Cookies on this website
We use cookies to ensure that we give you the best experience on our website. If you click 'Continue' we'll assume that you are happy to receive all cookies and you won't see this message again. Click 'Find out more' for information on how to change your cookie settings.

Researchers identify faulty molecular brake that interferes with heart muscle’s ability to contract and relax

Image of heart © Victoria Stoll, Oxford

Hypertrophic cardiomyopathy (HCM) is the most common genetic disease of the heart and a leading cause of sudden cardiac death in young people and athletes.

Scientists have long known that the condition’s cardinal feature—an unusually thick heart muscle that contracts and relaxes abnormally—is fueled by some glitch in the heart’s molecular machinery. Yet, the precise sparkplug that ignites such disordered muscle movement has thus far remained unknown.

Now a new study in Science Translational Medicine has pinpointed a faulty molecular brake that fuels disease development and identified a candidate compound that restores heart muscle function in human and mouse cells.

Our results reveal the presence of a unifying molecular mechanism that fuels the heart muscle dysfunction seen in the most common form of hypertrophic cardiomyopathy - Dr Christopher Toepfer



Dr Toepfer is a Sir Henry Wellcome fellow at the Radcliffe Deparment of Medicine at the Wellcome Centre for Human Genetics, as well as a researcher at the Blavatnik Institute at Harvard Medical School. The study was led by researchers at the Harvard Medical School, and co-authored by Professor Hugh Watkins at RDM.

If the team's findings are replicated by other studies, they can pave the way for the development of much-needed precision-targeted therapies that correct the underlying muscle-protein dysfunction in HCM, a vast improvement over current treatments that tackle the disease symptomatically but fail to address its root cause. Such approaches include medications that improve the heart’s pumping ability, surgery to shave the enlarged heart muscle or implanting tiny cardioverter defibrillators that shock the heart back into rhythm if its electrical activity ceases or goes haywire.

“Additionally, our findings offer a tantalizing avenue toward a pharmacological treatment that can correct the defect and normalize heart muscle function,” Dr Toepfer said.

Mischief in the motor

The study identified an aberration in the brake machinery of the motors that propel heart muscle movement. The glitch arises from a mutation in a gene that makes a protein called myosin-binding protein C3 (MYBPC3), the study showed. Experiments revealed that cells carrying the mutated gene had either too little of this molecular brake or none at all. This is the most common genetic mutation in HCM, and particularly prevalent in people of South Asian descent, affecting about 4 percent of this group.

Normally, the myBPC protein acts as a shackle on myosin—the protein motor that propels the cells of the heart muscle to contract and relax, beat after beat. But a series of experiments in human and mouse heart cells revealed that the mutated gene lacks this molecular brake. Its absence, the work showed, put the cells of the heart muscle into overdrive, causing them to contract too much and relax poorly.

To measure the effect of this abnormality, the scientists focused on a muscle component known as the sarcomere—the basic contractile unit of muscle cells. Muscles move when sarcomeres contract and relax. The shorter the sarcomere, the greater the contraction.

When scientists compared the sarcomere length in the beating heart cells of mice with and without the missing molecular brake, they noticed dramatically shorter sarcomeres in cells carrying the genetic mutation seen in HCM. Indeed, these sarcomeres showed 100 percent increase in contraction, compared with normal cells. And because shortened sarcomeres indicate greater contraction, the scientists hypothesized that the shortened sarcomeres portended abnormal muscle contraction and relaxation. To determine how the absence of the molecular brake affects the cardiac cells’ ability to relax, the researchers compared the duration of relaxation between heart beats in mice with and without the mutation. Mouse cells that lacked the molecular brake had abnormally prolonged relaxation between beats, a sign of disordered muscle relaxation, a feature present in people with the disease.

“What we saw in our experiments mirrored the features of the disease—increased contractility of the heart and poor relaxation,” Dr Toepfer said.

Muscle cells have a fleet of molecular motors—myosin proteins—that propel the cardiac muscle into motion. To initiate contraction, the heads of these myosin motors latch onto another protein called actin and pull it, then release it—the essence of contraction that fuels the blood-pumping, life-sustaining movements of the heart muscle. This cycle of coupling and detachment repeats itself over and over again heartbeat after heartbeat.

Under normal conditions, a subset of these motor heads should remain inactive, but the team’s experiments revealed that the absence of the normal braking mechanism set the inactive pool in motion, causing them to gobble up excess cellular energy and fuel excess muscle contractions—the hypercontractility seen in the disease.

Starving the engine

How could these primed molecular motors be halted, the researchers wondered. To do so, they turned to ATP, the universal fuel that propels all cellular activities, including myosin movement and muscle contraction.

The team used a chemical known to block the action of myosin ATPase—the enzyme that releases cellular fuel and propels motor movement. Use of the compound—now in human trials as a candidate treatment for heart muscle dysfunction— successfully restored normal contractility of cardiac cells. The compound is being developed by a biotech company, two of whose co-founders are authors on the study.

When applied to human and mouse heart cells, the ATPase-blocking compound slowed the motors’ fuel consumption by switching them off. The heart cells of mice carrying the mutation treated with the drug had 70 percent fewer active myosin heads compared with untreated cells. The treatment normalized myosin function and reduced muscle hyper-contractility in those cells.

The scientists observed a strikingly similar effect in heart cells obtained from people with HCM after heart muscle-reduction surgery.

The finding sets the stage for a drug therapy that can correct the underlying protein defect and restore heart muscle contractility in the hopes of averting the most dreaded complications of the disease—dangerous arrhythmias and cardiac arrest.

“Today, our treatment repertoire for HCM remains limited to symptom relief,” said study senior author Christine Seidman, a cardiovascular geneticist in the Department of Genetics at HMS and in the Cardiovascular Division at Brigham and Women's Hospital. “We hope that our findings can be translated into medicines that directly treat the fundamental malfunction in HCM.”

Text adapted based on Harvard Medical School News and Research.

Read the full paper at Science Translational Medicine.

We want to hear about your news!

Publishing a paper? Just won an award? Get in touch with communications@rdm.ox.ac.uk