Tubulin acetylation increases cytoskeletal stiffness to regulate mechanotransduction in striated muscle

Abstract Microtubules tune cytoskeletal stiffness to regulate the mechanics and mechanotransduction of striated muscle. While recent evidence suggests that microtubules enriched in detyrosinated α-tubulin are responsible for these effects in healthy muscle, and for their excess in disease, the possible contribution from several other α-tubulin modifications has not been investigated. Here we used genetic or pharmacologic strategies in isolated cardiomyocytes or skeletal myofibers to increase the level of acetylated α-tubulin without altering the level of detyrosinated α-tubulin. We show that microtubules enriched in acetylated α-tubulin contribute to the cytoskeletal stiffness and viscoelastic resistance, showing slowed rates of contraction and relaxation during unloaded contraction, and increased activation of NADPH Oxidase 2 (Nox2) by mechanotransduction. Together these findings add to growing evidence that microtubules contribute to the mechanobiology of striated muscle in health and disease.