A fluorescent folding reporter uncovers myosin misfolding as a driver of Hypertrophic Cardiomyopathy

Arnese, R.; Dexheimer, P. J.; Escobar Doncel, B.; Krueger, L.; Adhikari, G.; Krpan, N.; Sehr, D.; Kley, J.; Deszcz, L.; Meinhart, A.; Kirstein, J.; Clausen, T.

doi:10.1101/2025.02.10.636595

bioRxiv · 10.1101/2025.02.10.636595

A fluorescent folding reporter uncovers myosin misfolding as a driver of Hypertrophic Cardiomyopathy

Arnese, R.·Dexheimer, P. J.·Escobar Doncel, B.·Krueger, L.·Adhikari, G.·Krpan, N.·Sehr, D.·Kley, J.·Deszcz, L.·Meinhart, A.·Kirstein, J.·Clausen, T.

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Abstract

Hypertrophic cardiomyopathy (HCM) is a fatal genetic disorder causing the thickening of ventricular walls in the heart muscle. While certain mutations in cardiac myosin deregulate ATPase activity, the pathology mechanism of most HCM mutations is not known. Here, by designing a fluorescent reporter to monitor myosin folding in cells, we uncovered a distinct class of HCM mutations that cause graded defects in myosin maturation. Using C. elegans as a disease model, we found that folding deficient HCM variants cause myofilament disruption, impaired motility, and reduced lifespan. Dietary restrictions resulted in a near-complete recovery from these detrimental defects by activating autophagy pathways through insulin/TOR signaling. In conclusion, our study identifies myosin misfolding as an important driver of HCM, revealing therapeutic opportunities to counteract muscle protein disorders.

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Arnese, R., Dexheimer, P. J., Escobar Doncel, B., Krueger, L., Adhikari, G., Krpan, N., Sehr, D., Kley, J., Deszcz, L., Meinhart, A., Kirstein, J., Clausen, T.. 2025-02-11. A fluorescent folding reporter uncovers myosin misfolding as a driver of Hypertrophic Cardiomyopathy. https://doi.org/10.1101/2025.02.10.636595

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