Interplay between heart and skeletal muscle disease in heart failure: The 2011 George E. Brown memorial lecture

Elizabeth M. McNally*, Jeffery A. Goldstein

*Corresponding author for this work

Research output: Contribution to journalReview articlepeer-review

5 Scopus citations

Abstract

The study of single gene disorders often provides insight for more complex human disease. Mutations in the genes encoding the dystrophin protein complex cause muscular dystrophy and cardiomyopathy by destabilizing the plasma membrane of skeletal myofibers and cardiomyocytes. In these diseases, progressive skeletal muscle degeneration and weakness contribute to cardiac dysfunction. Moreover, the pace and pattern of muscle weakness, along with onset of cardiomyopathy, is highly variable even when associated with the same identical mutation. Using a mouse model of muscular dystrophy and cardiomyopathy, we identified genetic loci that modify muscle pathology and cardiac fibrosis. Distinct genetic modifiers were identified for diaphragm and abdominal musculature, and these genetic intervals differ from those that regulate pathology in the skeletal muscle of the limbs and the heart. One modifier gene was identified and highlights the importance of the transforming growth factor-β pathway in the pathogenesis of muscular dystrophy and cardiomyopathy. We determined that canonical transforming growth factor-β signaling contributes to heart and muscle dysfunction using a Drosophila model. Together, these studies demonstrate the value of using a genetically sensitized model to uncover pathways that regulate heart failure and muscle weakness.

Original languageEnglish (US)
Pages (from-to)749-754
Number of pages6
JournalCirculation research
Volume110
Issue number5
DOIs
StatePublished - Mar 2 2012

Keywords

  • cardiomyopathy
  • heart failure
  • modifiers
  • muscular dystrophy

ASJC Scopus subject areas

  • Physiology
  • Cardiology and Cardiovascular Medicine

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