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Cell biology of sarcomeric protein engineering: disease modeling and therapeutic potential.

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.
AuthorsBrian R Thompson, Joseph M Metzger
JournalAnatomical record (Hoboken, N.J. : 2007) (Anat Rec (Hoboken)) Vol. 297 Issue 9 Pg. 1663-9 (Sep 2014) ISSN: 1932-8494 [Electronic] United States
PMID25125179 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Review)
Copyright© 2014 Wiley Periodicals, Inc.
Chemical References
  • Muscle Proteins
Topics
  • Animals
  • Genetic Predisposition to Disease
  • Genetic Therapy
  • Heart Diseases (genetics, metabolism, pathology, physiopathology, therapy)
  • Humans
  • Muscle Proteins (genetics, metabolism)
  • Mutation
  • Myocardium (metabolism, pathology)
  • Phenotype
  • Protein Engineering
  • Sarcomeres (metabolism, pathology)

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