Molecular mechanisms of sarcomere dysfunction in dilated and hypertrophic cardiomyopathy

Aisha H. Frazier, Genaro A. Ramirez-Correa, Anne M. Murphy

Research output: Contribution to journalArticlepeer-review

Abstract

The sarcomeres form the molecular motor of the cardiomyocyte and consist of a complex multi-protein of thick and thin filaments which are anchored to the cytoskeleton. The thick filament, composed of myosin and associated proteins, and the thin filament composed of actin, tropomyosin and the troponins develop actin-myosin crossbridges which cycle in response to calcium resulting in the sliding of the filaments and contraction. The thin filament is fixed to the cardiomyocyte cytoskeleton at the Z-disc, a complex of structural and regulatory proteins. A giant protein, titin, provides an external scaffold and regulates passive force in diastole. Both genetic disorders and acquired conditions may affect proteins of the sarcomere. Genetic disorders of the thick and thin filament proteins are the predominant cause of hypertrophic cardiomyopathy. These mutations lead to abnormal sarcomere function, often an enhanced sensitivity to calcium, and impaired relaxation. This may result in secondary changes in calcium cycling and amplification of hypertrophic signaling cascades. Correcting the abnormal function of the sarcomere as well as intervening in later stages of the pathophysiologic cascades may ameliorate disease. In dilated cardiomyopathy genetic abnormalities in the sarcomere, Z-disc, calcium regulatory and cytoskeletal proteins as well as the dystrophin complex may be causal for disease. In dilated cardiomyopathy, disturbances in post-translational modifications of the sarcomere may also play a prominent role. Experimental models indicate that altered phosphorylation of sarcomeric proteins may impair systolic and diastolic functions as well as the response to heart rate and afterload. Thus correcting these post-translational changes is a legitimate target for future therapeutic strategies for dilated cardiomyopathy.

Original languageEnglish (US)
Pages (from-to)29-33
Number of pages5
JournalProgress in Pediatric Cardiology
Volume31
Issue number1
DOIs
StatePublished - Jan 2011

Keywords

  • Cardiac muscle
  • Dilated cardiomyopathy
  • Hypertrophic cardiomyopathy
  • Sarcomere

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Cardiology and Cardiovascular Medicine

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