Ubiquitin ligase Cbl-b is a negative regulator for insulin-like growth factor 1 signaling during muscle atrophy caused by unloading.
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 tyrosine(608)-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.
Nakao
Reiko
R
Department of Nutritional Physiology, Institute of Health Biosciences, University of Tokushima Graduate School, Kuramoto-cho, Tokushima, Japan.
Hirasaka
Katsuya
K
Goto
Jumpei
J
Ishidoh
Kazumi
K
Yamada
Chiharu
C
Ohno
Ayako
A
Okumura
Yuushi
Y
Nonaka
Ikuya
I
Yasutomo
Koji
K
Baldwin
Kenneth M
KM
Kominami
Eiki
E
Higashibata
Akira
A
Nagano
Keisuke
K
Tanaka
Keiji
K
Yasui
Natsuo
N
Mills
Edward M
EM
Takeda
Shin'ichi
S
Nikawa
Takeshi
T
D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism; D019417:Hindlimb Suspension; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007334:Insulin-Like Growth Factor I / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism* / Q000473:pathology; D009842:Oligopeptides / Q000235:genetics / Q000378:metabolism; D050721:Proto-Oncogene Proteins c-cbl / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D044843:SKP Cullin F-Box Protein Ligases / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D013026:Space Flight; D025801:Ubiquitin / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C118387:Cblb protein, mouse; C492213:Cblb protein, rat; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; C474033:FoxO3 protein, mouse; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D009124:Muscle Proteins; D009842:Oligopeptides; D025801:Ubiquitin; D007334:Insulin-Like Growth Factor I; C486691:Fbxo32 protein, mouse; D050721:Proto-Oncogene Proteins c-cbl; D044843:SKP Cullin F-Box Protein Ligases