# GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy

> **NIH NIH R01** · LOYOLA UNIVERSITY CHICAGO · 2021 · $371,069

## Abstract

PROJECT SUMMARY
Mortality from myocardial infarction is decreasing; however, survivors are at high risk of developing ischemic
cardiomyopathy (ICM). Understanding the mechanisms involved in that transition may help develop methods to
prevent it. Ischemic damage produces a form of dyssynchronous contraction that cannot be treated with
conventional therapies (Cardiac Resynchronization Therapy, CRT). However, the Principal Investigator
previously discovered a critical molecular mechanism of CRT: it reactivates glycogen synthase kinase 3β
(GSK-3β) and thus restores myofilament function. This proposal will leverage the molecular mechanism
discovered in CRT in a patient population that cannot respond to it, ICM patients. Preliminary data reveals that
human and mouse ICM samples exhibit myofilament calcium desensitization, and exogenous treatment with
GSK-3β restores calcium sensitivity, suggesting the functional defect is linked to deactivation of GSK-3β.
Further, new preliminary data has identified an independently regulated pool of GSK-3β localized to the
myofilament that decreases significantly in human ICM, which correlates with the decrease in calcium
sensitivity. Importantly, additional preliminary data suggest the localization of GSK-3β to the myofilament is
mediated by phosphorylation of GSK-3β at tyrosine 216. This could allow targeted modulation of the
myofilament pool of GSK-3β as a therapeutic strategy to improve myofilament function. Thus, based on these
new preliminary data, this proposal addresses the central hypothesis that ischemia de-activates a
myofilament pool of GSK-3β via altering tyrosine 216 (Y216) phosphorylation, decreasing
phosphorylation of its myofilament targets and depressing myofilament function. There are three
specific aims. Aim 1 will address the hypothesis that ICM decreases myofilament function in a GSK-3β
dependent manner. Genetic mouse models that alter GSK-3β activity will be subjected to surgical induction of
myocardial infarction to generate ICM and then myofilament function and GSK-3β activity will assayed. Human
tissue from ICM patients will be studied similarly. Aim 2 will address the the hypothesis that phosphorylation at
Y216 on GSK-3β modulates its binding to the myofilament and ICM decreases the amount and activity of GSK-
3β at the myofilament. Mutant forms of GSK-3β where the Y216 site is unphosphorylatable or mimic
constitutive phosphorylation will be expressed in cardiac myocytes to determine where and how GSK-3β binds
to the myofilament. Myofilament function will also be assessed to determine whether these mutant forms of
GSK-3β can restore function in the GSK-3β knock-out mouse. The last aim will address the hypothesis that
GSK-3β can normalize the myofilament phospho-proteome in ICM patients and ICM mouse tissue using state
of the art mass spectrometry approaches. The long-term objective of this project is to identify the mechanisms
by which GSK-3β affects myofilament function in the ICM heart, wi...

## Key facts

- **NIH application ID:** 10130596
- **Project number:** 5R01HL136737-05
- **Recipient organization:** LOYOLA UNIVERSITY CHICAGO
- **Principal Investigator:** JONATHAN A KIRK
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $371,069
- **Award type:** 5
- **Project period:** 2017-04-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130596

## Citation

> US National Institutes of Health, RePORTER application 10130596, GSK-3β Localizes to the Myofilament and Modifies its Function in Ischemic Cardiomyopathy (5R01HL136737-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10130596. Licensed CC0.

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