Graduate Student, Northern Arizona University
Homeothermic animals strive to maintain core body temperature across varying ambient temperatures. Studies have demonstrated that mice with the muscular dystrophy with myositis (mdm) mutation shiver at a lower than expected frequency, are heterothermic, and have reduced active muscle stiffness in vivo compared to wildtype mice. Mdm mice are characterized by a deletion in the N2A region of titin that results in a lower body mass, stiffer gait, and reduced lifespan. The underlying defect that leads to a lower shivering frequency is not known but could be caused by muscle properties. The titin protein is known to behave like a spring and contribute to passive muscle stiffness. Recent studies have shown that titin contributes to active muscle stiffness as well. This impairment in heat production could be due to the N2A deletion in the titin protein, leading to a more compliant spring and a lower shivering frequency. An alternative hypothesis is that the ability of mdm mice to use nonshivering thermogenesis and/or uncoupling Protein 1 (UCP1), found in brown adipose tissue (BAT), to generate heat during cold stress is impaired in these mice. The purpose of this study was to evaluate potential causes for the inability of mdm mice to maintain homeothermy during cold stress. We hypothesize that the inability of mdm mice to thermoregulate properly is due primarily to an impairment in heat production (e.g. shivering thermogenesis and nonshivering thermogenesis). Mice underwent a 4-day cold stress experiment during which they lived in a mouse cage that used a continuous system for indirect calorimetry. The cages were placed in an incubator so that ambient temperature could be controlled. During each experiment, temperature was controlled to either 34C, 29C, 24C, and 19C. Upon conclusion of the cold stress experiment, a nonshivering thermogenesis challenge was employed by administering 1.2 mg/kg of norepinephrine. Mdm mice increased metabolic rate during the cold challenge but failed to increase at the lowest temperature of 19C. Core body temperature for mdm mice decreased with decreasing ambient temperature within a range of 28C to 37C. During the nonshivering thermogenesis challenge, both groups increased their oxygen consumption between 2 and 3-fold with no difference between groups. These results suggest that mdm mice do not increase their capacity for nonshivering thermogenesis.
Abstract: In cold-exposed adult humans, significant or lethal decreases in body temperature are delayed by reducing heat loss via peripheral vasoconstriction and by increasing rates of heat production via shivering thermogenesis. This brief review focuses on the mechanisms of fuel selection responsible for sustaining long-term shivering thermogenesis. It provides evidence to explain large discrepancies in fuel selection measurements among shivering studies, and it proposes links between choices in fuel selection mechanism and human survival in the cold. Over the last decades, a number of studies have quantified the contributions of carbohydrate (CHO) and lipid to total heat generation. However, the exact contributions of these fuels still remain unclear because of large differences in fuel selection measurements even at the same metabolic rate. Recent advances on the mechanisms of fuel selection during shivering provide some plausible explanations for these discrepancies between shivering studies. This new evidence indicates that muscles can sustain shivering over several hours using a variety of fuel mixtures achieved by modifying diet (changing the size of CHO reserves) or by changing muscle fiber recruitment (increasing or decreasing the recruitment of type II fibers). From a practical perspective, how does the choice of fuel selection mechanism affect human survival in the cold? Based on a glycogen-depletion model, estimates of shivering endurance show that, whereas the oxidation of widely different fuel mixtures does not improve survival time, the selective recruitment of fuel-specific muscle fibers provides a substantial advantage for cold survival. By combining fundamental research on fuel metabolism and applied strategies to improve shivering endurance, future research in this area promises to yield important new information on what limits human survival in the cold.
Pub.: 15 Apr '06, Pinned: 21 Jun '17
Abstract: Alterations in nonshivering thermogenesis are presently discussed as being both potentially causative of and able to counteract obesity. However, the necessity for mammals to defend their body temperature means that the ambient temperature profoundly affects the outcome and interpretation of metabolic experiments. An adequate understanding and assessment of nonshivering thermogenesis is therefore paramount for metabolic studies. Classical nonshivering thermogenesis is facultative, i.e. it is only activated when an animal acutely requires extra heat (switched on in minutes), and adaptive, i.e. it takes weeks for an increase in capacity to develop. Nonshivering thermogenesis is fully due to brown adipose tissue activity; adaptation corresponds to the recruitment of this tissue. Diet-induced thermogenesis is probably also facultative and adaptive and due to brown adipose tissue activity. Although all mammals respond to injected/infused norepinephrine (noradrenaline) with an increase in metabolism, in non-adapted mammals this increase mainly represents the response of organs not involved in nonshivering thermogenesis; only the increase after adaptation represents nonshivering thermogenesis. Thermogenesis (metabolism) should be expressed per animal, and not per body mass [not even to any power (0.75 or 0.66)]. A 'cold tolerance test' does not examine nonshivering thermogenesis capacity; rather it tests shivering capacity and endurance. For mice, normal animal house temperatures are markedly below thermoneutrality, and the mice therefore have a metabolic rate and food consumption about 1.5 times higher than their intrinsic requirements. Housing and examining mice at normal house temperatures carries a high risk of identifying false positives for intrinsic metabolic changes; in particular, mutations/treatments that affect the animal's insulation (fur, skin) may lead to such problems. Correspondingly, true alterations in intrinsic metabolic rate remain undetected when metabolism is examined at temperatures below thermoneutrality. Thus, experiments with animals kept and examined at thermoneutrality are likely to yield an improved possibility of identifying agents and genes important for human energy balance.
Pub.: 24 Dec '10, Pinned: 21 Jun '17
Abstract: Shivering frequency scales predictably with body mass and is 10 times higher in a mouse than a moose. The link between shivering frequency and body mass may lie in the tuning of muscle elastic properties. Titin functions as a muscle 'spring', so shivering frequency may be linked to titin's structure. The muscular dystrophy with myositis (mdm) mouse is characterized by a deletion in titin's N2A region. Mice that are homozygous for the mdm mutation have a lower body mass, stiffer gait and reduced lifespan compared with their wild-type and heterozygous siblings. We characterized thermoregulation in these mice by measuring metabolic rate and tremor frequency during shivering. Mutants were heterothermic at ambient temperatures of 20-37°C while wild-type and heterozygous mice were homeothermic. Metabolic rate increased at smaller temperature differentials (i.e. the difference between body and ambient temperatures) in mutants than in non-mutants. The difference between observed tremor frequencies and shivering frequencies predicted by body mass was significantly larger for mutant mice than for wild-type or heterozygous mice, even after accounting for differences in body temperature. Together, the heterothermy in mutants, the increase in metabolic rate at low temperature differentials and the decreased tremor frequency demonstrate the thermoregulatory challenges faced by mice with the mdm mutation. Oscillatory frequency is proportional to the square root of stiffness, and we observed that mutants had lower active muscle stiffness in vitro. The lower tremor frequencies in mutants are consistent with reduced active muscle stiffness and suggest that titin affects the tuning of shivering frequency.
Pub.: 13 Jan '15, Pinned: 21 Jun '17