Ubiquitin Ligase Cbl-b Is a Negative Regulator for Insulin-Like Growth Factor 1 Signaling during Muscle Atrophy Caused by Unloading

Abstract

Skeletal muscle atrophy caused by unloading is characterized by both decreased responsiveness to myogenicThe impairment of growth factor signaling is a near-universal feature of skeletal myopathies induced by unloading (6, 13). Clinical trials have established that during unloading, muscle tissue fails to respond to IGF-1, a dominant myotrophic hormone (7,19,34). Under normal conditions and in response to hypertrophic stimuli, IGF-1 promotes muscle growth and suppresses muscle loss largely through the Akt-dependent phosphorylation and cytosolic sequestration of FOXO transcription factors in skeletal myocytes, which leads to the inhibition of FOXO-dependent gene expression (38, 41). In contrast, IGF-1-dependent Akt signaling is impaired during muscle atrophy, which decreases the phosphorylation and increases the transactivation of FOXO target genes. In particular, FOXO regulates the expression of atrophy-related genes (atrogenes) that encode atrogin-1/MAFbx and MuRF-1, which are RING-type ubiquitin ligases that are critical mediators of atrophic myopathies in vivo (3,14). Atrogin-1 and MuRF-1 regulate the degradation of key proteins involved in striated muscle growth and differentiation, including MyoD, calcineurin, and troponin-I (24, 27, 47). Although diminished growth factor responsiveness and enhanced proteolysis both are major atrophyrelated processes, the mechanisms by which skeletal muscle becomes refractory to the trophic actions of muscle growth factors during unloading are not well defined.In a previous study designed to evaluate changes in skeletal muscle gene expression in rats exposed to a 16-day spaceflight (30), we identified novel potential atrogenes (37) using microarray analysis. The response of skeletal muscle to mechanical stress is accompanied by marked alterations in atrogene expression, and we showed that microgravity induces Siah-1A, MuRF-1 (30), and atrogin-1 (see Table S1 in the supplemental material). Microgravity also resulted in the increased expression of Cbl-b (greater than eightfold). Cbl-b is another RING-type ubiquitin ligase previously established as a negative regulator of receptor tyrosine kinase signaling in a variety of cells (23,45). These results complement our recent finding that Cbl-b downregulates bone formation

Proteolysis in illness-associated skeletal muscle atrophy: from pathways to networks

“…Transduction of muscle with plasmid expressing Cbl-b induces atrophy. Finally, Cbl-b knock-out mice show sparing of muscle wasting and myofiber atrophy upon unloading, a finding that confirms an essential role of Cbl-b in this form of wasting 76 .…”

“…This RING finger containing ligase is involved in the down-regulation of a number of plasma membrane receptor tyrosine kinases (reviewed in 75 ) and results in decreased signaling. Atrophy induced by unloading has been observed to induce expression of Cbl-b and association of this ligase with IRS-1 (IRS, insulin receptor substrate), a key downstream signaling mediator of insulin and IGF1 76 . This results in degradation of IRS-1, decreased growth factor signaling and activation of MuRF-1 and MAFbx/Atrogin-1 expression.…”

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

“…Previous studies already linked the proteasome-mediated degradation of IRS1 to the inhibition of insulin action in response to hyperinsulinaemia [35,36] and inflammation [37]. In this context, multiple E3-ligases, including F-box only protein 40, CBLB, and F-box/WD repeat-containing protein 8, have been linked to IRS1 degradation in response to hyperinsulinaemia, inflammation and chronic exposure to insulin-like growth factor 1 [37][38][39][40][41]. Furthermore, increased expression of Fbxo32 and Murf1 associated with reduced activation of the PI3K/Akt pathway by insulin was described in skeletal muscle of db/db mice [42].…”

The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation

“…Cbl-b is a RING-type E3 ligase that ubiquitinates IRS-1, targeting it for degradation. (75). Transducing into muscle the phosphopentapeptide DGpYMP, which interferes with Cbl-IRS1 interaction, protects from glucocorticoid-induced myofiber atrophy (79).…”