Characterizing the role of Calcium cycling-mediated thermogenesis in rodents and humans.

在恒温动物中，需要内源性产生热量以在各种环境条件下维持升高且恒定的体温。这种产热的速率与热量损失到环境中的速率成比例地增加。随着环境温度的下降，骨骼肌通过颤抖的招募成为产热的主要来源。然而，其他非颤抖性产热源已被确定为补充产热源。棕色脂肪组织（BAT）长期以来被认为是啮齿动物产热的最重要的补充来源。然而，即使在缺乏BAT的动物中，颤抖已经被抑制，其他非颤抖的产热机制也可以被招募来维持正常的体温。事实上，ATP依赖的钙离子循环的SERCA最近已被确定为一种重要形式的非颤抖产热。例如，患有手术消融BAT，抑制颤抖和缺乏sarcolipin（一种负责SERCA功能的关键蛋白质）的小鼠无法保护其体温以应对急性寒冷挑战。缺乏UCP 1（负责BAT产热的蛋白质）的小鼠表现出对在白色脂肪组织中发现的可诱导产热脂肪细胞（称为米色脂肪细胞）中SERCA介导的钙循环的依赖性增强。然而，仍然存在几个关键问题：（1）这些非颤抖形式的产热是否足以显著适应长时间或重复的冷暴露，以取代颤抖依赖性产热;（2）位于肌细胞和脂肪细胞表面的肾上腺素能受体的激活在多大程度上负责这种SERCA介导的钙循环;（3）这些不依赖颤抖的产热机制是否存在于人类中，人类几乎完全依赖骨骼肌产热来在寒冷中产生热量。后者是特别重要的，因为肌磷脂的表达，一个关键的调节SERCA介导的钙循环，是几倍高的骨骼肌在人类比啮齿类动物。这表明，虽然SERCA介导的钙循环是小鼠产热的重要来源，但它对人类产热的贡献可能要大得多。 总体研究目标是阐明SERCA在啮齿动物和人类中ATP依赖性Ca 2+循环的作用。我们的总体假设是，SERCA介导的Ca 2+循环对于冷适应动物特别重要，特别是像人类这样的大型哺乳动物，它们几乎完全依赖骨骼肌在寒冷中产生热量。我们预计肌肉和米色脂肪细胞形式的SERCA介导的Ca 2+循环主要由肾上腺素能刺激介导。本研究的主要目的如下：1.通过SERCA研究ATP依赖性Ca ~（2+）循环在冷诱导的非颤抖性产热过程中的作用; 2.研究ATP依赖性Ca ~（2+）循环在冷诱导的非颤抖性产热过程中肾上腺素能的作用。这不可避免地影响室内气候法规和商业和住宅建筑的能源消耗，以及预测加拿大武装部队和一般劳动力的人员生理准备和表现。

In endotherms, the endogenous production of heat is required to maintain an elevated and constant body temperature under various environmental conditions. The rate of this heat production increases in proportion to the rate that heat is lost to the environment. As environmental temperatures fall, skeletal muscles become the predominant source of heat production through the recruitment of shivering. However, other non-shivering sources of heat production have been identified as complementary sources of heat production. Brown adipose tissue (BAT) has long been considered the most significant complementary source of heat production in rodents. However, even in animals lacking BAT and where shivering has been suppressed, other non-shivering mechanisms of heat production can be recruited to maintain a normal body temperature. Indeed, ATP-dependent Ca2+ cycling by SERCA has recently been identified as an essential form of non-shivering thermogenesis. For instance, mice with surgically ablated BAT, suppressed shivering and lacking sarcolipin, a key protein responsible for the function of SERCA, are unable to defend their body temperature in response to an acute cold challenge. Mice lacking UCP1, the protein responsible for BAT thermogenesis, show an accentuated reliance on SERCA-mediated calcium cycling in inducible thermogenic fat cells found in white adipose tissue, called beige adipocytes. However, several critical questions remain: (1) do these non-shivering forms of heat production adapt significantly enough in response to prolonged or repeated cold exposures to replace shivering-dependent thermogenesis; (2) to what extent is the activation of adrenergic receptors located at the surface of myocytes and adipocytes responsible for this SERCA-mediated calcium cycling, and; (3) are these shivering-independent mechanisms of heat production present in humans, who rely almost exclusively on skeletal muscle thermogenesis to produce heat in the cold. The latter is particularly important given that sarcolipin expression, a key regulator of SERCA-mediated calcium cycling, is several-fold higher in skeletal muscles in humans than in rodents. This suggests that, while SERCA-mediated calcium cycling is a significant source of thermogenesis in mice, its contribution to heat production is likely far greater in humans. The overall research goal is to elucidate the role of ATP-dependent Ca2+ cycling by SERCA in rodents and humans. Our overarching hypothesis is that SERCA-mediated Ca2+ cycling is of particular importance for cold-acclimated animals and especially large mammals like humans that rely almost exclusively on skeletal muscles to produce heat in the cold. We expect that both muscle and beige adipocyte forms of SERCA-mediated Ca2+ cycling are primarily mediated by adrenergic stimulation. The two aims are as follows: 1: Determine the role of ATP-dependent Ca2+ cycling by SERCA in cold-induced non-shivering thermogenesis in unacclimated and acclimated rodents and humans.2: Examine the adrenergic contribution of ATP-dependent Ca2+ cycling in rodent models and humans.The results of this proposal will have significant translational implications in the development of biophysical models of human thermal balance. This invariably impacts indoor climate regulations and the energy consumption of commercial and residential buildings, as well as predicting personnel physiological readiness and performance in Canadian Armed Forces and the general labour force.