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

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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.