Myosin folding boosts solubility in cardiac muscle sarcomeres

The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiom...

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Bibliographic Details
Published in:JCI insight 2024-04, Vol.9 (8)
Main Authors: Kelly, Colleen M, Martin, Jody L, Previs, Michael J
Format: Article
Language:English
Subjects:
Animals
Benzylamines
Cardiomyopathy, Hypertrophic - metabolism
Green Fluorescent Proteins - genetics
Green Fluorescent Proteins - metabolism
Humans
Male
Mice
Myocardial Contraction
Myocardium - metabolism
Myosins - metabolism
Protein Folding
Sarcomeres - metabolism
Solubility
Uracil - analogs & derivatives
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Summary:The polymerization of myosin molecules into thick filaments in muscle sarcomeres is essential for cardiac contractility, with the attenuation of interactions between the heads of myosin molecules within the filaments being proposed to result in hypercontractility, as observed in hypertrophic cardiomyopathy (HCM). However, experimental evidence demonstrates that the structure of these giant macromolecular complexes is highly dynamic, with molecules exchanging between the filaments and a pool of soluble molecules on the minute timescale. Therefore, we sought to test the hypothesis that the enhancement of interactions between the heads of myosin molecules within thick filaments limits the mobility of myosin by taking advantage of mavacamten, a small molecule approved for the treatment of HCM. Myosin molecules were labeled in vivo with a green fluorescent protein (GFP) and imaged in intact hearts using multiphoton microscopy. Treatment of the intact hearts with mavacamten resulted in an unexpected > 5-fold enhancement in GFP-myosin mobility within the sarcomere. In vitro biochemical assays suggested that mavacamten enhanced the mobility of GFP-myosin by increasing the solubility of myosin molecules, through the stabilization of a compact/folded conformation of the molecules, once disassociated from the thick filaments. These findings provide alternative insight into the mechanisms by which molecules exchange into and out of thick filaments and have implications for how mavacamten may affect cardiac contractility.
ISSN:2379-3708
2379-3708
DOI:10.1172/jci.insight.178131