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J. Biol. Chem., Vol. 282, Issue 9, 6812-6822, March 2, 2007

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Conditional Activation of MET in Differentiated Skeletal Muscle Induces Atrophy^*

Tiziana Crepaldi¹, Francesca Bersani, Claudio Scuoppo, Paolo Accornero², Chiara Prunotto, Riccardo Taulli, Paolo E. Forni, Christian Leo, Roberto Chiarle^¶, Jennifer Griffiths^||, David J. Glass^||3, and Carola Ponzetto

From the Center for Experimental Research and Medical Studies, Department of Anatomy, Pharmacology, and Forensic Medicine, and ^¶Department of Biomedical Sciences and Oncology, University of Turin, 10126 Turin, Italy and ^||Muscle Program, Regeneron Pharmaceuticals, Tarrytown, New York 10591

Skeletal muscle atrophy is a common debilitating feature of many systemic diseases, including cancer. Here we examined the effects of inducing expression of an oncogenic version of the Met receptor (Tpr-Met) in terminally differentiated skeletal muscle. A responder mouse containing the Tpr-Met oncogene and GFP (green fluorescent protein) as a reporter was crossed with a transactivator mouse expressing tTA under the control of the muscle creatine kinase promoter. Tpr-Met induction during fetal development and in young adult mice caused severe muscle wasting, with decreased fiber size and loss of myosin heavy chain protein. Concomitantly, in the Tpr-Met-expressing muscle the mRNA of the E3 ubiquitin ligases atrogin-1/MAFbx, MuRF1, and of the lysosomal protease cathepsin L, which are markers of skeletal muscle atrophy, was significantly increased. In the same muscles phosphorylation of the Met downstream effectors Akt, p38 MAPK, and IB was higher than in normal controls. Induction of Tpr-Met in differentiating satellite cells derived from the double transgenics caused aberrant cell fusion, protein loss, and myotube collapse. Increased phosphorylation of Met downstream effectors was also observed in the Tpr-Met-expressing myotubes cultures. Treatment of these cultures with either a proteasomal or a p38 inhibitor prevented Tpr-Met-mediated myotube breakdown, establishing accelerated protein degradation consequent to inappropriate activation of p38 as the major route for the Tpr-Met-induced muscle phenotype.

Received for publication, November 27, 2006

^* This work was supported by funds from Ministero dell'Istruzione dell'Università e della Ricerca Cofin programs and Telethon Project D095, the Sixth Research Framework Programme of the European Union, Project RIGHT (LSHB-CT-2004-005276), the Italian Association for Cancer Research, the Oncology Project Compagnia di San Paolo/FIRMS (Center for Experimental Research and Medical Studies), and Regione Piemonte-Ricerca Sanitaria Finalizzata. 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.

² Present address: Dept. of Veterinary Morphophysiology, University of Turin, 10095 Turin, Italy.

³ Present address: Novartis Institutes for Biomedical Research, Cambridge MA 02139.

¹ To whom correspondence should be addressed: Dept. of Anatomy, Pharmacology, and Forensic Medicine, Corso M. D'Azeglio 52, 10126 Turin, Italy. Tel.: 39-011-6707747; Fax: 39-011-6707732; E-mail: tiziana.crepaldi{at}unito.it.

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