# Detyrosinated microtubules in cardiomyocyte mechanics

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $402,500

## Abstract

Project Summary:
“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.

## Key facts

- **NIH application ID:** 9914295
- **Project number:** 5R01HL133080-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Benjamin Lears Prosser
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2016-07-01 → 2021-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9914295

## Citation

> US National Institutes of Health, RePORTER application 9914295, Detyrosinated microtubules in cardiomyocyte mechanics (5R01HL133080-05). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/9914295. Licensed CC0.

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