Cell biology of sarcomeric protein engineering: Disease modeling and therapeutic potential

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The cardiac sarcomere is the functional unit for myocyte contraction. Ordered arrays of sarcomeric proteins, held in stoichiometric balance with each other, respond to calcium to coordinate contraction and relaxation of the heart. Altered sarcomeric structure-function underlies the primary basis of disease in multiple acquired and inherited heart disease states. Hypertrophic and restrictive cardiomyopathies are caused by inherited mutations in sarcomeric genes and result in altered contractility. Ischemia-mediated acidosis directly alters sarcomere function resulting in decreased contractility. In this review, we highlight the use of acute genetic engineering of adult cardiac myocytes through stoichiometric replacement of sarcomeric proteins in these disease states with particular focus on cardiac troponin I. Stoichiometric replacement of disease causing mutations has been instrumental in defining the molecular mechanisms of hypertrophic and restrictive cardiomyopathy in a cellular context. In addition, taking advantage of stoichiometric replacement through gene therapy is discussed, highlighting the ischemia-resistant histidine-button, A164H cTnI. Stoichiometric replacement of sarcomeric proteins offers a potential gene therapy avenue to replace mutant proteins, alter sarcomeric responses to pathophysiologic insults, or neutralize altered sarcomeric function in disease. Anat Rec, 297:1663-1669, 2014.

Original languageEnglish (US)
Pages (from-to)1663-1669
Number of pages7
JournalAnatomical Record
Volume297
Issue number9
DOIs
StatePublished - Sep 2014

Bibliographical note

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

Keywords

  • Acute genetic engineering
  • Adult cardiac myocytes
  • Calcium sensitivity
  • Molecular dynamics
  • Myofilament, troponin
  • Sarcomere

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