乳酸摄取机制可能会给受伤的大脑提供燃料

Lactate-uptake mechanism may fuel the injured brain

 

 

乳酸穿梭是大自然做事情的方式。

 

 

 

乔治·布鲁克斯(George Brooks)是一名综合生物学教授。

同样的帮助运动员在跑步机上发展耐力的基本生物学机制,可能有一天被医生应用在重症监护病房保护和改善创伤性脑损伤患者的生活,据由乔治·布鲁克斯,一位教授在加州大学伯克利分校的综合生物学、与在神经外科学系加州大学的洛杉矶分校的同事合作的研究。

 

布鲁克斯是代谢调节领域的权威,发展了乳酸穿梭(Lactate Shuttle Theory)理论,这是一种基本的生物机制,它允许肌肉通过“穿梭”在细胞内和细胞之间的转运蛋白来吸收乳酸。在肌肉和其他细胞内的线粒体网-细胞内的能量工厂使用乳酸作为燃料。随着持续的训练,线粒体质量的增加,燃烧乳酸的效率更高。

 

布鲁克斯说,事实证明,最近的研究表明,这一过程并不仅仅局限于肌肉组织。

 

他说:“我们在肌肉中看到的同样的乳酸转运体,通过运动训练改变了它们的表达方式,同样也出现在大脑中同样的代谢途径中。” “乳酸穿梭在大脑中发生

 

当布鲁克斯近40年前开始他在乳酸代谢领域的开创性研究时,他无法预见到他的工作的深远应用。上世纪60年代,作为皇后学院(Queens College)的田径运动员 布鲁克斯在他的颇具争议的博士论文中,挑战了有关乳酸的传统智慧。布鲁克斯证明,对运动员来说,乳酸远不是有毒的代谢废物-毒害他们的肌肉,乳酸被肌肉大量摄入作为有效的能量来源。

 

 

图示:乔治·布鲁克斯教授()和他的团队在运动生理学实验室监测一名学生志愿者参与了一项在剧烈运动期间乳酸代谢的研究。

 

在接下来的几十年里,布鲁克斯继续他在加州大学伯克利分校的运动生理学实验室的研究。在这里,他研究了乳酸的形成和清除的途径,在运动中和运动后,在2006年提出了乳酸穿梭理论(Lactate Shuttle Theory)

 

 

在他与加州大学洛杉矶分校(UCLA)的三年合作中,布鲁克斯正在考虑在脑损伤后关键的几个小时内使用乳酸作为大脑的有效替代燃料,当大脑使用葡萄糖(被认为是大脑能量的主要来源)的能力被抑制时。

 

布鲁克斯和他的同事在加州大学洛杉矶分校对38名创伤性脑损伤患者进行了追踪研究,以测量进入和离开大脑的乳酸含量。科学家们将这种乳酸与C13(一种非放射性同位素)标记在一起,并将其添加到含有异丙肾上腺素的静脉注射液中,这是一种合成的肾上腺素,用于支持病人虚弱的心血管系统。

 

他们发现,在受伤后的第一个到1214个小时内,大脑由于缺乏葡萄糖而摄入乳酸。事实上,它更喜欢它,布鲁克斯说。当血乳酸上升时,大脑停止使用葡萄糖,撤换到乳酸。当这种情况发生时,病人的情况改善。

 

问题是,为什么? 布鲁克斯推测,大脑更有效地利用乳酸来产生能量来康复。他指着大脑中的星形细胞(Astrocyte)-大脑中一种星形的细胞。他们的职责是吸收葡萄糖并把神经元(Neurons)浸泡乳酸盐中。神经元依赖乳酸运行。这是乳酸穿梭,同样的术语。

 

 

 

 

一旦布鲁克斯能够证明这种乳酸穿梭可以用来绕过大脑中葡萄糖代谢的堵塞,他将寻求用乳酸盐和酯类化合物支持那些受伤人员的大脑。

 

他说:“在外伤性损伤中,存在着代谢缺陷。”“如果我们能帮助大脑新陈代谢,也许这些人就能挺过来。

 

然而,进行这样的研究是极其困难的,因为目前能接触的患者是有限的。由于潜在的研究对象是昏迷的,他们刚刚遭受了潜在的危及生命的脑损伤,他们的家人需要在最糟糕的时间里得到许可使用乳酸标记物。布鲁克斯说,因此,他们进行研究的能力是偶然的,尤其是考虑到目前对患者没有直接的益处。

 

加州大学伯克利分校和加州大学洛杉矶分校的医学委员会将不得不允许我们用乳酸盐来补充这些人。只有这样,广泛的应用才会出现。”Brooks说。他补充说,为了实现这一目标,我们需要在受伤的大脑中显示积极但抑制的新陈代谢,我们可以控制乳酸的传递,以促进康复过程。

 

如果他们成功了,这项研究将会对病人在遭受毁灭性的脑损伤后的关键时刻如何在急诊室治疗,并希望对他们的生存率和恢复能力有深远的影响。

 

加州大学伯克利分校的合作只是加州大学伯克利分校和其他依赖乳酸穿梭机制的研究项目之一。例如,布鲁克斯集团的一名研究生Rajaa Hussien正在研究癌症肿瘤内的乳酸穿梭,希望能有选择性地杀死癌细胞,同时保持健康的组织完好无损。伯克利化学工程的宋李教授正在用乳酸支架作为培养干细胞的基础。因此,比起20世纪20年代的观点,运动中的肌肉制造并释放一种代谢毒素,这些运动肌肉产生一种物质,乳酸,它有几个有益的功能,其中之一是作为重要的能量来源。

 

尽管布鲁克斯承认,在他开始他的乳酸研究时,他从未考虑过这些广泛的应用,但他并不惊讶于运动生理学方面研究的广度。

 

他说:乳酸穿梭是大自然做事情的方式。

 

Lactate-uptake mechanism may fuel the injured brain

 

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November 22, 2010

By: Monica Friedlander, College of Letters & Science

George Brooks is a professorof integrative biology. (George Brooks)

The same fundamental biological mechanism that helps athletes develop endurance on a treadmill may someday be tapped into by doctors in intensive care units to save and improve the lives of patients with traumatic brain injuries, according to research being conducted by George Brooks, a professor in UC Berkeley’s Department of Integrative Biology, in collaboration with colleagues in the Department of Neurosurgery at the University of California, Los Angeles.

