The nature and significance of metabolic suppression in mammalian hibernation

我的研究将帮助我们了解冬眠者是如何通过降低代谢率来度过寒冷的冬天的。吸入性动物，如哺乳动物和鸟类，利用内部新陈代谢产生的热量来维持37摄氏度左右的高温和恒定的体温。当暴露在寒冷中时，大多数吸热动物会增加新陈代谢，例如通过颤抖或激活棕色脂肪组织。这种策略在寒冷的环境中保持较高的体温，但需要大量的食物来为高新陈代谢提供动力。相比之下，小型冬眠动物，如沙鼠、土拨鼠和一些蝙蝠，使它们的体温降至接近冰点，代谢率下降90%以上。这一策略可以在食物稀缺的寒冷冬季节约能源。例如，我们研究的地松鼠在整个冬天都不吃东西，只利用体内储存的脂肪生存。我的研究团队发现，在冬眠期间，肝脏、骨骼肌和心肌中线粒体的活动--消耗氧气产生化学能和热量的细胞结构--的活动减少了70%。在这项拨款申请中提出的研究将确定这种代谢抑制的确切时间和在哪些组织中发生。它还将确定线粒体代谢的哪些成分受到抑制，以及受抑制的机制是什么。我们还将评估全球气候变化对冬眠者新陈代谢和能量储存的潜在影响。我们最近的研究表明，动物进入冬眠非常早，在体温从37摄氏度下降到30摄氏度之前，线粒体新陈代谢受到抑制。以心率为指标，当整个动物的新陈代谢在冬眠早期开始下降时，我们将对肝脏线粒体进行采样，从而最大限度地提高我们检测线粒体代谢重要变化的能力。我们还将评估棕色脂肪组织中的线粒体，那里的新陈代谢和产热在整个冬眠期间变化很大。我们将使用只有美国国立卫生研究院才有的积分球光谱设备来寻找导致这种线粒体代谢抑制的分子机制。这些研究还将表明，当动物进入冬眠时，动物体内的哪些信号会触发新陈代谢的降低。我们将使用这些信号来尝试诱导非冬眠动物线粒体的代谢抑制，从而导致实际应用。最后，我们将通过改变松鼠在受控条件下冬眠的环境温度，来研究冬季气温上升对冬眠模式、新陈代谢和能量储存的影响。这些基于发现的研究将推动基础科学的发展，但也有可能对临床和应用科学做出重大贡献。了解冬眠者是如何可逆地降低线粒体新陈代谢的，将进一步加深我们对这一迷人的生物学现象的理解，以及我们对代谢调节的了解。了解线粒体代谢如何在自然模型中发生如此剧烈的变化，将有助于我们理解涉及线粒体功能障碍的疾病。从非冬眠体中成功地诱导线粒体代谢抑制，将是降低移植器官新陈代谢、延长其存活率的重要一步。了解气温上升如何影响冬眠新陈代谢，将使保护生物学家和政策制定者了解全球气候变化对冬眠动物生存和地理分布的潜在影响。此外，我还将培训至少6名研究生，他们将继续为加拿大社会做出贡献。

My research will help us to understand how hibernators are able to survive cold winters by reducing their rate of metabolism.Endotherms, such as mammals and birds, use heat derived from internal metabolism to maintain high and constant body temperatures near 37C. When exposed to cold most endotherms increase metabolism, for example by shivering or activating brown adipose tissue. This strategy maintains high body temperatures in cold environments, but requires a great deal of food to power the high rates of metabolism. In contrast small hibernators, such as ground squirrels, marmots and some bats, allow their body temperatures to fall close to freezing, and metabolic rate to decrease by over 90%. This strategy conserves energy over the cold winters when food is scarce. For example, the ground squirrels that we study do not eat throughout the winter, and survive using only the fat stored within their bodies.My research team discovered that during hibernation the activity of mitochondria - cellular structures that consume oxygen to produce chemical energy and generate heat - is reduced by up to 70% in liver, skeletal muscle and cardiac muscle. The research proposed in this grant application will determine exactly when this metabolic suppression occurs and in what tissues. It will also identify which components of mitochondrial metabolism are suppressed, and by what mechanisms. We will also evaluate potential effects of global climate change on hibernator metabolism and energy stores.Our recent research showed that mitochondrial metabolism is suppressed very early as animals enter into hibernation, before body temperature falls from 37C to 30C. Using heart rate as an indicator, we will sample liver mitochondria when whole-animal metabolism begins to decline early in hibernation, maximizing our ability to detect important changes in mitochondrial metabolism. We will also evaluate mitochondria from brown adipose tissue, where metabolism and heat production change greatly throughout hibernation.We will seek the molecular mechanisms responsible for this mitochondrial metabolic suppression using integrating sphere spectroscopy equipment available only at the US National Institutes of Health. These studies will also suggest what signals within the animal trigger the reduction in metabolism as animal enter hibernation. We will use these signals to attempt to induce metabolic suppression in mitochondria from non-hibernating animals, leading to practical applications. Finally, we will examine the effects of rising winter temperatures on hibernation patterns, metabolism and energy stores by varying the environmental temperature at which ground squirrels hibernate under controlled conditions.These discovery-based studies will advance fundamental science, but also have the potential to contribute significantly to clinical and applied science. Understanding how hibernators reversibly decrease mitochondrial metabolism will further our understanding of this fascinating biological phenomenon and our knowledge of metabolic regulation. Understanding how mitochondrial metabolism can change so dramatically in a natural model will be useful for our understanding of diseases involving mitochondrial dysfunction. Successfully inducing metabolic suppression in mitochondria from a non-hibernator would be a major step towards reducing the metabolism of organs used in transplants, prolonging their viability. Understanding how rising temperatures affect hibernation metabolism will inform conservation biologists and policy-makers about potential consequences of global climate change to winter survival and geographic distribution of hibernators. In addition, I will train at least 6 graduate students who will continue to contribute to Canadian society.