Sandy Martin, The University of Colorado, Denver
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When winter comes there are several ways to survive; one is to wear a thick coat to stay warm; another is to surrender to the cold and enter a state of hibernation. But with a body temperature sitting – in some cases – just above freezing – how do you bring yourself back to life? Working with hibernating squirrels, Sandy Martin has found that the animals store up not just nuts for winter but a population of messenger RNA molecules that can rapidly reboot their heat-producing brown fat tissue every two weeks...
Sandy - One of the big mysteries of hibernation is how these animals are able to rewarm their body temperatures from near-freezing back to temperatures like ours in just a matter of hours and one of the really key organs is a tissue called brown fat. It has lots of little energy power houses called mitochondria but it also has lipids that will be used as fuel to run metabolism at very high rates, not making the energy currency that normal mitochondria make called ATP but all the energy that comes from burning the fat is turned into heat. And they do this periodically, approximately every 2 weeks. So, we were interested in how this organ was able to function immediately at the time the animal decided it needed to rewarm in a few hours.
Chris - How quickly does it do that? So when the squirrel says, “Right. I’m gonna wake up. It’s been two weeks, I’m now gonna come back to life for a little while.” How quickly does their body temperature recover?
Sandy - Not even two hours.
Chris - Wow!
Sandy - Somewhere between an hour and a half and two hours.
Chris - That’s very quick, isn’t it?
Sandy - It is. They do the first part completely with the metabolic activity of brown fat and then as they get a little warmer, they start to shiver as well. And so shivering also contributes to the rewarming process.
Chris - And this is somewhat paradoxical because at these very low – sustained low temperatures – with very low metabolic activity, it’s hard to imagine how the cells would very quickly put themselves into a state where they could generate so much metabolic activity literally at the flick of a switch like that.
Sandy - Yes, that’s right. And although we know the signal comes from the brain, at the molecular level in the cells there has to be machinery that does the work to make the heat. That machinery’s been shut off during the long period of torpor and yet suddenly, it has to work. Originally, we were looking for changes in gene expression that cycled with the activity of brown adipose tissue.
Chris - So by comparing metabolically what’s going on in the two states, you can say, “Well, what’s different between the tissue in those two conditions?”
Sandy - Yes, except we’re looking more on it now at a molecular genetic level. So, we’re going one step back in this study. We were looking at the messenger RNAs at given times across the torpor-arousal cycle. So, if you can imagine, we have animals entering torpor. Two weeks torpid and then rewarming very rapidly; and ask, “What happens to the mRNA population in brown fat?” And the big surprise to us was that there was a culprit of messenger RNAs that actually increased in abundance when the animals were very cold. And we knew from previous work, transcription didn’t work in ground squirrels whose body temperature was near-freezing.
Chris - So, it’s also paradoxical, isn’t it? You’ve got these very, very cold cells and environment where they shouldn’t be able to make very efficiently at all any more of these messenger RNA transcripts, yet their numbers are rising?
Sandy - Exactly, and that was the big surprise. And so, if you think about it, there are two ways to change the abundance of a single RNA given a pool of a lot of other RNAs. You can either make more, i.e. transcribe it, but we’ve already said we don’t think there’s any new transcription in the cold or you could protect some transcripts from being degraded while allowing the bulk population to be degraded.
Chris - And which is it? Is it the protecting, or is it the making more mechanism which is at play here?
Sandy - Right! At the end of the 2 weeks of torpor, the change in that of RNA seems to be strictly due to protection.
Chris - And when the animal wants to reawaken itself, how does it then deploy these transcripts? And then when it wants to go to sleep again, how does it get rid of them so that it doesn’t stay too hot?
Sandy - Yeah. There’s a whole lot we don’t know for sure but our data suggests there’s a mechanism for stabilizing transcripts that involves a particular class of proteins, called poly (c) binding proteins. And they’re shown to have effects on stabilization of mRNAs and affect the ability of those mRNAs to be taken the next step further in the gene expression program, and that means to make the actual proteins that do the work. So our thought is that as animals enter torpor they can sequester the group of RNAs that are most important for metabolic heat production – i.e. that process of rewarming – at the end of the torpor bout they just hold those in a safe place; don’t allow them to be used but don’t allow them to be degraded. Meanwhile, the bulk of messenger RNAs in the cell are being slowly degraded. By the end of the torpor bout, these are the dominant RNAs in the cell and maybe by virtue of their interaction with these specialized proteins, are the first to go back on to ribosomes for translation and therefore the first to be replenished and activated during the arousal process. So, that’s our model of how it works.