 

An authority in the area of metabolic adjustment to exercise, Brooks developed the lactate shuttle theory, a fundamental biological mechanism that allows muscles to take up lactate via transporter proteins that “shuttle” lactate within and between cells. Inside muscle and other cells is the mitochondrial reticulum, the intracellular energy factory that uses the lactate as fuel. With sustained training, mitochondrial mass increases, burning lactate more efficiently for energy.

 

As it turns out, Brooks says, more recent research demonstrated that the process is not restricted to muscle tissue only.

 

The same lactate transporters that we see in muscle, that change their expression with exercise training, also appear in the brain in the same kind of metabolic pathway,” he says. “The lactate shuttle occurs in the brain.”

 

When Brooks embarked on his pioneering research in the area of lactate metabolism nearly 40 years ago, he could not have foreseen the far-reaching applications of his work. A track runner at Queens College in the 1960s, he challenged the conventional wisdom about lactate in his controversial Ph.D. dissertation. Far from being a bane for athletes, poisoning their muscles with waste product, lactate is devoured by muscle as an efficient energy source, Brooks demonstrated.

 

 

 

 

Professor George Brooks (r) and his team in the Exercise Physiology Laboratory monitor a student volunteer participating in a study of lactate metabolism during intense exercise. (George Brooks)

In the decades that followed, Brooks has continued his research in his Exercise Physiology Laboratory at UC Berkeley. Here he looked at pathways for lactate formation and removal before, during and after exercise and came up with the lactate shuttle theory in 2006.

 

In his three-year-old collaboration with UCLA, Brooks is considering using lactate as an efficient replacement fuel for the brain in the crucial hours following a traumatic brain injury, when the brain’s ability to use glucose — considered the primary source of energy for the brain – is suppressed.

 

Brooks and his colleagues conducted tracer-based studies on 38 patients with traumatic brain injuries at UCLA in order to measure the amount of lactate entering and leaving their brains. The scientists labeled the lactate with C13, a non-radioactive isotope and added it to the IV solution containing isoproterenol, a synthetic epinephrine supplied to support patients’ weakened cardiovascular systems.

 

What they found is that during the first to 12 to 14 hours after the injury, the brain, starved for glucose, takes up lactate. “In fact, it prefers it,” Brooks says. “When blood lactate rises, the brain stops using glucose and switches to lactate. And when that happens, the patients do better.”

 

The question is, why? Brooks hypothesizes that the brain uses lactate more efficiently to generate energy for recovery. He points to astrocytes, star-shaped cells in the brain. “Their job is to take up glucose and bathe the neurons in lactate. And the neurons run on lactate. That’s the lactate shuttle again — the same term.”

 

Once Brooks can demonstrate that this lactate shuttle can be used to bypass the blockage of glucose metabolism in the brain, he will seek to support the brains of injured people with various lactate compounds, such as lactate salts and esters.

 

In traumatic injuries, there is this metabolic deficit,” he says. “If we can help support the brain metabolically, maybe these people can get through.”

 

Conducting such research, however, is extremely difficult because of the inherent limited access to patients right now. Since the potential research subjects are unconscious, having just suffered potentially life-threatening brain injuries, their families need to be approached for permission to use the lactate markers at the worst possible time. As a result, Brooks says, their ability to conduct the studies is “episodic,” especially considering that at the moment there is no direct benefit to the patient.

 

Medical boards at UC Berkeley and UCLA will have to allow us to supplement these people with lactate salts. Only then the widespread applications will be forthcoming,” Brooks says. For that to happen, he adds, “we need to show active but suppressed metabolism in the injured brain and that we can manipulate the lactate delivery to facilitate the recovery process.”

 

Should they be successful, this research could have far-reaching implications on how patients are treated in emergency rooms in the crucial hours after sustaining a devastating brain injury, and hopefully on their survival rates and recovery beyond.

 

The UCLA-UC Berkeley collaboration is only one of a number of studies being conducted at Berkeley and elsewhere that rely on the lactate shuttle mechanism. For instance, Rajaa Hussien, a graduate student in Brooks’ group, is studying lactate shuttles within cancer tumors in the hope of selectively killing the cancer cells while leaving healthy tissue intact. And Professor Song Lee in chemical engineering at Berkeley is using lactate scaffolding as a base to grow stem cells.  So, rather than the 1920’s view that working muscles make and release a metabolic poison, those working muscles make a substance, lactate, that has several beneficial functions, one of which is to serve as an important energy source.

 

Although Brooks admits he never considered these broad applications when he started his lactate research, he is not surprised by the breadth of work that came out of research in exercise physiology.

Lactate shuttles,” he says, “are the way nature does things.”

 

Lactate-uptake mechanism may fuel the injured brain | Research UC Berkeley  https://vcresearch.berkeley.edu/news/lactate-uptake-mechanism-may-fuel-injured-brain