Sleeping squirrel. Image credit: Photo by Alexas_Fotos on Unsplash (CC0)
A squirrel sleeping through winter is doing something remarkable: reducing its metabolism to a fraction of its normal rate, then switching it back on without damage. This state is called torpor – a reversible reduction in body temperature, heart rate and oxygen consumption that animals enter when energy is scarce. Hibernation is essentially a prolonged series of torpor bouts.
Animals in torpor have an unusual ability to withstand interruptions to their blood supply. This is particularly interesting for medicine because heart attacks and strokes damage tissue by depriving it of oxygen. Although mice do not hibernate throughout winter, they can enter torpor on a daily basis when they lack sufficient energy to keep themselves warm.
Recent studies have begun to unravel how the brain controls this process in mice, revealing that torpor is triggered by a small group of neurons in the hypothalamus, a brain region involved in regulating body temperature and appetite. Torpor occurs in a wide range of mammals, including some primates. This raises the question whether all mammals are able to enter torpor, and whether some have just stopped doing it. If so, could this dormant response be reawakened?
Until now, researchers had studied the protective effects of torpor only in animals that naturally enter this state. It was therefore unclear whether this protection is a specialised adaptation of hibernating animals or a more widely conserved biological mechanism. Elley et al. set out to investigate whether they could induce a torpor-like state in rats – which do not naturally enter torpor – by activating the equivalent brain cells. And, if so, whether this would protect their hearts from injury. The answer could help determine whether torpor research has potential relevance for human medicine.
To do this, the researchers used genetically engineered viruses to deliver instructions that enable targeted neurons to produce a new protein on their surface. This protein acts as a molecular switch, allowing us to activate the neurons using a drug. They found that stimulating neurons in the same hypothalamic region that triggers torpor in mice induced a convincing torpor-like state in rats. Their body temperature dropped to around 31°C, their heart rate fell by 24%, and their oxygen consumption decreased by 43%.
Elley et al. then examined whether this state protected the heart. Hearts removed from these rats and studied in isolation sustained around 40% less damage following a period without oxygen. Remarkably, this protection was still observed when they activated the same brain region but kept the rats warm, preventing their body temperature from falling. Further analysis of cardiac proteins revealed that pathways promoting cell survival had been activated, while those involved in cell death were suppressed.
This is early-stage laboratory research, and any potential benefit for patients remains a long way off. Ultimately, this work could have implications for people at risk of interrupted blood supply to their organs, including during heart attacks, strokes, cardiac arrest, organ transplantation and major surgery. Before this approach could be translated into medicine, however, researchers need to establish whether it can protect organs when activated after an injury has already begun, identify the signals the brain sends to the heart, and find a way to trigger these protective mechanisms using drugs.
