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

表征钙循环介导的生热作用在啮齿动物和人类中的作用。

• 批准号: 571423-2021
• 负责人: Blondin, DenisDPJ
• 金额: $ 3.28万
• 依托单位: Université de Sherbrooke
• 依托单位国家: 加拿大
• 项目类别: Alliance Grants
• 财政年份: 2022
• 资助国家: 加拿大
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=753428
• 关键词: Characterizing; role; Calcium; cycling; mediated

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.

在恒温动物中，内源性产热需要在各种环境条件下保持较高和恒定的体温。这种产热速率与热量散失到环境中的速率成正比。随着环境温度的下降，骨骼肌通过寒战的补充成为主要的产热来源。然而，其他非寒颤热源已被确定为补充热源。棕色脂肪组织（BAT）一直被认为是啮齿类动物最重要的热能补充来源。然而，即使在缺乏BAT的动物和颤抖被抑制的动物中，也可以利用其他非颤抖的产热机制来维持正常体温。事实上，atp依赖性Ca2+循环的SERCA最近被确定为非寒颤产热的基本形式。例如，手术切除BAT的小鼠，抑制了颤抖，缺乏肌肽（一种负责SERCA功能的关键蛋白质），无法在急性寒冷挑战中保护自己的体温。缺乏UCP1（负责BAT产热的蛋白质）的小鼠，在白色脂肪组织（称为米色脂肪细胞）中发现的可诱导产热脂肪细胞中，表现出对serca介导的钙循环的高度依赖。然而，几个关键问题仍然存在：(1)这些非寒战形式的产热是否足够适应长时间或反复的寒冷暴露，以取代寒战依赖的产热；(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serca介导的钙循环；(3)这些与颤抖无关的产热机制是否存在于人类身上，人类在寒冷中几乎完全依靠骨骼肌产热来产热。后者尤其重要，因为sarcolipin的表达是serca介导的钙循环的关键调节因子，在人类骨骼肌中的表达比在啮齿动物中高几倍。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Ca2+循环的作用。我们的首要假设是，serca介导的Ca2+循环对寒冷适应的动物，特别是像人类这样几乎完全依靠骨骼肌在寒冷中产生热量的大型哺乳动物特别重要。我们预计肌肉和米色脂肪细胞形式的serca介导的Ca2+循环主要是由肾上腺素能刺激介导的。两个目的如下：1：确定atp依赖性Ca2+循环的SERCA在冷诱导的非寒战产热在未适应和已适应的啮齿动物和人类的作用。2：在啮齿动物模型和人类中检查atp依赖性Ca2+循环的肾上腺素能贡献。这一建议的结果将对人类热平衡的生物物理模型的发展具有重要的转化意义。这必然会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。