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MUSCLE CELL BIOLOGY AND CELL MOTILITY

-Defensin overexpression induces progressive muscle degeneration in mice

Departments of ¹Geriatric Medicine, ²Respiratory Medicine, and ³Physiological Chemistry and Metabolism, Graduate School of Medicine, The University of Tokyo, Bunkyo-ku, Tokyo; ⁴Division of Integrative Cell Biology, Department of Embryogenesis, Institute of Molecular Embryology and Genetics, and Divisions of ⁵Reproductive Engineering and ⁶Transgenic Technology, Center for Animal Resources and Development, Kumamoto University, Kumamoto-shi, Kumamoto; and ⁷Department of Biochemistry, National Cardiovascular Center Research Institute, Suita-ku, Osaka, Japan

Submitted 27 May 2006 ; accepted in final form 4 January 2007

Defensins comprise a family of cationic antimicrobial peptides characterized by conserved cysteine residues. They are produced in various organs including skeletal muscle and are identified as key elements in the host defense system as potent effectors. At the same time, defensins have potential roles in the regulation of inflammation and, furthermore, can exert cytotoxic effects on several mammalian cells. Here, we developed transgenic mice overexpressing mouse -defensin-6 to explore the pathophysiological roles of the defensin family as a novel mediator of inflammatory tissue injury. Unexpectedly, the transgenic mice showed short lifespan, poor growth, and progressive myofiber degeneration with functional muscle impairment, predominant centronucleated myofibers, and elevated serum creatine kinase activity, as seen in human muscular dystrophy. Furthermore, some of the transgenic myofibers showed IB accumulation, which would be related to the myofiber apoptosis of limb-girdle muscular dystrophy type 2A. The present findings may unravel a concealed linkage between the innate immune system and the pathophysiology of degenerative diseases.

muscular dystrophy; innate immunity; NF-B

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