Muscles control the body clock

The 2017 Nobel prize for physiology or medicine was awarded for research on the biological rhythms that dictate the lives of all of us. The circadian clock ticks chemically and genetically in every one of our cells, matching metabolism and growth to the demands of the time of day. And our understanding was that the brain contains a master clock - a cluster of interconnected nerve cells called the suprachiasmatic nucleus - and these use hormones and nerve signals to set the times of all of the “peripheral clocks” elsewhere in the body. So imagine Chris Ehlen’s surprise when he accidentally discovered that if you knock out BMAL1 - one of the genes that runs the clock - in skeletal muscle cells, the brain can’t keep time properly until it’s restored. Chris Smith heard how...

Chris E: BMAL1 is a core circadian clock gene. There's a molecular circadian clock in all our cells that keep time and BMAL1 is necessary for that clock functioning. But we really didn’t know how it was involved in sleep. So we had this mouse where BMAL1 was removed and what we did was we put it back. In one of the animals, we put it back in the brain. In one of the animals, we put it back in the muscle. The muscle was originally designed to be a control, but what we found was that it was only when we returned BMAL1 to the muscle that we saw normal sleep regulation.

Chris: It is bizarre, isn’t it, because the way in which we think that the circadian clock ticks is that there is this segment of the brain – the suprachiasmatic nucleus – where there is this genetic clock ticking which keeps time and we regard that as the master which then tells the rest of the brain and the rest of the body via various mechanisms what to do. And you're saying actually in fact, that some components of sleep might be originating from muscles.

Chris E: Yeah. You described that perfectly and we were very surprised, almost in disbelief. We really did expect to just return it in the brain and we would kind of eliminate the periphery as an influence and then go on and investigate where in the brain it would work. It turns out that muscle is really critical to cause this sleep phenotype. We went on to conditionally knockout BMAL1 in the muscle. So we used an animal where we could deliver a drug and then BMAL1 would only be turned off in muscle and what we found out is that when we just knockout BMAL1 in the muscle, we also see the same kind of phenotype that we see in a whole body knockout mouse.

Chris: So this argues then that the brain isn’t operating in isolation in telling the body cells what to do. There is some kind of signal which is being regulated by the circadian clock ticking in muscle which is feeding back to the nervous system and telling the nervous system what time it is.

Chris E: Right. That’s exactly what we think and that’s one of the things we’re interested in is, what is this factor and how does it work?

Chris: Well first of all, before we explore what the connection might be between the periphery and brain, why do you think it has evolved like that? Why does the nervous system have this dependence on the periphery when it could have all the components of the clock work just in this cluster of nerve cells in the brain and not rely on the periphery?

Chris E: It’s always hard to kind of predict what evolution was thinking, but I think it really seems obvious that there are peripheral processes that sleep benefits. Benefits to the muscle and other organs, and that maybe there needs to be some communication from the periphery, telling the brain that, “Alright, it’s time to get some rest. We need sleep too.”
Chris: Do you think that this is the reason why people classically say that when they're psychologically tired, they don’t sleep as well as when they're physically tired?

Chris E: That could be true, yeah. That’s a great point and I actually had not thought of that.

Chris: So what is the connection then between what is going on in the muscle and the brain? How does the muscle talk back to the nervous system?

Chris E: That’s the question we’re working on now. Unfortunately, we don’t have answers. We know there are some factors released from muscle that can affect the brain. So we’re starting to look at low-hanging fruit so to speak, the factors that we know are released from muscle and communicate with the brain. But we are just in the beginning stages of trying to figure out exactly what's going on.

Chris: So putting all these together then, what are the implications of the fact that we seem to have a clock ticking in the brain, we’ve got parallel clocks all over the body, keeping time as well, but previously, unbeknown to us was that these parallel peripheral clocks appear to be influencing and critical to some of the function of the central brain clock?

Chris E: The biggest implication is that it is providing a whole new area for research into sleep regulation. I don’t know that there were many people looking in the periphery to really understand how sleep is regulated. We were in the dark about a lot of the factors especially in sleep homeostasis so the effect of increased waking and sleep pressure and how that was regulated. So, this opens up the possibility that a lot of these processes may lie outside the brain and so, it gives us another place to look. It also might explain some effects that we see. For instance, there's problems with sleep and ageing. We know that there's a loss of muscle mass with ageing. We know that some skeletal muscular disorders are associated with sleep phenotypes. So it could be that if you have muscle problems that might be part of what's causing the sleep problems that are associated.