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bioRxiv · 10.1101/348920

Cardiac and Skeletal Actin Substrates Uniquely Tune Cardiac Myosin Strain-Dependent Mechanics

Wang, Y.·Ajtai, K.·Burghardt, T. P.
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Abstract

Native cardiac ventricular myosin ({beta}mys) translates actin under load by transducing ATP free energy into mechanical work on actin during muscle contraction. Unitary {beta}mys translation of actin is the myosin step-size. In vitro and in vivo {beta}mys regulates contractile force and velocity by remixing 3 different step-sizes with stepping frequencies autonomously adapted to workload. Cardiac and skeletal actin isoforms have a specific 1:4 stoichiometry in normal adult human ventriculum. Human adults with inheritable hypertrophic cardiomyopathy (HCM) up-regulate skeletal actin in ventriculum suggesting that increasing skeletal/cardiac actin stoichiometry also adapts myosin force-velocity to respond to the muscles inability to meet demand.\n\nNanometer scale displacement of quantum dot (Qdot) labeled actin under resistive load when impelled by {beta}mys measures single myosin force-velocity in vitro in the Qdot assay. Unitary displacement classification constraints introduced here better separates myosin based signal from background upgrading step-size spatial resolution to the sub-nanometer range. Single {beta}mys force-velocity for skeletal vs cardiac actin substrates was compared using the Qdot assay.\n\nTwo competing myosin strain-sensitive mechanisms regulate step-size choices dividing mechanical characteristics into low- and high-force regimes. The actin isoforms alter myosin strain-sensitive regulation such that onset of the high-force regime, where a short step-size is a large or major contributor, is offset to higher loads by a unique cardiac ELC N-terminus/cardiac-actin contact at Glu6/Ser358. It modifies {beta}mys force-velocity by stabilizing the ELC N-terminus/cardiac-actin association. Uneven onset of the high-force regime for skeletal vs cardiac actin dynamically changes force-velocity characteristics as skeletal/cardiac actin fractional content increases in diseased muscle.

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Wang, Y., Ajtai, K., Burghardt, T. P.. 2018-06-15. Cardiac and Skeletal Actin Substrates Uniquely Tune Cardiac Myosin Strain-Dependent Mechanics. https://doi.org/10.1101/348920

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