Scientists have identified how the hearts of grizzly bears change when they hibernate. A researcher says that this discovery may lead to developing improved drugs for people with heart failure.
Hibernating grizzly bears make conformational changes to certain proteins in the heart so that adenosine triphosphate (ATP) no longer activates them as easily. The heart beats more slowly and its energy consumption declines as the rest of the bear’s body shuts down.
New research on this discovery has been published in Molecular Metabolism.
A researcher involved in the study says that scientists now understand better what happens when bears hibernate and that this knowledge may improve treatment for people with heart disease.
“For example, people with heart failure risk having energy deficiency in the heart, and medication available today mimics what bears’ hearts do when they hibernate – reducing energy consumption. This new knowledge of the mechanisms behind the transition from an active heart to a hibernating heart may enable us to develop better medication in the future for treating people with heart failure,” explains Julien Ochala, Associate Professor, Department of Biomedical Sciences, University of Copenhagen, Denmark.
Bears survive by minimising resource use
Although researchers have extensively studied what happens in the bodies of bears when they hibernate, the details are still a bit blurry.
Bears lower their metabolism and energy consumption to survive a long winter while using minimal resources, but the underlying molecular mechanisms in each organ remain to be determined.
Julien Ochala and colleagues therefore analysed heart tissue taken from hibernating and active grizzly bears to identify differences between the two states.
“The heart is key because hibernation affects cardiac output by reducing heart rate and energy consumption. The big question is how this is enabled,” says Julien Ochala.
Proteins reduce energy consumption
The researchers specifically examined cardiac myosin, the most abundant motor protein in the heart. Myosin converts the chemical energy stored in ATP into mechanical energy, causing the heart to contract, thereby pumping blood around the body.
Using electron microscopy and other methods, the researchers investigated the bond between ATP and myosin and found that the myosin taken from active bears consumed much more ATP than the myosin taken from hibernating bears.
This showed that deactivating myosin enables bears to hibernate.
The researchers further examined the myosin and found that the conformation of myosin differed between active bears and hibernating bears. This potentially activates myosin and thus the whole heart.
“Hibernating bears modify their myosin conformation so that myosin blocks the site at which ATP binds to myosin and ATP therefore has much more difficulty in binding to and activating it. This reduces activity throughout the heart. This is our main finding: myosin changes conformation and can no longer use as much ATP, which explains why the heart’s energy consumption declines,” notes Julien Ochala.
Myosin is similar in bears and humans
The researchers focused on hibernating bears, but the research may be relevant to people. One problem with heart failure is that the people who have it can experience energy deficiency, with the heart receiving insufficient energy to function.
The fact that bears can reduce their heart’s energy consumption by changing the conformation of myosin could be useful. Perhaps using medication to do this for people could ensure that the heart still gets enough energy even under conditions of energy deficiency,.
“If we can slow down the heart somewhat using medication, we can avoid energy deficiency and reduce the risk of death, thus transferring our results so they become relevant to people. In addition, myosin is similar in bears and humans, so since changing the conformation of myosin in bears can shut down its activity, this may be possible for people,” says Julien Ochala.
Improving heart failure medication
The researchers further investigated how myosin blocks access to the ATP binding site and found that the conformational change resulted from phosphorylation: adding or removing phosphate groups from sites on myosin.
This causes myosin to change form, and the researchers could determine this because phosphate groups were attached to different sites on myosin in the hearts of active bears versus hibernating bears.
According to Julien Ochala, understanding how phosphorylation changes the conformation of myosin may enable drugs to be designed to do this.
Julien Ochala suggests that a medication on the market called mavacamten has been developed specifically for people with heart failure. This mimics what happens in the hearts of hibernating bears but does not work for everyone.
“Our study obtained greater insight into what is needed for a drug to work for more people with heart failure. The great clinical perspective of our findings is that we found some hints about how to improve this type of medication,” concludes Julien Ochala.
