The initiation factor eIF3-f is a major target for atrogin1/MAFbx function in skeletal muscle atrophy.
In response to cancer, AIDS, sepsis and other systemic diseases inducing muscle atrophy, the E3 ubiquitin ligase Atrogin1/MAFbx (MAFbx) is dramatically upregulated and this response is necessary for rapid atrophy. However, the precise function of MAFbx in muscle wasting has been questioned. Here, we present evidence that during muscle atrophy MAFbx targets the eukaryotic initiation factor 3 subunit 5 (eIF3-f) for ubiquitination and degradation by the proteasome. Ectopic expression of MAFbx in myotubes induces atrophy and degradation of eIF3-f. Conversely, blockade of MAFbx expression by small hairpin RNA interference prevents eIF3-f degradation in myotubes undergoing atrophy. Furthermore, genetic activation of eIF3-f is sufficient to cause hypertrophy and to block atrophy in myotubes, whereas genetic blockade of eIF3-f expression induces atrophy in myotubes. Finally, eIF3-f induces increasing expression of muscle structural proteins and hypertrophy in both myotubes and mouse skeletal muscle. We conclude that eIF3-f is a key target that accounts for MAFbx function during muscle atrophy and has a major role in skeletal muscle hypertrophy. Thus, eIF3-f seems to be an attractive therapeutic target.
Lagirand-Cantaloube
Julie
J
Laboratoire de Génomique Fonctionnelle et Myogenèse, UMR866 Différenciation Cellulaire et Croissance, INRA UM II, Campus INRA/SUPAGRO, Montpellier, France.
Offner
Nicolas
N
Csibi
Alfredo
A
Leibovitch
Marie P
MP
Batonnet-Pichon
Sabrina
S
Tintignac
Lionel A
LA
Segura
Carlos T
CT
Leibovitch
Serge A
SA
D000818:Animals; D002460:Cell Line; D004195:Disease Models, Animal; D039621:Eukaryotic Initiation Factor-3 / Q000378:metabolism*; D005260:Female; D006801:Humans; D006984:Hypertrophy / Q000201:enzymology / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000378:metabolism / Q000473:pathology; D009124:Muscle Proteins / Q000502:physiology*; D018482:Muscle, Skeletal / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D009133:Muscular Atrophy / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism / Q000502:physiology; D025941:Protein Interaction Mapping; D044843:SKP Cullin F-Box Protein Ligases / Q000502:physiology*; D054875:Ubiquitination
D039621:Eukaryotic Initiation Factor-3; D009124:Muscle Proteins; C486691:Fbxo32 protein, mouse; D044843:SKP Cullin F-Box Protein Ligases; D046988:Proteasome Endopeptidase Complex