2. Academic Validation
  3. Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway

Novel obscurins mediate cardiomyocyte adhesion and size via the PI3K/AKT/mTOR signaling pathway

  • J Mol Cell Cardiol. 2017 Oct;111:27-39. doi: 10.1016/j.yjmcc.2017.08.004.
Maegen A Ackermann 1,  Brendan King 2,  Nicole A P Lieberman 2,  Prameela J Bobbili 3,  Michael Rudloff 4,  Christopher E Berndsen 4,  Nathan T Wright 4,  Peter A Hecker 5,  Aikaterini Kontrogianni-Konstantopoulos 6
Affiliations

Affiliations

  • 1 Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, Baltimore, MD 21201, United States; Department of Physiology and Cell Biology, Wexner College of Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States. Electronic address: maegen.ackermann@osumc.edu.
  • 2 Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, Baltimore, MD 21201, United States.
  • 3 Department of Physiology and Cell Biology, Wexner College of Medicine, Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University, Columbus, OH 43210, United States.
  • 4 Department of Chemistry and Biochemistry, James Madison University, Harrisonburg, VA 22807, United States.
  • 5 Division of Cardiology and Department of Medicine, University of Maryland, Baltimore, MD 20201, United States.
  • 6 Department of Biochemistry and Molecular Biology, University of Maryland, School of Medicine, Baltimore, MD 21201, United States. Electronic address: akontrogianni@som.umaryland.edu.
PMID: 28826662 DOI: 10.1016/j.yjmcc.2017.08.004
Abstract

The intercalated disc of cardiac muscle embodies a highly-ordered, multifunctional network, essential for the synchronous contraction of the heart. Over 200 known proteins localize to the intercalated disc. The challenge now lies in their characterization as it relates to the coupling of neighboring cells and whole heart function. Using molecular, biochemical and imaging techniques, we characterized for the first time two small obscurin isoforms, obscurin-40 and obscurin-80, which are enriched at distinct locations of the intercalated disc. Both proteins bind specifically and directly to select Phospholipids via their pleckstrin homology (PH) domain. Overexpression of either isoform or the PH-domain in cardiomyocytes results in decreased cell adhesion and size via reduced activation of the PI3K/Akt/mTOR pathway that is intimately linked to cardiac hypertrophy. In addition, obscurin-80 and obscurin-40 are significantly reduced in acute (myocardial infarction) and chronic (pressure overload) murine cardiac-stress models underscoring their key role in maintaining cardiac homeostasis. Our novel findings implicate small obscurins in the maintenance of cardiomyocyte size and coupling, and the development of heart failure by antagonizing the PI3K/Akt/mTOR pathway.

Keywords

Intercalated disc; Obscurin; PI3K/AKT/mTOR; Phosphatidyl-inositol bisphosphates; Pleckstrin homology domain.

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