α- and β-myosin II can be non-uniformly distributed within the cardiac sarcomere.

In humans, the forces of the heartbeat are generated by both "fast" α-myosin II and "slow" β-myosin II molecular motors. Here, we report that α-myosin II and β-myosin II can take on an anisotropic arrangement within cardiac sarcomeres, the minimal contractile unit of cardiac muscle. In induced pluripotent stem cell (iPSC)-derived cardiac myocytes, we find that α-myosin II is distributed primarily within the central region of the filaments, being mostly absent from the distal ends, whereas β-myosin II is distributed along the entire filament. We measure that the outer bounds of α-myosin II in filament stacks are shorter than those of β-myosin II in both the zebrafish embryo and adult human myocardium. Our findings suggest that the two motors that drive the human heartbeat can have a specific and non-uniform arrangement within cardiac thick filaments, which may be thus divided into two distinct mechanical regions based on myosin II motor composition. We suggest potential roles for each motor during contraction-relaxation based on these distributions and recent literature.