Beta-defensin overexpression induces progressive muscle degeneration in mice.
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 beta-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 IkappaBalpha 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.
Yamaguchi
Yasuhiro
Y
Dept. of Geriatric Medicine, Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo, 113-0033, Japan.
Nagase
Takahide
T
Tomita
Tetsuji
T
Nakamura
Kyoko
K
Fukuhara
Shigetomo
S
Amano
Tomokazu
T
Yamamoto
Hiroshi
H
Ide
Yukie
Y
Suzuki
Misao
M
Teramoto
Shinji
S
Asano
Tomoichiro
T
Kangawa
Kenji
K
Nakagata
Naomi
N
Ouchi
Yasuyoshi
Y
Kurihara
Hiroki
H
D000375:Aging; D000818:Animals; D023082:Defensins / Q000235:genetics / Q000378:metabolism*; D005260:Female; D005786:Gene Expression Regulation; D051550:I-kappa B Kinase / Q000378:metabolism; D007738:Kyphosis; D008136:Longevity; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000235:genetics* / Q000378:metabolism*; D015430:Weight Gain
C434952:Defb6 protein, mouse; D023082:Defensins; D051550:I-kappa B Kinase