ATP directly modulates thick filament structure and function in porcine myocardium

Area of Science:

• Cardiology
• Biophysics
• Biochemistry

Background:

• Cardiac contraction relies on myosin-actin cross-bridge cycling powered by ATP hydrolysis.
• In heart failure, reduced myocardial ATP impairs cardiac output and cross-bridge function.
• The direct role of ATP in regulating thick filament activation remains unclear.

Purpose of the Study:

• To investigate the direct effect of adenosine triphosphate (ATP) on cardiac thick filament activation.
• To determine how varying ATP concentrations influence myosin head structural states and cross-bridge kinetics in porcine myocardium.

Main Methods:

• Permeabilized porcine myocardium was exposed to increasing concentrations of ATP.
• Small-angle X-ray diffraction was used to analyze structural transitions in myosin heads.
• Mechanical measurements assessed tension, shortening velocity, and cross-bridge kinetics.

Main Results:

• Increased ATP concentrations induced a structural transition of myosin heads from OFF to ON states.
• Higher ATP accelerated myosin attachment and detachment rates, increasing power output and shortening velocity.
• ATP did not alter maximum calcium-activated tension but right-shifted the tension-calcium curve.

Conclusions:

• Adenosine triphosphate (ATP) directly activates cardiac thick filaments by promoting myosin head detachment from the thick filament backbone.
• Altered ATP levels may contribute to diastolic dysfunction and impaired relaxation in heart failure.
• This study reveals a novel mechanism for ATP in regulating cardiac contractility and suggests potential therapeutic strategies.