Calcium diffusion and mechanosensing

 The first part of my project aims at collecting as much as possible (AKA "all") the current knowledge of the mechanosensing mechanism, or WHY and HOW the super-relaxed myosin heads decide to rise up and start the actomyosin cycle to produce force.

Here, I report a striking result from Brunello and Fusi, at King's College of London, published in PNAS in march 2020. 

The applied the X-ray diffraction technique to study the thick filament structure in cardiac muscle. Small angle XRay diffraction is one of the most used techniques to dynamically analyze the state of the thick filament, thanks to the different spacing that the myosin motors have in each state. The interpretation of the data is made through mathematical models of predicted X-ray diffractions from different populations. Despite it is necessarily based on some assumptions, its interpretation can be considered well established in the literature.

I do not report here the beautiful pictures reported in the paper but you can access it directly from the link above. The beauty of this paper, from the mechanical perspective, is that the authors implemented the model to distinguish the state of the myosin motors in the different parts of the thick filament, especially:

- the C-zone, a central region of the "half thick filament" in which is present the Myosin binding protein C (MyBPC)

-the D-zone, the last part of the half thick filament, toward the Z-line, where the MyBPC is not present

Their data show a different activation during a twitch of the different parts of the thick filament. The motors in the D-zone are closer to the calcium release units in mammalian muscles, so are probably the first to be activated. Their activation induced the activation of the motors in the C-zone through the mechanosensing mechanism, and at the peak of the twitch only these motors are sustaining the force. 

I have already shown in-silico through a mathematical model, that the principle of the mechanosensing, i.e. the idea that the thick filament sense the tension sustained by it to regulate the probability of activation of the myosin motors, implicitly lead to differences in the local activation, from the tip of the thick filament to the M-line, the center of the sarcomere (link).  Each motor generate tension on the thick filament only from its position toward the M-line, because of the geometry of the sarcomere, so the tip is the region with the lowest number of force-activated motors.

The new results shown in Brunelli, Fusi et al. suggests that also the calcium diffusion has a specific role in the sequential activation of the thick filament. Therefore part of the project aims at analyzing the effect of the calcium diffusion within the sarcomeres.