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Significance This paper represents a major advance in understanding intrinsic heart beat regulation, because it provides an integrated view of the Frank–Starling law that combines mechanical, structural, and energetic aspects of heart performance. We show that mechanosensing in the myosin filament adjusts the number of myosin motors recruited from the off, ATP hydrolysis-unavailable state to the systolic force. In this way, the energetic cost of the heart beat is tuned to the end systolic pressure–volume relation. These results elucidate a plausible mechanistic link between the mutations that affect the structure of the myosin filament and cause hypercontractility and/or loss of contractile efficiency and dysregulation of the control by the stress-sensing mechanism on the state of the myosin motors.

Myosin filament activation in the heart is tuned to the mechanical task