Metabolic suppression in mammalian hibernation - Mechanisms and implications

哺乳动物冬眠中的代谢抑制 - 机制和影响

• 批准号: RGPIN-2020-06421
• 负责人: Staples, James
• 金额: $ 4.01万
• 依托单位: University of Western Ontario
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=741200
• 关键词: Metabolic; suppression; mammalian; hibernation; Mechanisms

Through my research I aim to understand how hibernators survive cold prairie winters without eating. In the cold most small mammals increase metabolic heat production by shivering or activating brown adipose tissue. This strategy keeps body temperatures high and constant, but requires a great deal of food to power the high metabolic rates. By contrast hibernators allow their body temperature to fall close to freezing, and metabolic rate to decrease by over 90%. This strategy conserves energy over the winter when food is scarce. In 13-lined ground squirrels we discovered that the activity of mitochondria - cellular structures that consume oxygen to produce chemical energy and generate heat - is rapidly reduced by 70% during hibernation. This reduction corresponds with specific alterations to mitochondrial proteins, and we were able to reverse these changes in the lab. We will continue to explore what other protein alterations also occur. In addition, we will measure levels of hydrogen sulphide (H2S), and the enzymes that synthesize it, in hibernating ground squirrels. In large doses H2S is toxic, but some animal tissues actually synthesize it, and it may be important for regulating mitochondrial metabolism. This research will be valuable to biologists, but may also be important for developing techniques to prolong the viability of tissues used for transplantation In hibernation heart rate falls from 300 to 2 beats/minute and blood flow to many tissues virtually halts. Ground squirrels do not hibernate continuously throughout the winter, but arouse approximately every 12 days, increasing heart rate, metabolism and body temperature for approximately 18 hours. The decrease in heart rate followed by an abrupt increase is similar to what occurs in heart attack or stroke, and can produce a burst of reactive oxygen species which damage tissues. Ground squirrels are inherently resistant to this loss of blood flow, especially in the winter hibernation season. We predict that ground squirrel mitochondria produce fewer reactive oxygen species or have superior antioxidant defenses when they hibernate. Understanding how these animals cope with oxidative stress under natural conditions may help improve therapies for treating similar pathological conditions. Our ground squirrels are from Manitoba but this species ranges from Saskatchewan to Texas, and we do not know if hibernation patterns differ over this 20° latitudinal span. We will trap animals from 5 locations across this range, house them under identical, constant conditions and compare hibernation patterns. We will then use molecular biology to identify genetic markers that correspond with differences in hibernation patterns among populations. This approach may allow us to identify genes that regulate hibernation and inform us about how climate change may affect hibernators.

通过我的研究，我的目标是了解冬眠动物如何在不吃东西的情况下在寒冷的草原冬季生存。在寒冷的环境中，大多数小型哺乳动物通过颤抖或激活棕色脂肪组织来增加代谢产热。这种策略保持体温高和恒定，但需要大量的食物来驱动高代谢率。相比之下，冬眠者允许他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短缺的冬天节省能量。在13线地松鼠中，我们发现线粒体的活动-消耗氧气产生化学能和产生热量的细胞结构-在冬眠期间迅速减少了70%。这种减少与线粒体蛋白的特定改变相对应，我们能够在实验室中逆转这些变化。我们将继续探索其他蛋白质的变化也发生。此外，我们还将测量冬眠的地松鼠体内硫化氢（H2S）的水平以及合成硫化氢的酶。大剂量的硫化氢是有毒的，但一些动物组织实际上会合成它，它可能对调节线粒体代谢很重要。这项研究对生物学家很有价值，但对开发延长用于移植的组织活力的技术也很重要。在冬眠中，心率福尔斯从每分钟300次下降到每分钟2次，许多组织的血流几乎停止。地松鼠在整个冬季不会持续冬眠，但大约每12天醒来一次，增加心率，新陈代谢和体温约18小时。心率下降后突然增加类似于心脏病发作或中风，会产生破坏组织的活性氧簇。地松鼠天生就能抵抗这种血液流动的损失，特别是在冬季冬眠季节。我们预测地松鼠线粒体在冬眠时产生较少的活性氧或具有上级抗氧化防御。了解这些动物在自然条件下如何应对氧化应激可能有助于改善治疗类似病理条件的疗法。我们的地松鼠来自马尼托巴，但这个物种的范围从萨斯喀彻温省到得克萨斯州，我们不知道冬眠模式是否在这20 °的纬度跨度不同。我们将从这个范围内的5个地点捕捉动物，将它们安置在相同的恒定条件下，并比较冬眠模式。然后，我们将使用分子生物学来识别与种群之间冬眠模式差异相对应的遗传标记。这种方法可以让我们识别出调节冬眠的基因，并告诉我们气候变化如何影响冬眠动物。