Muscle force is directly proportional to the number of myosin motors going through the so-called cross-bridge cycle, the ATP-driven interaction between myosin proteins, protruding from the thick filament, and actin proteins, forming the thin filament. Classically, the calcium concentrations ([Ca2+]) in the myofibrillar space is known to modulate the activation of the thin filament and, through it, the number of detached but active (ON, pointing toward the thin filament) myosin motors, which generate the cross-bridges.
However, in 2010, two detached states have been identified, biochemically defined on the basis of their rate of ATP consumption: a classical disordered relaxed state (DRX) and an unexpected stable state with an ATPase rate of one order of magnitude lower, the super-relaxed state (SRX). This SRX state has also been proposed to be the biochemical counterpart of the structurally defined detached state where motors lie on the thick filament and are unable to interact with activated actin (OFF state).
Importantly, ground-breaking data in 2015 have proved the existence of an internal mechano-sensing (MS) mechanism that relates the ratio of ON-to-OFF motors to the tension sustained by the thick myosin filament (Figure 1).
Yet the molecular bases of the MS mechanism remain mostly unknown, and this limits the strategies to address cardiac pathologies related to its dysfunction.
The MS mechanism creates a critical cellular feedback mechanism, in which malfunction can be at play in hypertrophic cardiomyopathies (HCM). Accordingly, the pharmacological “stabilization” of the OFF state has been shown to prevent or reduce HCM consequences, a therapeutic option that already reached the clinical stage. Then, the MS mechanism play a fundamental role in our basic understanding of the physiological aspects of the skeletal and cardiac muscle contraction, but also it has implications in the treatment of hypertrophic and dilated cardiomyopathies, allowing the developed of a drug for the treatment of HCM that, in essence, is a stabilizer of the OFF state.
On these grounds, the project wants to shape the theoretical description of this mechanism and usher it into a multiscale model - from the molecule to the organ. Doing so will enable to create a benchmark to drive pharmacological applications, aiming at reducing the failure rate in this drug discovery pipeline.
At its conclusion, the project made a substantial contribution to highlight the differences between the biochemically defined SRX state and structurally defined Off state, and the interconnected mechanism between the thin filament activation and the thick filament activation through a cross-talk mechanism. Moreover, the project shown the need to characterize the diffusion of calcium ions inside the muscle cell, to properly understand the mechanical activation of the thick filament.
As a long-term goal reached by the project, a cluster of researchers with complementary expertise has been created at the University of Padova and integrated, as a crucial node, in an international network of collaborations, both within Europe and outside it. The collaboration will foster new results in the aim of personalized medicine.
