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Skeletal Myopathy in Transgenic Mice Carrying Human Prototype c-Ha-ras Gene

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan, Tsuchiya.Takayuki@ mf.m-pharma.co.jp

Kiyoshi Kobayashi

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Tetsuya Sakairi

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Kazuhiro Goto

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Miyoko Okada

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Fumiko Sano

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Jiro Sugimoto

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Tetsuo Morohashi

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Toshimi Usui

Central Institute of Experimental Animals, Miyamae-ku, Kawasaki 216-0001, Japan

Mamoru Mutai

Toxicology Laboratory, Research Center, Mitsubishi-Tokyo Pharmaceuticals, Inc, Chiba-ken 292-0812, Japan

Skeletal myopathy was found in almost all-transgenic mice carrying the human prototype c-Ha-ras gene (rasH2 mouse). Microscopically, variation of the muscle fiber size, centrally placed nuclei, regenerating fibers, and interstitial fibrosis were evident; hyalinization and necrosis were sometimes observed in the skeletal muscle (femoralis and pectoralis) of the rasH2 mice. Inflammatory changes in the skeletal muscle or abnormality of adjacent peripheral nerve were not observed. The features were essentially similar to those of muscular dystrophy. Although the severity was relatively mild compared to 34-week-old rasH2 mice, the skeletal myopathy was also observed in younger male (10 weeks of age) rasH2 mice. In nontransgenic littermates, skeletal myopathy was not observed. The mRNA of human c-Ha-ras product was detected in femoral muscle from the rasH2 mice by RT-PCR. In conclusion, these data suggest that skeletal myopathy is occurring in almost all rasH2 mice. Integration of c-Ha- ras gene is thought to be crucial to pathogenesis of skeletal myopathy in the rasH2 mice. Further characterization of the muscular lesion and its pathogenesis are needed to explore the possibility of rasH2 mouse becoming a new model for muscular dystrophy.

Key Words: Skeletal muscle • muscular dystrophy • rasH2 mouse • ras gene • histopathology • spontaneous.

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