Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice

Alison R. Amenta, Atilgan Yilmaz, Sasha Bogdanovich, Beth A. McKechnie, Mehrdad Abedi, Tejvir S. Khurana, Justin R. Fallon

Research output: Contribution to journalArticle

90 Scopus citations

Abstract

Duchenne muscular dystrophy (DMD) is caused by mutations in dystrophin and the subsequent disruption of the dystrophin-associated protein complex (DAPC). Utrophin is a dystrophin homolog expressed at high levels in developing muscle that is an attractive target for DMD therapy. Here we show that the extracellular matrix protein biglycan regulates utrophin expression in immature muscle and that recombinant human biglycan (rhBGN) increases utrophin expression in cultured myotubes. Systemically delivered rhBGN upregulates utrophin at the sarcolemma and reduces muscle pathology in the mdx mouse model of DMD. RhBGN treatment also improves muscle function as judged by reduced susceptibility to eccentric contraction-induced injury. Utrophin is required for the rhBGN therapeutic effect. Several lines of evidence indicate that biglycan acts by recruiting utrophin protein to the musclemembrane. RhBGN is well tolerated in animals dosed for as long as 3 months. We propose that rhBGN could be a therapy for DMD.

Original languageEnglish (US)
Pages (from-to)762-767
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume108
Issue number2
DOIs
StatePublished - Jan 11 2011

Keywords

  • Biotherapeutics
  • Protein therapeutics

ASJC Scopus subject areas

  • General

Fingerprint Dive into the research topics of 'Biglycan recruits utrophin to the sarcolemma and counters dystrophic pathology in mdx mice'. Together they form a unique fingerprint.

  • Cite this