Key result
Cytoplasmic actin deletion protects against pressure overload-induced cardiac hypertrophy by boosting sarcolemmal stability.
Why the study?
The role of the cardiomyocyte cytoplasmic β-actin and γ-actin network in sarcolemmal membrane integrity and cardiac disease is understudied and unclear.
Deletion of the cytoplasmic β- and γ-actin network in adult mouse cardiomyocytes paradoxically protects the heart from pressure overload and dystrophin-deficiency by inducing compensatory α-actin expression and augmenting sarcolemmal stability.
Hypothesis-generating for actin isoform compensation in hypertrophy; leaves open translation to human pressure-overload disease.
The actin cytoskeleton of the cardiomyocyte is organized into two structurally and functionally distinct filament networks. The sarcomeric thin filaments, built primarily from cardiac α-actin (αCA), generate contractile force, whereas a separate subsarcolemmal cytoplasmic network, built from β-actin ( Actb gene) and γ-actin ( Actg1 gene), lies beneath the sarcolemma and is comparatively understudied in the mature heart. We hypothesized that this cytoplasmic actin network is required for sarcolemmal membrane integrity, signal transduction, and mechanosensing in the adult cardiomyocyte, and we generated cardiomyocyte-specific Actb and Actg1 double-gene deleted mice, using loxP (fl)-targeted Actb fl/fl and Actg1 fl/fl alleles combined with an αMHC (Myh6) promoter-driven Cre-recombinase transgene, to test this directly. Deletion of cytoplasmic β-actin and γ-actin from cardiomyocytes ( Actb/g1 fl/fl-Myh6-Cre mice) drove compensatory upregulation of a γ-interferon like stress response with compensatory upregulation of skeletal α-actin (αSKA) and smooth muscle α-actin (αSMA) protein in adult cardiomyocytes, without altering baseline cardiac structure or function. To test if lost β-actin and γ-actin in the mouse heart impacts sarcolemmal stability, we crossed Actb/g1 fl/fl-Myh6-Cre mice onto the dystrophin-deficient mdx background, which is characterized by a fragile sarcolemma. Unexpectedly, hearts from Actb/g1 fl/fl-Myh6- Cre ; mdx mice showed greater membrane stability than mdx hearts alone with intact Actb / Actg1 . We also observed that Actb/g1 fl/fl-Myh6-Cre mice subjected to chronic pressure overload by transverse aortic constriction (TAC) were protected and developed less cardiac hypertrophy, had better preserved systolic function, and improved survival. Together, these data indicate induction of the cytoplasmic β-actin/γ-actin network in the heart during disease stimulation is maladaptive and weakens the sarcolemma, and 2 downstream mechanisms are considered that could mediate this effect.
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Kuwabara et al. (2026) studied Heart disease (pressure overload and muscular dystrophy models). Cardiomyocyte-specific Actb and Actg1 deletion vs. Control mice with intact Actb and Actg1 was evaluated on Cardiac hypertrophy, systolic function, and survival (post-TAC), and membrane stability (mdx model). Cardiomyocyte-specific deletion of cytoplasmic β-actin and γ-actin in mice induced compensatory upregulation of αSKA and αSMA, which augmented sarcolemmal stability and protected against pressure overload-induced cardiac hypertrophy and dysfunction.
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