ability to regenerate.
此酶是一種，從組蛋白移除甲基，從而降低各種基因活性，所謂的組蛋白去甲基化酶。此基因活性的變化，導致心肌細胞變得不成熟，因此重新獲得再生能力。
Braun sees the study as a real breakthrough: "By reprogramming the metabolism, we double the number of heart muscle cells, and after an infarction, heart function is almost completely restored."
Braun認為，該研究是一項真正的突破：「藉由重新編碼新陳代謝的指令序列，我們倍增了心肌細胞的數量，且在梗塞後，幾乎完全恢復心臟功能。」
In addition, it is possible in principle to pharmacologically block the activity of the enzyme CPT1B -the gene product of Cpt1b. The development of an inhibitor that can be used to affect the activity of the CPT1B enzyme is the next step on the road to developing a therapy that may eventually be used in humans.
此外基本上，從藥理學上阻斷CPT1B酶(Cpt1b的基因產物)的活性，這是可能的。開發一種能被用來影響CPT1B酶活性之抑制劑的開發，是在開發一種，最終可能被用於人類療法道路上的下一步。
However, Yuan and Braun emphasize, "We still have a long way to go before reliable treatments in humans become possible. The implementation of new findings from basic research is lengthy and expensive and is often accompanied by many unexpected problems. Nevertheless, we are confident that we will be able to therapeutically stimulate the regenerative capacity of the heart in the future."
不過，Yuan及Braun強調：「在於人類的可靠治療法成為可能之前，我們仍有漫長的路。來自基礎研究之新發現的實行，是漫長且花費高昂的。因此經常伴隨諸多意想不到的問題。儘管如此，我們有信心，於未來將能治療性刺激心臟的再生能力。」
網址：https://www.mpg.de/20981292/1020-pfor-cardiac-regeneration-becomes-possible-through-reprogramming-of-cell-metabolism-149770-x?c=2249
翻譯：許東榮
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