Abstract
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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Amino Acid Sequence
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Animals
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Cell Line
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Forkhead Box Protein O3
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Forkhead Transcription Factors / metabolism
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Hindlimb Suspension*
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Humans
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Insulin Receptor Substrate Proteins / genetics
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Insulin Receptor Substrate Proteins / metabolism
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Insulin-Like Growth Factor I / genetics
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Insulin-Like Growth Factor I / metabolism*
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Male
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Mice
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Mice, Inbred C57BL
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Mice, Knockout
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Molecular Sequence Data
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Muscle Proteins / genetics
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Muscle Proteins / metabolism
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Muscle, Skeletal / metabolism
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Muscle, Skeletal / pathology
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Muscular Atrophy / metabolism*
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Muscular Atrophy / pathology
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Oligopeptides / genetics
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Oligopeptides / metabolism
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Proto-Oncogene Proteins c-cbl / genetics
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Proto-Oncogene Proteins c-cbl / metabolism*
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Rats
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Rats, Sprague-Dawley
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SKP Cullin F-Box Protein Ligases / genetics
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SKP Cullin F-Box Protein Ligases / metabolism
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Signal Transduction / physiology*
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Space Flight*
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Ubiquitin / metabolism
Substances
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Adaptor Proteins, Signal Transducing
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Cblb protein, mouse
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Cblb protein, rat
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Forkhead Box Protein O3
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Forkhead Transcription Factors
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FoxO3 protein, mouse
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Insulin Receptor Substrate Proteins
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Irs1 protein, mouse
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Muscle Proteins
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Oligopeptides
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Ubiquitin
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Insulin-Like Growth Factor I
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Fbxo32 protein, mouse
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Proto-Oncogene Proteins c-cbl
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SKP Cullin F-Box Protein Ligases