The nature and significance of metabolic suppression in mammalian hibernation

我的研究将帮助我们了解冬眠动物是如何通过降低新陈代谢率来度过寒冷的冬天的。恒温动物，如哺乳动物和鸟类，利用来自内部新陈代谢的热量来维持接近37摄氏度的高温和恒定的体温。当暴露在寒冷中时，大多数吸热型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代谢率提供动力。相比之下，小型冬眠动物，如地松鼠、土拨鼠和一些蝙蝠，允许它们的体温下降到接近冰点，代谢率下降超过90%。这种策略可以在食物匮乏的寒冷冬季保存能量。例如，我们研究的地松鼠整个冬天都不吃东西，只靠体内储存的脂肪生存。我的研究小组发现，在冬眠期间，肝脏、骨骼肌和心肌中的线粒体（消耗氧气产生化学能和热量的细胞结构）的活性降低了70%。这项拨款申请中提出的研究将确切地确定这种代谢抑制何时发生以及发生在什么组织中。它还将确定线粒体代谢的哪些成分被抑制，以及通过什么机制。我们还将评估全球气候变化对冬眠动物代谢和能量储存的潜在影响。我们最近的研究表明，在体温福尔斯从37 ℃下降到30 ℃之前，动物进入冬眠时，线粒体代谢很早就受到抑制。使用心率作为指标，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，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，在整个冬眠过程中，棕色脂肪组织的代谢和产热变化很大。我们将使用美国国立卫生研究院提供的积分球光谱设备来寻找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，动物体内的什么信号触发了新陈代谢的减少。我们将使用这些信号来尝试诱导非冬眠动物线粒体中的代谢抑制，从而导致实际应用。最后，我们将通过改变地松鼠在受控条件下冬眠的环境温度，研究冬季温度升高对冬眠模式、新陈代谢和能量储存的影响。这些基于发现的研究将推进基础科学，但也有可能对临床和应用科学做出重大贡献。了解冬眠动物如何可逆地降低线粒体代谢，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巨大的变化，将有助于我们了解涉及线粒体功能障碍的疾病。成功地在非冬眠动物的线粒体中诱导代谢抑制，将是减少移植器官代谢、延长其生存能力的重要一步。了解温度升高如何影响冬眠代谢将为保护生物学家和政策制定者提供有关全球气候变化对冬季生存和冬眠动物地理分布的潜在影响的信息。此外，我将培养至少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.