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J. Biol. Chem., Vol. 279, Issue 39, 41114-41123, September 24, 2004

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Skeletal Muscle FOXO1 (FKHR) Transgenic Mice Have Less Skeletal Muscle Mass, Down-regulated Type I (Slow Twitch/Red Muscle) Fiber Genes, and Impaired Glycemic Control^*

Yasutomi Kamei¶, Shinji Miura, Miki Suzuki, Yuko Kai, Junko Mizukami||, Tomoyasu Taniguchi||, Keiji Mochida**, Tomoko Hata, Junichiro Matsuda, Hiroyuki Aburatani, Ichizo Nishino¶¶, and Osamu Ezaki

From the PRESTO, Japan Science and Technology Agency, Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, ^||Lead Generation Research Laboratory, Tanabe Seiyaku Co., Ltd., 3-16-89 Kashima, Yodogawa-ku, Osaka 532-8505, ^**Bioresource Center, Institute of Physical and Chemical Research, 3-1-1 Koyadai, Tsukuba-shi, Ibaraki 305-0074, the Department of Veterinary Science, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo 153-8904, and the ^¶¶Department of Neuromuscular Research, National Institute of Neuroscience, National Center of Neurology and Psychiatry, 4-1-1 Ogawahigashi-cho, Kodaira, Tokyo 187-8502, Japan

FOXO1, a member of the FOXO forkhead type transcription factors, is markedly up-regulated in skeletal muscle in energy-deprived states such as fasting and severe diabetes, but its functions in skeletal muscle have remained poorly understood. In this study, we created transgenic mice specifically overexpressing FOXO1 in skeletal muscle. These mice weighed less than the wild-type control mice, had a reduced skeletal muscle mass, and the muscle was paler in color. Microarray analysis revealed that the expression of many genes related to the structural proteins of type I muscles (slow twitch, red muscle) was decreased. Histological analyses showed a marked decrease in size of both type I and type II fibers and a significant decrease in the number of type I fibers in the skeletal muscle of FOXO1 mice. Enhanced gene expression of a lysosomal proteinase, cathepsin L, which is known to be up-regulated during skeletal muscle atrophy, suggested increased protein degradation in the skeletal muscle of FOXO1 mice. Running wheel activity (spontaneous locomotive activity) was significantly reduced in FOXO1 mice compared with control mice. Moreover, the FOXO1 mice showed impaired glycemic control after oral glucose and intraperitoneal insulin administration. These results suggest that FOXO1 negatively regulates skeletal muscle mass and type I fiber gene expression and leads to impaired skeletal muscle function. Activation of FOXO1 may be involved in the pathogenesis of sarcopenia, the age-related decline in muscle mass in humans, which leads to obesity and diabetes.

Received for publication, January 21, 2004 , and in revised form, July 9, 2004.

^* This work was supported in part by research grants from the Japanese Ministry of Health, Labor, and Welfare (Tokyo) and by a grant from the Promotion of Fundamental Studies in Health Sciences of the Organization for Pharmaceutical Safety and Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains Information 1 and 2.

^¶ To whom correspondence should be addressed: Division of Clinical Nutrition, National Institute of Health and Nutrition, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8636, Japan. Tel.: 81-3-3203-5725; Fax: 81-3-3207-3520; E-mail: ykamei{at}nih.go.jp.

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