Nonmuscle α-Actinin-4 Couples Sarcomere Function to Cardiac Remodeling

Area of Science:

• Cardiovascular Biology
• Muscle Physiology
• Molecular Cardiology

Background:

• Cardiac myocytes (CMs) utilize nonmuscle sarcomere proteins with unclear roles.
• The relevance of nonmuscle sarcomere proteins to heart function is largely unknown.

Purpose of the Study:

• To investigate the function and localization of nonmuscle alpha-actinin-4 (ACTN4) in cardiac myocytes.
• To determine the impact of ACTN4 on sarcomere assembly, contractility, and cardiac remodeling.

Main Methods:

• Compared expression of nonmuscle vs. muscle-specific sarcomere proteins in CMs.
• Utilized siRNA, overexpression, and pharmacological methods to study ACTN4 in iPSC-CMs.
• Evaluated ACTN4's role in zebrafish and mouse models, and human heart failure cohorts.

Main Results:

• ACTN4 localizes to the sarcomere Z-disc with ACTN2 in human, mouse, and zebrafish.
• ACTN4 depletion in iPSC-CMs increased sarcomere assembly, contractility, and hypertrophy.
• ACTN4 knockout in zebrafish caused hypercontractility and atrial enlargement.
• Ventricular ACTN4 upregulation occurred in mouse pressure overload and is linked to human heart failure.

Conclusions:

• Nonmuscle alpha-actinin-4 (ACTN4) populates the cardiac Z-disc and regulates sarcomeric architecture.
• ACTN4 influences cardiac contractility at cellular and tissue levels.
• Altered ventricular ACTN4 levels are associated with cardiac remodeling and may affect heart failure prognosis.