The superhealing MRL background improves muscular dystrophy

Ahlke Heydemann, Kayleigh A. Swaggart, Gene H. Kim, Jenan Holley-Cuthrell, Michele Hadhazy, Elizabeth M. McNally*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

21 Scopus citations

Abstract

Background: Mice from the MRL or " superhealing" strain have enhanced repair after acute injury to the skin, cornea, and heart. We now tested an admixture of the MRL genome and found that it altered the course of muscle pathology and cardiac function in a chronic disease model of skeletal and cardiac muscle. Mice lacking γ-sarcoglycan (Sgcg), a dystrophin-associated protein, develop muscular dystrophy and cardiomyopathy similar to their human counterparts with limb girdle muscular dystrophy. With disruption of the dystrophin complex, the muscle plasma membrane becomes leaky and muscles develop increased fibrosis.Methods: MRL/MpJ mice were bred with Sgcg mice, and cardiac function was measured. Muscles were assessed for fibrosis and membrane leak using measurements of hydroxyproline and Evans blue dye. Quantitative trait locus mapping was conducted using single nucleotide polymorphisms distinct between the two parental strains.Results: Introduction of the MRL genome reduced fibrosis but did not alter membrane leak in skeletal muscle of the Sgcg model. The MRL genome was also associated with improved cardiac function with reversal of depressed fractional shortening and the left ventricular ejection fraction. We conducted a genome-wide analysis of genetic modifiers and found that a region on chromosome 2 was associated with cardiac, diaphragm muscle and abdominal muscle fibrosis.Conclusions: These data are consistent with a model where the MRL genome acts in a dominant manner to suppress fibrosis in this chronic disease setting of heart and muscle disease.

Original languageEnglish (US)
Article number26
JournalSkeletal Muscle
Volume2
Issue number1
DOIs
StatePublished - Dec 5 2012

Keywords

  • Cardiomyopathy
  • Fibrosis
  • MRL
  • Muscular dystrophy

ASJC Scopus subject areas

  • Orthopedics and Sports Medicine
  • Molecular Biology
  • Cell Biology

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