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20 MUSCLE FIBER REGENERATION IMPAIRED IN DYSTROPHIN/GUANIDINOACETATE METHYLTRANSFERASE-DEFICIENT MICE COMPARED WITH MDX MICE.
  1. K. A. Horiuchi1
  1. 1University of Colorado School of Medicine, Denver, CO.

Abstract

Duchenne muscular dystrophy (DMD) is characterized by mutations in a gene located on the X chromosome, which codes for the dystrophin protein. These mutations result in loss of functional dystrophin protein, making the muscle fragile and susceptible to damage. The mdx mouse is a well-studied model of human DMD because it also lacks dystrophin protein. However, the mdx phenotype is benign compared with that of human boys. In an attempt to better characterize and understand human DMD, this lab has generated a mouse model believed to be more representative of the human DMD phenotype. A putative modifier gene coding for guanidinoacetate methyltransferase or GAMT (a key enzyme involved in creatine synthesis), which is up-regulated in mdx mice and down-regulated in boys with DMD, may be important in the generation of the human phenotype. The mouse generated by this lab, the double null (dn) mouse, is lacking dystrophin and GAMT and is more crippled than the mdx mouse. Pathologically, the appearance of dn muscles is more similar to human DMD muscles as well. With immunofluorescent and histologic techniques, we find that the dn mouse has these three characteristics, all suggesting less successful regeneration: (1) the dn has 62% central nucs versus 70% in mdx, (2) the dn mouse has no embryonic myosin heavy chain (MHC) fibers versus 6% in mdx, and (3) the dn mouse has smaller fibers cross-sectional areas 3,000 square microns/fiber versus 3,500 in mdx. It seems that although its degeneration pattern is similar to that of the mdx mouse, because of its dystrophin and GAMT null state, the dn mouse is not able to regenerate muscle fibers as well as the mdx mouse.

Acknowledgments: NIH NIAMS, Sharp Family Foundation, The Young Fund.

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