The MYPT2-regulated striated muscle-specific myosin light chain phosphatase limits cardiac myosin phosphorylation in vivo.

Autor:	Lee E; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., May H; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Kazmierczak K; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA., Liang J; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA., Nguyen N; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Hill JA; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Gillette TG; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA., Szczesna-Cordary D; Department of Molecular and Cellular Pharmacology, University of Miami Miller School of Medicine, Miami, Florida, USA., Chang AN; Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas, Texas, USA; Pak Center for Mineral Metabolism and Clinical Research, UTSW Medical Center, Dallas, Texas, USA. Electronic address: AudreyN.Chang@UTSouthwestern.edu.
Jazyk:	angličtina
Zdroj:	The Journal of biological chemistry [J Biol Chem] 2024 Feb; Vol. 300 (2), pp. 105652. Date of Electronic Publication: 2024 Jan 13.
DOI:	10.1016/j.jbc.2024.105652
Abstrakt:	The physiological importance of cardiac myosin regulatory light chain (RLC) phosphorylation by its dedicated cardiac myosin light chain kinase has been established in both humans and mice. Constitutive RLC-phosphorylation, regulated by the balanced activities of cardiac myosin light chain kinase and myosin light chain phosphatase (MLCP), is fundamental to the biochemical and physiological properties of myofilaments. However, limited information is available on cardiac MLCP. In this study, we hypothesized that the striated muscle-specific MLCP regulatory subunit, MYPT2, targets the phosphatase catalytic subunit to cardiac myosin, contributing to the maintenance of cardiac function in vivo through the regulation of RLC-phosphorylation. To test this hypothesis, we generated a floxed-PPP1R12B mouse model crossed with a cardiac-specific Mer-Cre-Mer to conditionally ablate MYPT2 in adult cardiomyocytes. Immunofluorescence microscopy using the gene-ablated tissue as a control confirmed the localization of MYPT2 to regions where it overlaps with a subset of RLC. Biochemical analysis revealed an increase in RLC-phosphorylation in vivo. The loss of MYPT2 demonstrated significant protection against pressure overload-induced hypertrophy, as evidenced by heart weight, qPCR of hypertrophy-associated genes, measurements of myocyte diameters, and expression of β-MHC protein. Furthermore, mantATP chase assays revealed an increased ratio of myosin heads distributed to the interfilament space in MYPT2-ablated heart muscle fibers, confirming that RLC-phosphorylation regulated by MLCP, enhances cardiac performance in vivo. Our findings establish MYPT2 as the regulatory subunit of cardiac MLCP, distinct from the ubiquitously expressed canonical smooth muscle MLCP. Targeting MYPT2 to increase cardiac RLC-phosphorylation in vivo may improve baseline cardiac performance, thereby attenuating pathological hypertrophy. Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article. (Published by Elsevier Inc.)
Databáze:	MEDLINE
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