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Abstract 390: Actin Arcs are Essential Templates for Sarcomere Assembly in Cardiomyocytes

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Τίτλος: Abstract 390: Actin Arcs are Essential Templates for Sarcomere Assembly in Cardiomyocytes
Συγγραφείς: Dylan T Burnette, Aidan Fenix, Nilay Taneja, Annabelle Williams, David Bader, Jennifer Gutzman, Matthew Tyska
Πηγή: Circulation Research. 121
Στοιχεία εκδότη: Ovid Technologies (Wolters Kluwer Health), 2017.
Έτος έκδοσης: 2017
Θεματικοί όροι: 0301 basic medicine, 03 medical and health sciences, 0302 clinical medicine
Περιγραφή: The sarcomere is the basic contractile unit within cardiomyocytes. The proper assembly of sarcomeres during development and their maintenance during homeostasis are critical for the contraction of the heart. How molecular components of sarcomeres assemble remains a major unanswered question. Here we use newly plated h uman i nduced pluripotent stem cell-derived c ardio m yocytes (hiCM) combined with high-resolution microscopy to elucidate the steps of de novo sarcomere assembly. We found that sarcomere formation was preceded by bundles of actin filaments resembling the so-called “actin arcs” prevalent in migrating non-muscle cells. Live-cell imaging revealed that sarcomeres appeared along the length of actin arcs; suggesting they are acting as a template for sarcomere assembly. Actin arc formation in non-muscle cells is dependent on the actin filament nucleator, formin, and the molecular motor, n on-muscle m yosin II (NMII). Inhibiting formin with the small molecule SMIFH2 in hiCM stopped the formation of actin arcs and subsequent sarcomere assembly, but had no effect on pre-assembled sarcomeres. We found that two isoforms of NMII, NMIIA and NMIIB, localized to the actin arcs in hiCM. Knockdown of NMIIB, but not NMIIA, in hiCM resulted in a loss of sarcomere assembly, but, much like formin inhibition, did not affect pre-assembled sarcomeres. To test if loss of NMIIB resulted in less sarcomere assembly in vivo , we knocked down NMIIB in zebrafish embryos, and found a significant loss of sarcomeres within both the atrium and ventricle. Finally, we use super-resolution microscopy to show that NMII and the muscle isoform, β m yosin II (βMII), are found in the same filaments in hiCM and in vivo in neonatal mice and in human patients with hypertrophic cardiomyopathy, suggesting individual molecular components within actin arcs (e.g., NMII) could be acting as seeds for their muscle counterparts (e.g., βMII). Taken together, our data supports a model in which contractile systems in cardiomyocytes evolved from non-muscle contractile systems. Furthermore, cardiomyocytes still use some non-muscle contractile components for sarcomere assembly during development, and potentially during aberrant sarcomere formation during hypertrophic cardiomyopathy.
Τύπος εγγράφου: Article
Γλώσσα: English
ISSN: 1524-4571
0009-7330
DOI: 10.1161/res.121.suppl_1.390
Αριθμός Καταχώρησης: edsair.doi...........ebbc0e1077de40ca3878ef7ba4c98bea
Βάση Δεδομένων: OpenAIRE
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  Data: The sarcomere is the basic contractile unit within cardiomyocytes. The proper assembly of sarcomeres during development and their maintenance during homeostasis are critical for the contraction of the heart. How molecular components of sarcomeres assemble remains a major unanswered question. Here we use newly plated h uman i nduced pluripotent stem cell-derived c ardio m yocytes (hiCM) combined with high-resolution microscopy to elucidate the steps of de novo sarcomere assembly. We found that sarcomere formation was preceded by bundles of actin filaments resembling the so-called “actin arcs” prevalent in migrating non-muscle cells. Live-cell imaging revealed that sarcomeres appeared along the length of actin arcs; suggesting they are acting as a template for sarcomere assembly. Actin arc formation in non-muscle cells is dependent on the actin filament nucleator, formin, and the molecular motor, n on-muscle m yosin II (NMII). Inhibiting formin with the small molecule SMIFH2 in hiCM stopped the formation of actin arcs and subsequent sarcomere assembly, but had no effect on pre-assembled sarcomeres. We found that two isoforms of NMII, NMIIA and NMIIB, localized to the actin arcs in hiCM. Knockdown of NMIIB, but not NMIIA, in hiCM resulted in a loss of sarcomere assembly, but, much like formin inhibition, did not affect pre-assembled sarcomeres. To test if loss of NMIIB resulted in less sarcomere assembly in vivo , we knocked down NMIIB in zebrafish embryos, and found a significant loss of sarcomeres within both the atrium and ventricle. Finally, we use super-resolution microscopy to show that NMII and the muscle isoform, β m yosin II (βMII), are found in the same filaments in hiCM and in vivo in neonatal mice and in human patients with hypertrophic cardiomyopathy, suggesting individual molecular components within actin arcs (e.g., NMII) could be acting as seeds for their muscle counterparts (e.g., βMII). Taken together, our data supports a model in which contractile systems in cardiomyocytes evolved from non-muscle contractile systems. Furthermore, cardiomyocytes still use some non-muscle contractile components for sarcomere assembly during development, and potentially during aberrant sarcomere formation during hypertrophic cardiomyopathy.
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