Proposed mechanism for the length dependence of the force developed in maximally activated muscles

Abstract

The molecular bases of the Frank-Starling law of the heart and of its cellular counterpart, the length dependent activation (LDA), are largely unknown. However, the recent discovery of the thick filament activation, a second pathway beside the well-known calcium mediated thin filament activation, is promising for elucidating these mechanisms. The thick filament activation is mediated by the tension acting on it through the mechano-sensing (MS) mechanism and can be related to the LDA via the titin passive tension. Here, we propose a mechanism to explain the higher maximum tension at longer sarcomere lengths generated by a maximally activated muscle and test it in-silico with a single fiber and a ventricle model. The active tension distribution along the thick filament generates a reservoir of inactive motors at its free-end that can be activated by passive tension on a beat-to-beat timescale. The proposed mechanism is able to quantitatively account for the observed increment in tension at the fiber level, however, the ventricle model suggests that this component of the LDA is not crucial in physiological conditions.

Cardiac myosin super relaxation (SRX): a perspective on fundamental biology, human disease and therapeutics

“…These include pre-load of the ventricle and post-translational modification. It has become clear that SRX recruitment contributes to the Frank-Starling law and is important in adapting cardiac output ( Marcucci et al, 2019 ; Reconditi et al, 2017 ). Myosin SRX has its fundamental roots in earlier evolutionary phylogenies of myosins, and is intricately controlled by the interactions that form the basis of the myosin interacting heads motif (IHM) ( Alamo et al, 2016 ).…”

Sarcomere protein modulation: The new frontier in cardiovascular medicine and beyond

“…Thus, on the one hand, the force generated by the sarcomere depends on the proportion of open-headed myosins and on the number of myosin-actin cross-bridge interactions; on the other, SRX myosins are deemed essential for long-term, sustainable performance of the heart muscle. At any given cardiac cycle, only a fraction of myosin heads are engaged in contraction: maintenance of the SRX state is an evolutionarily conserved energy-saving mechanism critical for maintaining contractile and energetic homeostasis within the cardiomyocyte, allowing a decrease in the metabolic rate during periods of myocardial stress [20,21]. In HCM hearts, SRX myosin dysregulation has been proposed as a main driver of pathophysiology, since disease-causing mutations tend to increase the number of open-headed myosins and promote exaggerated cross-bridge interactions.…”

Increase of resting muscle stiffness, a less considered component of age-related skeletal muscle impairment

“…75 Leaving apart more mechanistic models based on the Huxley 1957 original framework, 76 needed to explain new experimental data at the fiber level (see for instance our previous works). [77][78][79] Hill's model, which contains a passive elastic element to represents the along-fiber passive component due to intra-sarcomeric proteins, has dominated the field for several decades and is still today a widely used tool to model muscle macroscopically. The Hill's model is very flexible, and several implementations have been made to match more detailed behaviors.…”