Key result
HCM-linked myosin mutations cause graded defects in myosin folding that disrupt myofilaments and reduce lifespan in C. elegans, effects that are mitigated by caloric restriction and autophagy activation.
Why the study?
While certain cardiac myosin mutations deregulate ATPase activity in hypertrophic cardiomyopathy, the pathological mechanism of most HCM mutations is not known.
Do dietary restrictions improve myofilament disruption, motility, and lifespan in a C. elegans model of Hypertrophic Cardiomyopathy?
Do dietary restrictions improve myofilament disruption, motility, and lifespan in a C. elegans model of Hypertrophic Cardiomyopathy?
Myosin misfolding is identified as a driver of HCM, and dietary restriction-induced autophagy can counteract these defects in a C. elegans model.
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 et al. (2025) studied Hypertrophic Cardiomyopathy. Caloric restriction and insulin/TOR signaling inhibition vs. Well-fed state / wildtype signaling was evaluated on Myosin folding and C. elegans motility. HCM-linked myosin mutations cause graded defects in myosin folding that disrupt myofilaments and reduce lifespan in C. elegans, effects that are mitigated by caloric restriction and autophagy activation.
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