Study reveals molecular mechanisms behind hibernation in mammals

Researchers have shed light on the molecular mechanisms underlying hibernation, publishing their findings today as a Reviewed preprint I eLife

Their research, in small and large hibernating mammals, is described by the editors as an important study that advances our knowledge of the role of myosin in structure and energy consumption. Molecular mechanisms of hibernation, supported by solid methodology and evidence. The results also suggest that myosin – a type of motor protein involved in Muscle contraction-Plays a role in nonshivering thermogenesis during hibernation, where heat is produced independent of shivering muscle activity.

Hibernation is a survival strategy used by many animals, characterized by a state of deep sleep and a profound reduction in metabolic activity, body temperature, heart rate and respiration. During hibernation, animals rely on stored energy reserves, especially fat, to maintain their physiological functions. Metabolic slowness allows the hibernator to conserve energy and withstand long periods of food deprivation and harsh environmental conditions during the winter. However, the underlying cellular and molecular mechanisms behind hibernation are incompletely understood.

Small hibernating mammals experience a hypermetabolic state known as torpor, in which their body temperature drops significantly and is spontaneously interrupted by intermittent athermic arousals (IBA). is—where they temporarily raise their body temperature to restore certain physiological functions, such as eliminating waste and eating more food.

This is in contrast to larger mammals, whose body temperature is much lower during hibernation and remains fairly constant. Skeletal muscles, which comprise about half of the body of mammals, play a key role in determining their heat production and energy utilization.

“Until recently, energy consumption in skeletal muscle was thought to be primarily related to the activity of myosin, which is involved in muscle contraction. However, there is increasing evidence that when they are at rest, skeletal muscle “, explains lead author Christopher Lewis, a postdoctoral researcher at the Department of Biomedical Sciences, University of Copenhagen, Denmark.

“Myosin heads in inactive muscle can be in different resting states: the ‘random-relaxed,’ or DRX state, and the ‘superrelaxed,’ or SRX state. Myosin heads in the DRX state use ATP— Energy currency cells – five to ten times faster than the SRX state,” added Lewis.

Lewis and colleagues hypothesized that changes in the proportion of myosin in the DRX or SRX states may contribute to reduced energy consumption during hibernation. To test this, they took Muscles attached to structures Samples of two small hibernators—the thirteen-lined ground squirrel and the garden door mouse—and two large hibernators—the American black bear and brown bear.

First, they sought to determine whether myosin states, and their relative ATP consumption rates, differed between active periods and hibernation. They looked at muscle fibers taken from two breeds of bears during their active summer phase (SA), and their winter hibernation period.

They found no difference in the proportion of myosin in the DRX or SRX state between the two phases. To measure the rate of ATP consumption by myosin, they used a special test called the Mant-ATP chase assay. This showed that the rate of myosin energy consumption was also unchanged. This may be to prevent significant muscle loss in bears during hibernation.

The team also performed a Manat-ATP chase assay on samples taken from Small mammals During SA, IBA and torpor. As in large hibernators, they observed no difference in the percentage of myosin heads forming SRX or DRX between the three stages. However, they discovered that the ATP turnover time of myosin molecules in both formations was shorter in IBA and torpor than in SA phase, leading to an overall unexpected increase in ATP consumption.

Because small mammals undergo a more significant drop in body temperature during hibernation than larger mammals, the team tested whether this unexpected increase in ATP consumption also occurred at lower temperatures. They reran the Mant-ATP chase assay at 8°C, compared to the 20°C ambient lab temperature used previously. Lowering the temperature decreased the ATP turnover times associated with DRX and SRX in SA and IBA, leading to increased ATP consumption.

Metabolic organs, such as skeletal muscle, are known to grow. Core body temperature in response to significant cold exposure, either by shivering or by non-shivering thermogenesis. Cold exposure causes an increase in ATP consumption by myosin in samples obtained during SA and IBA, suggesting that myosin may contribute to non-shivering thermogenesis in small hibernators.

The team did not observe cold-induced changes in myosin. Energy consumption In samples obtained during torpor. They suggest that this is likely a protective mechanism to maintain a lower core body temperature and maintain the broader metabolic shutdown, which is seen during torpor.

Finally, the researchers wanted to understand the changes that occur at protein levels during the different hibernating stages. They examined whether hibernation affects the structure of two myosin proteins from the thirteen-lined ground squirrel, Myh7 and Myh2. Although they observed no hibernation-related changes in the structure of Myh7, they discovered that Myh2 underwent significant phosphorylation—an important process for energy storage—during torpor, compared with SA and IBA.

They also analyzed the structure of two proteins in brown bears, finding no structural differences between SA and hibernation. They therefore conclude that Myh2 hyperphosphorylation is specifically associated with torpor rather than hibernation in general, and suggest that it increases myosin stability in small mammals. This may serve as a possible molecular mechanism to reduce myosin-associated increases in skeletal muscle expenditure in response to cold exposure during periods of torpor.

eLifeThe editors note that some parts of the study warrant further study. That is, muscle samples were taken exclusively from the legs of the animals studied. Given the different core body and limb temperatures, investigation of muscle samples from other parts of the body will further validate the team’s findings.

“Overall, our results suggest that ATP turnover adaptations in the DRX and SRX myosin states occur in small mammals such as the thirteen-lined ground squirrel during hibernation in cold environments. In contrast, large mammals such as the American black bear Mammals show no such changes, possibly due to their stable body temperature during hibernation,” concluded senior author Julian Ochala, associate professor at the Department of Biomedical Sciences, University of Copenhagen. “Our results also suggest that myosin can act as a contributor to non-shivering thermogenesis in skeletal muscle during Hibernation“