Publication:

Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice (1998)

Author(s): F. Duclos;V. Straub;S. A. Moore;D. P. Venzke;R. F. Hrstka;R. H. Crosbie;M. Durbeej;C. S. Lebakken;A. J. Ettinger;J. van der Meulen;K. H. Holt;L. E. Lim;J. R. Sanes;B. L. Davidson;J. A. Faulkner;R. Williamson;K. P. Campbell

  • : Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice

Abstract: Limb-girdle muscular dystrophy type 2D (LGMD 2D) is an autosomal recessive disorder caused by mutations in the alpha-sarcoglycan gene. To determine how alpha-sarcoglycan deficiency leads to muscle fiber degeneration, we generated and analyzed alpha-sarcoglycan- deficient mice. Sgca-null mice developed progressive muscular dystrophy and, in contrast to other animal models for muscular dystrophy, showed ongoing muscle necrosis with age, a hallmark of the human disease. Sgca-null mice also revealed loss of sarcolemmal integrity, elevated serum levels of muscle enzymes, increased muscle masses, and changes in the generation of absolute force. Molecular analysis of Sgca-null mice demonstrated that the absence of alpha-sarcoglycan resulted in the complete loss of the sarcoglycan complex, sarcospan, and a disruption of alpha-dystroglycan association with membranes. In contrast, no change in the expression of epsilon-sarcoglycan (alpha-sarcoglycan homologue) was observed. Recombinant alpha-sarcoglycan adenovirus injection into Sgca-deficient muscles restored the sarcoglycan complex and sarcospan to the membrane. We propose that the sarcoglycan-sarcospan complex is requisite for stable association of alpha-dystroglycan with the sarcolemma. The Sgca-deficient mice will be a valuable model for elucidating the pathogenesis of sarcoglycan deficient limb-girdle muscular dystrophies and for the development of therapeutic strategies for this disease.

  • Short Title: Progressive muscular dystrophy in alpha-sarcoglycan-deficient mice
  • Date: Sep 21
  • Journal: J Cell Biol
  • Volume: 142
  • Issue: 6
  • Pages: 1461-71
  • Publication type: Article
  • Bibliographic status: Published

Keywords: Amino Acid Sequence Animals Base Sequence Carrier Proteins/biosynthesis/physiology Cytoskeletal Proteins/ deficiency/genetics DNA, Complementary Disease Progression Dystrophin/metabolism Gene Transfer Techniques Glycoproteins/metabolism Membrane Glycoproteins/ deficiency/genetics Membrane Proteins/biosynthesis/physiology Mice Mice, Inbred C57BL Mice, Knockout Molecular Sequence Data Muscle Contraction Muscular Dystrophy, Animal/ etiology/physiopathology Neoplasm Proteins Sarcoglycans Sarcolemma/metabolism

Staff

Professor Volker Straub
Harold Macmillan Professor of Medicine