# ATP directly modulates thick filament structure and function in porcine myocardium

## TL;DR

This study shows that ATP directly affects the structure and function of thick filaments in pig heart muscle, influencing contraction and relaxation.

## Contribution

The study reveals a direct structural and functional role of ATP in modulating thick filament activation in cardiac muscle.

## Key findings

- Higher ATP concentrations caused myosin heads to transition from ordered OFF states to disordered ON states.
- Increased ATP accelerated myosin attachment and detachment rates and improved power output and shortening velocity.
- Reduced ATP may impair relaxation and contribute to diastolic dysfunction in heart diseases.

## Abstract

Cardiac contraction is achieved through cyclic cross-bridge interactions between overlapping myosin-containing thick filaments and actin-containing thin filaments. This process is powered by ATP hydrolysis by myosin, which must be sufficient for maintaining cardiac output. Myocardial ATP concentration is tightly maintained via several mechanisms. However, in decompensated end-stage heart failure, these mechanisms fail, resulting in depressed myocardial ATP levels, impaired cross-bridge kinetics, and reduced cardiac output. Here, we tested the hypothesis that ATP has a direct effect on thick filament activation by subjecting permeabilized porcine myocardium to increasing concentrations of ATP. Small-angle x-ray diffraction showed that higher ATP concentrations caused a structural transition in myosin heads from quasihelically ordered OFF states, where they are held in close proximity to the thick filament backbone, to disordered ON states, where they are free to move closer to thin filaments. Mechanically, high ATP did not alter maximum calcium-activated tension, although increasing ATP right-shifted the tension versus calcium (Ca2+) curve and accelerated both myosin attachment and detachment rates, consistent with prior studies. Power output and maximum unloaded shortening velocity also significantly increased with increased ATP concentration. Together, our structural and functional results indicate that ATP can directly turn thick filaments ON in porcine myocardium, suggesting a potential mechanism for the excessive proportion of myosin in the inactivated state in certain heart diseases. The profound effect on cross-bridge kinetics also suggests that reduced ATP concentration impairs relaxation and may also play a role in diastolic dysfunction.