Conditional activation of MET in differentiated skeletal muscle induces atrophy.
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 IkappaBalpha 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.
Crepaldi
Tiziana
T
Center for Experimental Research and Medical Studies, University of Turin, 10126 Turin, Italy. tiziana.crepaldi@unito.it
Bersani
Francesca
F
Scuoppo
Claudio
C
Accornero
Paolo
P
Prunotto
Chiara
C
Taulli
Riccardo
R
Forni
Paolo E
PE
Leo
Christian
C
Chiarle
Roberto
R
Griffiths
Jennifer
J
Glass
David J
DJ
Ponzetto
Carola
C
D000818:Animals; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins; D051379:Mice; D008822:Mice, Transgenic; D009133:Muscular Atrophy / Q000209:etiology*; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism* / Q000502:physiology; D032496:Satellite Cells, Skeletal Muscle / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D049452:Green Fluorescent Proteins; D019859:Proto-Oncogene Proteins c-met; D048051:p38 Mitogen-Activated Protein Kinases