Dilated cardiomyopathy myosin mutants have reduced force-generating capacity

Area of Science:

• Cardiovascular Biology
• Molecular Muscle Physiology
• Biochemistry

Background:

• Dilated cardiomyopathy (DCM) and hypertrophic cardiomyopathy (HCM) are serious heart conditions.
• Cardiac myosin mutations are a known cause of these cardiomyopathies.
• Understanding myosin's motor domain function is crucial for disease mechanisms.

Purpose of the Study:

• To functionally characterize the motor domains of five DCM-causing mutations in human β-cardiac myosin.
• To elucidate the specific kinetic alterations in the ATPase cycle caused by DCM mutations.
• To compare the functional effects of DCM mutations with previously studied HCM mutations.

Main Methods:

• Kinetic analyses of individual ATPase cycle steps.
• Measurement of rate constants for ATP binding, hydrolysis, and ADP release.
• Determination of altered affinities for ATP, ADP, and actin.
• Modeling of the complete ATPase contraction cycle.

Main Results:

• Each DCM mutation altered distinct steps in the myosin ATPase cycle.
• Four DCM mutations reduced the myosin duty ratio by decreasing force-holding complex occupancy.
• DCM mutations blunted the load-induced increase in ADP release rate.
• DCM mutants showed more economical ATP utilization compared to wild-type and HCM mutants.

Conclusions:

• DCM-causing myosin mutations lead to impaired force generation and holding capacity.
• Deficits in the force-holding state underlie the functional impairment in DCM.
• The kinetic alterations caused by DCM mutations differ from those in HCM, despite similar phenotypes.