The role of alpha actinin paralogs in cardiac hypertrophy and contractile force production.

Abstract

Sarcomeres are the basic contractile unit within heart muscle cells (cardiac myocytes) that drive each heartbeat. New sarcomere formation (sarcomerogenesis) is concomitant with cardiac myocytes enlargement and is associated with physiological heart growth and cardiomyopathies. A detailed understanding of sarcomerogenesis is of high interest as it would inform our knowledge of both normal and pathological heart biology. Each sarcomere is bordered by Z-lines which mechanically link adjacent sarcomeres within myofibrils to transmit the forces of contraction. A key structural protein at Z-lines is the muscle-specific actin filament bundler, α-actinin 2. Depletion of α-actinin 2 from cardiac myocytes disrupts sarcomerogenesis, but nothing is known about the roles of other α-actinin paralogs. α-actinin 4—sometimes called a “non-muscle” paralog—is expressed in cardiac myocytes ∼30 fold lower than α-actinin 2. Using an assay we developed using cultured iPSC-derived cardiac myocytes, we show that α-actinin 4 colocalizes with α-actinin 2 both in the precursors of sarcomeres as well as within the Z lines of sarcomeres. Unlike the loss of sarcomeres due to the depletion of α-actinin 2, depletion of α-actinin 4 resulted in larger cardiac myocytes with more sarcomeres. Our data indicates that this is due to a stabilization of α-actinin 2. We hypothesized that depletion of α-actinin 4 in vivo would result in an enlargement of the heart. Therefore, we depleted α-actinin 4 from zebrafish embryos. Zebrafish have a two chambered heart, which consists of an atrium and ventricle. To our surprise, only the atrium was significantly enlarged. Ongoing work is suggestive of a mechanism in which the presence of α-actinin 4 within cardiac myocytes of the atrium reduces the number, size, and force producing capabilities of sarcomeres. This mechanism could explain why the atrium is physically weaker than the ventricle.