?Detyrosinated microtubules in cardiomyocyte mechanics? The microtubule cytoskeleton performs a number of cellular functions including cargo transport and structural support. In certain forms of heart disease there is an extensive proliferation and post-translational modification of the microtubule network that correlates with declining contractility. It has previously been suggested that the increased density of microtubules may provide an intrinsic mechanical resistance to cardiac contraction, and therefore that targeting microtubules may restore contractility in heart disease. However, a detailed mechanistic understanding of how microtubules provide resistance is lacking, and this line of research has stalled. The PI and colleagues have made two important advances to move this field forward. First, we have developed imaging and labeling tools to observe and characterize microtubule behavior in beating heart cells. We observe that microtubules function like springs in the beating heart, a challenge to the conventional view. These spring like microtubules provide a mechanical resistance to heart cell contraction and stretch. Second, we have identified a novel element that appears to regulate the mechanical properties of the cytoskeleton. In new published (Kerr et al. Nature Communications, 2015) and preliminary evidence we show that detyrosination, a post-translational modification of tubulin, regulates the compression-resistance of the cytoskeleton and alters the spring-like behavior of microtubules. Importantly, reducing detyrosination decreases mechanical resistance and increases myocyte contractility, suggesting a potential therapeutic benefit in heart disease. In this proposal we will thus test the hypothesis that detyrosination increases cytoskeletal compression resistance, and that specifically reducing detyrosination can improve contractility in heart failure. We have 3 major goals of our proposal: 1) to determine if increasing detyrosination is sufficient to impair myocyte mechanics; 2) to determine the molecular mechanism by which detyrosination influences cytoskeletal mechanics; 3) to determine if increased detyrosination impairs myocyte function in human heart disease. Our team of cardiomyocyte physiologists, cytoskeletal biologists, and a cardiac physician scientist are ideally suited to achieving these goals. The successful completion of this work will reveal mechanistic insight into how detyrosination alters cytoskeletal mechanics, a finding with broad relevance to cell biology and with specific translational implications for human cardiac disease.
This proposal will determine how a modification of the microtubule cytoskeleton can increase the internal, mechanical resistance to heart cell contraction. We will determine if elevated levels of this modification, called detyrosination, impair cardiomyocyte contraction in human heart failure, and if therapeutic reductions of detyrosination are beneficial in restoring contractile function in failing heart cells.
| Chen, Christina Yingxian; Caporizzo, Matthew A; Bedi, Kenneth et al. (2018) Suppression of detyrosinated microtubules improves cardiomyocyte function in human heart failure. Nat Med 24:1225-1233 |
| Caporizzo, Matthew Alexander; Chen, Christina Yingxian; Salomon, Alexander Koizumi et al. (2018) Microtubules Provide a Viscoelastic Resistance to Myocyte Motion. Biophys J 115:1796-1807 |
| Robison, Patrick; Prosser, Benjamin L (2017) Microtubule mechanics in the working myocyte. J Physiol 595:3931-3937 |
| Robison, Patrick; Caporizzo, Matthew A; Ahmadzadeh, Hossein et al. (2016) Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes. Science 352:aaf0659 |
