Team led by scientists from Cincinnati Children’s discovers the molecular process behind dangerous heart muscle loss
In many situations, cardiac muscle cells do not respond to external stress in the same way as skeletal muscle cells. But under certain conditions, both heart and skeletal muscles can dwindle at deadly rates, according to a new study led by experts at Cincinnati Children’s.
The new findings, based on studies on mouse models, represent an important milestone in a long effort to prevent or even reverse cardiac atrophy, which can lead to fatal heart failure with severe weight loss or prolonged weightlessness in space. Detailed results were published online on June 24, 2021 in Nature communication.
“NASA is very interested in cardiac atrophy,” said Jeffery Molkentin, PhD, co-director of the Heart Institute at Cincinnati Children’s. “It could be the single biggest problem for long-term space flights and astronaut health, especially when re-entering a higher-gravity situation, be it arriving on Mars or returning to Earth.”
Astronauts and cosmonauts have been training in orbit to minimize muscle loss since doctors observed years ago that returning astronauts can often barely walk when they return to Earth. Along the way, clinicians have also observed an increased risk of heart problems during the recovery period.
Molkentin and colleagues’ new findings help explain why the heart is also affected by muscle wasting, which in turn suggests possible new ways to prevent or treat the problem.
A tripartite attack on heart cells
The research team examined mouse models in various ways to attribute the wilting of heart cells to a three-step molecular process.
Like skeletal muscle, the heart can either get larger or smaller depending on the workload. The new research identifies a process by which the thrombospondin-1 gene can lead to a dramatic loss of heart mass.
The overexpression of thrombospondin-1 in the hearts of mice leads to a rapid and fatal loss of heart mass, known as atrophy, by directly activating the signal protein called PERK. Excessive PERK activity in turn triggers a reaction of the transcription factor ATF4, which together directly program the atrophy of heart muscle cells.
The longer these genes are active, the more severe the atrophy becomes. Eliminating or reducing the activity of these genes would block or reduce the atrophy response, which could be an attractive new strategy to combat cardiac muscle loss during prolonged periods of space travel.
“Our results describe a new way of breaking down muscle,” says Molkentin. “More research is needed to develop methods or drugs that can interrupt this signaling pathway through these genes in order to stop cardiac atrophy once it is discovered.”
Researchers have yet to confirm that the process observed in mice also occurs in humans. More work is also needed to determine whether drugs exist (or need to be developed) that can safely control the molecular activity that the research team has identified.
Even if we are unable to replace lost heart muscle tissue in humans, it should be possible to restore weakened or atrophied heart muscle cells to their original state.
About this study
In addition to Molkentin, the co-first authors Davy Vanhoutte, PhD, and Tobias Schips, PhD, (now at Janssen Pharmaceuticals) are involved in this study. Alexander Vo, BS, Kelly Grimes, PhD, Tanya Baldwin, PhD, Matthew Brody, PhD, (now at University of Michigan), Federica Accorero, PhD, (now at Ohio State University), and Michelle Sargent, BS.
Sources of funding for this study include the National Institutes of Health an Molkentin (2R01HL105924) and a grant from the Deutsche Forschungsgemeinschaft an Schips (SCHI 1290 / 1-1).