Findings from cardiac atrophy study sets course for preventing harm during space travel

The new results are a significant step forward in the long battle to prevent, or even cure cardiac atrophy, which can cause fatal heart failure when the body spends a lot of time in space experiencing weightlessness. (Photo credit: TWC India [NASA])

Heart muscle cells do not respond to external stressors in the same manner as skeletal muscle cells do in many instances. According to a recent study led by scientists at Cincinnati Children’s Hospital Medical Center, the heart and skeletal muscles may both waste away at fatally fast rates under certain situations.

The latest findings, which are based on mice studies, are a major step forward in the lengthy struggle to avoid or even reverse cardiac atrophy, which may lead to catastrophic heart failure when the body loses a lot of weight or spends a lot of time in space.

“NASA is very interested in cardiac atrophy,” says Jeffery Molkentin, PhD, Co-Director of the Heart Institute at Cincinnati Children’s. “It might be the single biggest issue for long-period space flights and astronaut health, especially when re-entering a higher-gravity situation, whether that’s arriving at Mars or returning to Earth.”

Since physicians noticed years ago that returning spacefarers were frequently hardly able to walk when they returned to Earth, astronauts and cosmonauts have been exercising in orbit to reduce muscle mass loss. Clinicians have also seen an increased risk of cardiac problems throughout the healing period.

The new discoveries by Molkentin and colleagues help to identify why muscle-wasting diseases impact the heart as well, suggesting new strategies to avoid or cure the problem.

The researchers used a variety of mice models to link cardiac cell withering to a three-step biochemical mechanism. The heart, like skeletal muscle, may grow bigger or smaller depending on effort. The current study identifies a mechanism through which the gene thrombospondin-1 might cause a significant decrease of cardiac mass.

By directly activating the signaling protein PERK, overexpression of thrombospondin-1 in the hearts of mice resulted in a fast and fatal decrease of cardiac mass, known as atrophy. Excessive PERK activity, in turn, generates a response from the transcription factor ATF4, which, in turn, causes heart muscle cells to atrophy.

The atrophy gets more severe the longer these genes are active. The atrophy response may be blocked or reduced by removing or decreasing the activation of these genes, which could be an appealing new method for treating heart muscle loss over long durations of space flight.

“Our findings describe a new pathway of muscle mass loss,” Molkentin says. “More research is needed to develop methods or drugs that can interrupt this signaling pathway through these genes to stop cardiac atrophy once detected.”

Researchers now must validate that the mechanism shown in mice occurs in humans. More research is needed to see if medicines exist (or need to be created) that can safely control the molecular activity discovered by the research team.

The findings were reported in detail in Nature Communications on June 24, 2021.

Abstract. The thrombospondin (Thbs) family of secreted matricellular proteins are stress- and injury-induced mediators of cellular attachment dynamics and extracellular matrix protein pro-duction. Here we show that Thbs1, but not Thbs2, Thbs3 or Thbs4, induces lethal cardiacatrophy when overexpressed. Mechanistically, Thbs1 binds and activates the endoplasmicreticulum stress effector PERK, inducing its downstream transcription factor ATF4 andcausing lethal autophagy-mediated cardiac atrophy. Antithetically,Thbs1−/−mice developgreater cardiac hypertrophy with pressure overload stimulation and show reduced fasting-induced atrophy. Deletion of Thbs1 effectors/receptors, including ATF6α, CD36 or CD47does not diminish Thbs1-dependent cardiac atrophy. However, deletion of the gene encodingPERK in Thbs1 transgenic mice blunts the induction of ATF4 and autophagy, and largelycorrects the lethal cardiac atrophy. Finally, overexpression of PERK or ATF4 using AAV9gene-transfer similarly promotes cardiac atrophy and lethality. Hence, we identified Thbs1-mediated PERK-eIF2α-ATF4-induced autophagy as a critical regulator of cardiomyocyte sizein the stressed heart.

Results. Thbs1 is induced in diseased hearts where it mediates ERstress. Thbs1 protein expression is strongly induced in the adultmouse heart with injury or stress stimulation, such as duringcardiac hypertrophy mediated by 2 weeks of transverse aorticconstriction (TAC) or cardiomyocyte-specific overexpression ofactivated calcineurin (ΔCnA TG)14(Fig.1a). Thbs1 was alsoinduced in the hearts ofCsrp3−/−mice15, a model of dilatedcardiomyopathy (Fig.1a). Immunohistochemical characterizationof hearts fromΔCnA TG mice (Fig.1b) and mice subjected to2 weeks of TAC (Fig.1c) showed that Thbs1 protein was robustlyinduced and localized inside cardiomyocytes, with appreciablyless Thbs1 protein expression observed withinfibroblasts orendothelial cells as marked by vimentin expression

Vanhoutte, D., Schips, T.G., Vo, A. et al. Thbs1 induces lethal cardiac atrophy through PERK-ATF4 regulated autophagy. Nat Commun 12, 3928 (2021). https://doi.org/10.1038/s41467-021-24215-4

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