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Molecular and Cellular Biology, September 2009, p. 4798-4811, Vol. 29, No. 17
0270-7306/09/$08.00+0 doi:10.1128/MCB.01347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
Ubiquitin Ligase Cbl-b Is a Negative Regulator for Insulin-Like Growth Factor 1 Signaling during Muscle Atrophy Caused by Unloading
,
Reiko Nakao,1
Katsuya Hirasaka,1
Jumpei Goto,1
Kazumi Ishidoh,2
Chiharu Yamada,1
Ayako Ohno,1
Yuushi Okumura,1
Ikuya Nonaka,3
Koji Yasutomo,4
Kenneth M. Baldwin,5
Eiki Kominami,6
Akira Higashibata,7
Keisuke Nagano,8
Keiji Tanaka,9
Natsuo Yasui,10
Edward M. Mills,11
Shin'ichi Takeda,12 and
Takeshi Nikawa1*
Departments of Nutritional Physiology,1 Immunology and Parasitology,4 Orthopaedics, Institute of Health Biosciences, University of Tokushima Graduate School, Tokushima 770-8503, Japan,10 Institute for Health Sciences, Tokushima-Bunri University, Tokushima 770-8514, Japan,2 Departments of Ultrastructural Research,3 Molecular Therapy, National Institute of Neuroscience, National Center of Neurology and Psychiatry, Tokyo 187-8502, Japan,12 Department of Physiology and Biophysics, University of California, Irvine, California 92697,5 Department of Biochemistry, Juntendo University School of Medicine, Tokyo 113-8421, Japan,6 Institute of Space and Astronautical Science, Japan Aerospace Exploration Agency (JAXA), Tsukuba, Ibaraki 305-8505, Japan,7 First Institute of New Drug Discovery, Otsuka Pharmaceutical Co., Tokushima 771-0192, Japan,8 Laboratory of Frontier Science, Tokyo Metropolitan Institute of Medical Science, Tokyo 113-8613, Japan,9 Division of Pharmacology/Toxicology, College of Pharmacy, University of Texas, Austin, Texas 78712,11
Received 24 August 2008/ Returned for modification 25 October 2008/ Accepted 8 June 2009
Skeletal muscle atrophy caused by unloading is characterized by both decreased responsiveness to myogenic growth factors (e.g., insulin-like growth factor 1 [IGF-1] and insulin) and increased proteolysis. Here, we show that unloading stress resulted in skeletal muscle atrophy through the induction and activation of the ubiquitin ligase Cbl-b. Upon induction, Cbl-b interacted with and degraded the IGF-1 signaling intermediate IRS-1. In turn, the loss of IRS-1 activated the FOXO3-dependent induction of atrogin-1/MAFbx, a dominant mediator of proteolysis in atrophic muscle. Cbl-b-deficient mice were resistant to unloading-induced atrophy and the loss of muscle function. Furthermore, a pentapeptide mimetic of tyrosine608-phosphorylated IRS-1 inhibited Cbl-b-mediated IRS-1 ubiquitination and strongly decreased the Cbl-b-mediated induction of atrogin-1/MAFbx. Our results indicate that the Cbl-b-dependent destruction of IRS-1 is a critical dual mediator of both increased protein degradation and reduced protein synthesis observed in unloading-induced muscle atrophy. The inhibition of Cbl-b-mediated ubiquitination may be a new therapeutic strategy for unloading-mediated muscle atrophy.
* Corresponding author. Mailing address: Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, 3-18-15 Kuramoto-cho, Tokushima 770-8503, Japan. Phone: 81-88-633-9248. Fax: 81-88-633-7086. E-mail: nikawa{at}nutr.med.tokushima-u.ac.jp
Published ahead of print on 22 June 2009.
Supplemental material for this article may be found at http://mcb.asm.org/.
Molecular and Cellular Biology, September 2009, p. 4798-4811, Vol. 29, No. 17
0270-7306/09/$08.00+0 doi:10.1128/MCB.01347-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.
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