# Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility and Atrial Fibrillation

> **NIH NIH R01** · UNIVERSITY OF ILLINOIS AT CHICAGO · 2024 · $626,075

## Abstract

Project Summary / Abstract
Thromboembolic stroke is a leading cause of death from atrial fibrillation (AF). Current strategies to prevent
AF-induced stroke, such as oral anticoagulants, have significant risks and incompletely suppress stroke. Atrial
contractility is significantly reduced in AF and contributes to stroke risk; however, an incomplete understanding
of mechanisms regulating sarcomere function has hindered development of therapeutic approaches targeting
atrial contractile dysfunction. Recent insights from our lab and others have demonstrated that hypo-
phosphorylation of atrial myosin light chain (MLC2a) is a major contributor to atrial contractile dysfunction in
AF. Furthermore, we have demonstrated that the protein phosphatase 1 regulatory subunit 12C (PPP1R12C)
contributes to MLC2a dephosphorylation and atrial hypocontractility in AF. The long-term goal of this project is
to determine the mechanisms by which protein phosphatase regulatory and catalytic subunits regulate MLC2a
phosphorylation and myofilament Ca2+ sensitivity, and determine how reduced MLC2a phosphorylation
contributes to atrial hypocontractility, AF susceptibility, and stroke. The objective of this application is to
evaluate PPP1R12C protein expression and activity as a regulator of atrial Ca2+ sensitivity and atrial
contractility in vivo. Whereas we have shown that increased PPP1R12C protein expression is associated with
MLC2a dephosphorylation in human AF patients and mouse models of AF, the mechanisms regulating
PPP1R12C expression remain unknown. Furthermore, the functional significance of PPP1R12C deletion or
pharmacologic PPP1R12C inhibition remain untested. The central hypothesis is that there is an inverse
relationship between PPP1R12C activity and atrial contractility, and that inhibition of PPP1R12C expression or
activity will increase atrial contractility in AF. To test this hypothesis, three Specific Aims are proposed: Aim 1-
To determine the mechanism whereby AngII signaling increases PPP1R12C expression; Aim 2- To assess
whether genetic knockout of Ppp1r12c in mice increases atrial contractility; Aim 3 - To validate pharmacologic
approaches to modifying PPP1R12C activity in vivo. The innovation of our project is that we are evaluating
atrial hypocontractility, the only limb of Virchow's triad unaddressed for stroke prevention in AF. The proposed
project would, for the first time, attempt to intervene upon the atrial contractile substrate and modify atrial
cardiomyopathy in vivo. Our expected outcome from completion of the proposed Aims is an enhanced
understanding of the mechanisms underlying atrial contractile dysfunction in AF, and validation of targets to
increase atrial contractility and reduce stroke risk in AF.

## Key facts

- **NIH application ID:** 10819480
- **Project number:** 5R01HL151508-05
- **Recipient organization:** UNIVERSITY OF ILLINOIS AT CHICAGO
- **Principal Investigator:** Mark D McCauley
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $626,075
- **Award type:** 5
- **Project period:** 2020-04-01 → 2026-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10819480

## Citation

> US National Institutes of Health, RePORTER application 10819480, Myosin Light Chain Dephosphorylation by PPP1R12C Promotes Atrial Hypocontractility and Atrial Fibrillation (5R01HL151508-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10819480. Licensed CC0.

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