Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PL012

Keynote Lecture

Tuning the heart beat through cytoskeletal regulation

B. L. Prosser1

1. University of Pennsylvania, Pennsylvania, Pennsylvania, United States.

The pumping of the heart is controlled by the coordinated contraction of around 9 billion cardiomyocytes, muscle cells that stretch and contract with each heart beat. Internal cytoskeletal networks must somehow accommodate these large and rapid geometric changes while maintaining their structural integrity. We have found that with each beat, cardiomyocyte microtubules buckle into short wavelength sinusoids, providing an almost-spring like resistance to cardiomyocyte contraction (Robison et al., Science 2016). This buckling behavior depends on the post-translational "detyrosination" of microtubules, which influences the buckling mode by cross-linking microtubules to other cytoskeletal elements and increasing microtubule stability. This cross-linked cytoskeletal network provides a viscous resistance to myocyte motion, stiffening the myocyte during both contraction and diastolic stretch. Further, we identified a stark upregulation and stabilization of microtubules and intermediate filaments as a conserved signature of end-stage human heart failure. This cytoskeletal upregulation increases the viscous impediment to myocyte motion and contributes to contractile dysfunction in patient cells. Using pharmacologic and genetic approaches to manipulate microtubules and specifically to reduce detyrosination, we can robustly lower the stiffness and improve the contractility of failing human cardiomyocytes (Chen et al., Nature Med 2018). Together, this work identifies detyrosinated microtubules as a novel mechanical element within the beating heart cell and a promising new target for the treatment of human heart failure.

Where applicable, experiments conform with Society ethical requirements