A balance of cytoskeletal forces maintains nuclear architecture in the cardiomyocyte

2020

Julie Heffler's cover article in Circulation Research describes how a balance of cytoskeletal forces is required to maintain the integrity of the nucleus of the heart cell. Her work shows that desmin intermediate filaments and their attachments to the nucleus are critical for nuclear homeostasis, and shed light on how disruptions to desmin may lead to "desminopathies", a diverse group of cardiac and skeletal muscle disorders. Click on the link to view the full article!


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Microtubules increase diastolic stiffness in human myocardium

2020

Stiffening of the myocardium and diastolic dysfunction is a prevalent and intractable feature of several types of heart failure. Matt Caporizzo's work demonstrates that microtubules contribute to this stiffening in patient myocardial tissue, and that depolymerizing microtubules can improve diastolic mechanics. His work also indicates that the microtubule contribution to diastolic mechanics becomes less prevalent with large stretches and in heavily fibrotic tissue, where other factors likely contribute more to myocardial stiffness. This work helps refine a patient target population that may benefit from a microtubule based therapy. Click on the link for the full text!


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Cardiac microtubules in health and heart disease

2019

Matt Caporizzo and Christina Chen provide a comprehensive review on the role of microtubules in the cardiomyocyte - their contribution to various homeostatic and mechanical functions in the cell, and how these may be altered in disease. The work also highlights the many unknowns regarding the diverse roles of microtubules in the heart. Click the link for full text!


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Suppressing detyrosinated microtubules improves contractility in human heart failure

2018

Work by Chen et al. demonstrates two key findings: 1) that there is a proliferation and stabilization of microtubules and intermediate filaments in human heart failure, regardless of disease origin. 2) that suppressing detyrosinated microtubules with either genetic or pharmacologic approaches can rescue the contractile function of heart cells from patients with heart failure, about 40-50% back to "normal." This work highlights detyrosinated microtubules as a promising therapeutic target for the treatment of heart failure.
Click on the link to read the paper, or check out the press release here : http://www.newswise.com/articles/view/695927/


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Detyrosinated microtubules buckle and bear load in contracting cardiomyocytes

2016

Our work, in collaboration with folks in Engineering (Caporizzo, Shenoy groups) and Medicine (Margulies), shows that microtubules buckle and bear compressive load in a beating cardiomyocyte. The ability of microtubules to function as molecular shock absorbers is graded by "detyrosination", a post-translational modification of tubulin. Further, we found that detyrosination is increased in cardiomyopathy and correlates with functional decline in certain patient populations. The Prosser lab is actively investigating the efficacy of targeting detyrosination therapeutically to improve cardiac function in heart disease. Patrick Robison is the first author on this manuscript published in Science (a full text link is provided below).


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Press for microtubule buckling in the heart!

2016

Our work on microtubules as molecular "struts" or "shock absorbers" in the beating heart has been featured in the popular press, and in the blog of NIH director Francis Collins. Check out a sampling below:
NIH director blog: https://directorsblog.nih.gov/2016/05/03/a-look-inside-a-beating-heart-cell/
Gizmodo: http://gizmodo.com/microscopic-tubes-inside-beating-heart-cells-work-like-1774530830
Business Insider: http://www.businessinsider.com/a-rare-view-inside-a-beating-heart-cell-2016-5


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Super-Resolution View of Cardiac Microtubules

2015

Current work in the lab is focused on the microtubule cytoskeleton and how it regulates the mechanobiology of heart cells. We are using novel techniques to manipulate and measure cell stress while using advanced imaging to examine how these stresses influence intracellular processes.

Image: STED super-resolution microscopy reveals intricate details of microtubule networks in the heart.


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Roles of Cardiac MyBP-C

2015

In this work we describe a novel function for the cardiac regulatory protein MyBP-C, whose role has remained elusive. We propose that MyBP-C (red), which localizes to the sarcomere distant to the sites of calcium release (green), increases the calcium sensitivity of the contractile apparatus at this distant site in order to offset any non-uniformity in the calcium dependent activation of the sarcomere.

Image: Image acquired using STORM super-resolution imaging.


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Measuring Force in Single Heart Cells

2014

We have developed and patented techniques to attach muscle cells (green, below) to mechanical apparatus using a novel biological adhesive called MyoTak (red). Using this system we can precisely record and control force and length in single cardiomyocytes to mimic the changes in mechanical stress heart cells experience in vivo. Image is a 3D reconstruction of confocal Z-stacks through a heart cell attached to MyoTak coated glass rods.

Item A: Webinar on measuring force in heart cells given by Dr. Prosser


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Mechanobiology of the Heart

2014

Our lab studies mechanotransduction in the heart, the process of converting mechanical forces to intracellular signals.

Image: The artists at Science Signaling graphically summed up our research focus!


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