γ-sarcoglycan deficiency leads to muscle membrane defects and apoptosis independent of dystrophin

Andrew A. Hack, Chantal T. Ly, Fang Jiang, Cynthia J. Clendenin, Kirsten S. Sigrist, Robert L. Wollmann, Elizabeth M. McNally*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

242 Scopus citations

Abstract

γ-Sarcoglycan is a transmembrane, dystrophin-associated protein expressed in skeletal and cardiac muscle. The murine γ-sarcoglycan gene was disrupted using homologous recombination. Mice lacking γ-sarcoglycan showed pronounced dystrophic muscle changes in early life. By 20 wk of age, these mice developed cardiomyopathy and died prematurely. The loss of γ- sarcoglycan produced secondary reduction of β-and δ-sarcoglycan with partial retention of α- and ε-sarcoglycan, suggesting that β-, γ-, and δ-sarcoglycan function as a unit. Importantly, mice lacking γ-sarcoglycan showed normal dystrophin content and localization, demonstrating that myofiber degeneration occurred independently of dystrophin alteration. Furthermore, β-dystroglycan and laminin were left intact, implying that the dystrophin-dystroglycan-laminin mechanical link was unaffected by sarcoglycan deficiency. Apoptotic myonuclei were abundant in skeletal muscle lacking γ- sarcoglycan, suggesting that programmed cell death contributes to myofiber degeneration. Vital staining with Evans blue dye revealed that muscle lacking γ-sarcoglycan developed membrane disruptions like those seen in dystrophin- deficient muscle. Our data demonstrate that sarcoglycan loss was sufficient, and that dystrophin loss was not necessary to cause membrane defects and apoptosis. As a common molecular feature in a variety of muscular dystrophies, sarcoglycan loss is a likely mediator of pathology.

Original languageEnglish (US)
Pages (from-to)1279-1287
Number of pages9
JournalJournal of Cell Biology
Volume142
Issue number5
DOIs
StatePublished - Sep 7 1998

Keywords

  • Apoptosis
  • Dystrophin
  • Extracellular matrix
  • Muscular dystrophy
  • Sarcolemma

ASJC Scopus subject areas

  • Cell Biology

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