Recent experimental evidence in skeletal muscle demonstrated the existence of a thick-filament mechanosensing mechanism, acting as a second regulatory system for muscle contraction, in addition to calcium-mediated thin filament regulation. These two systems cooperate to generate force, but the extent to which their interaction is relevant in physiologically contracting muscle was not yet assessed experimentally. Therefore, we included both regulatory mechanisms in a mathematical model of rat trabecula and whole ventricle. No additional regulatory mechanisms were considered in our model. Our simulations suggested that mechanosensing regulation is not limited to the initial phases of contraction but, instead, is crucial during physiological contraction. An important consequence of this finding is that titin mediated thick filament activation can account for several sarcomere length dependencies observed in contracting muscle. Under the hypothesis that a similar mechanism is acting on cardiac muscle, and within the limits of a finite element left ventricle model, we predict that these two regulatory mechanisms are crucial for the molecular basis of the Frank-Starling law of the heart.