The SCF-Fbxo40 Complex Induces IRS1 Ubiquitination in Skeletal Muscle, Limiting IGF1 Signaling

Shi, Jun; Luo, Laihui; Eash, John K.; Ibebunjo, Chikwendu; Glass, David J.

doi:10.1016/j.devcel.2011.09.011

Cited by 127 publications

(129 citation statements)

References 34 publications

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“…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].…”

Section: Discussionmentioning

confidence: 99%

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

Wiza

Nascimento

et al. 2013

Diabetologia

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Aims/hypothesis The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). Methods Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine-induced insulin resistance. Results PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p<0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p<0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p<0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p<0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p<0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases Fbox protein 32 (also known as atrogin-1) and muscle RINGfinger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. Conclusions/interpretation Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action.

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Section: Discussionmentioning

confidence: 99%

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

Wiza

Nascimento

et al. 2013

Diabetologia

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“…Transducing into muscle the phosphopentapeptide DGpYMP, which interferes with Cbl-IRS1 interaction, protects from glucocorticoid-induced myofiber atrophy (79). Another ubiquitin ligase targeting IRS-1 is SCF-Fbxo40, which, upon IGF-I stimulation, promotes the degradation of IRS-1 (95). It is also upregulated following denervation-induced atrophy (122), and its knockdown in mice using small-interfering RNA (siRNA) leads to thicker myotubes (95).…”

Section: The Ups Regulates Signaling Pathwaysmentioning

confidence: 99%

“…Another ubiquitin ligase targeting IRS-1 is SCF-Fbxo40, which, upon IGF-I stimulation, promotes the degradation of IRS-1 (95). It is also upregulated following denervation-induced atrophy (122), and its knockdown in mice using small-interfering RNA (siRNA) leads to thicker myotubes (95). Recently, Trim72 has been shown to ubiquitinate IRS-1 and the insulin receptor (99,123).…”

Section: The Ups Regulates Signaling Pathwaysmentioning

confidence: 99%

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

Bilodeau

Coyne

Wing

2016

American Journal of Physiology-Cell Physiology

136

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Bilodeau PA, Coyne ES, Wing SS. The ubiquitin proteasome system in atrophying skeletal muscle: roles and regulation. Am J Physiol Cell Physiol 311: C392-C403, 2016. First published August 10, 2016; doi:10.1152/ajpcell.00125.2016.-Muscle atrophy complicates many diseases as well as aging, and its presence predicts both decreased quality of life and survival. Much work has been conducted to define the molecular mechanisms involved in maintaining protein homeostasis in muscle. To date, the ubiquitin proteasome system (UPS) has been shown to play an important role in mediating muscle wasting. In this review, we have collated the enzymes in the UPS whose roles in muscle wasting have been confirmed through loss-of-function studies. We have integrated information on their mechanisms of action to create a model of how they work together to produce muscle atrophy. These enzymes are involved in promoting myofibrillar disassembly and degradation, activation of autophagy, inhibition of myogenesis as well as in modulating the signaling pathways that control these processes. Many anabolic and catabolic signaling pathways are involved in regulating these UPS genes, but none appear to coordinately regulate a large number of these genes. A number of catabolic signaling pathways appear to instead function by inhibition of the insulin/IGF-I/protein kinase B anabolic pathway. This pathway is a critical determinant of muscle mass, since it can suppress key ubiquitin ligases and autophagy, activate protein synthesis, and promote myogenesis through its downstream mediators such as forkhead box O, mammalian target of rapamycin, and GSK3␤, respectively. Although much progress has been made, a more complete inventory of the UPS genes involved in mediating muscle atrophy, their mechanisms of action, and their regulation will be useful for identifying novel therapeutic approaches to this important clinical problem.hormones; muscle atrophy SKELETAL MUSCLE SERVES TWO essential functions, a contractile function for locomotion/maintenance of posture and a metabolic function as the protein reservoir of the body. The myofibers that make up the muscle consist primarily of myofibrillar proteins. The ability of the body to maintain posture or to move arises from the precise organization of myofibrillar proteins into a contractile unit called the sarcomere. The sarcomere consists of thick filaments containing primarily myosin that can slide over thin filaments containing primarily actin. Both types of filaments contain additional regulatory proteins and are linked to the ␣-actinin-containing Z disk, the thin filaments directly so and the thick filaments via titin. Vimentin and desmin are intermediate filaments that serve to anchor sarcomeres properly at the Z disks. These myofibrillar proteins, as well as the sarcoplasmic proteins, also serve as the protein reservoir of the body. Upon fasting, once hepatic glycogen stores are depleted, muscle protein degradation must be activated to provide amino acids to the liver for gluconeogenesis. These amino a...

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“…27 A muscle-specific F-box protein was foun in 2007, 28 which induces the ubiquitination of insulin receptor substrate 1 thereby providing a negative feedback on the IGF1R/IRS1/PI3K/Akt pathway by early signal termination. 29 In addition 2010, tumour necrosis factor (TNF) receptorassociated factor has been found to play a critic al role in atrophy as an E3 ubiquitin ligase. 30 Cancer cachexia animal models are showing significant wasting of the myocardium.…”

Section: Current Developments On Muscle Mass Lossmentioning

confidence: 99%

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

Drescher

Konishi

Ebner

et al. 2016

International Journal of Cardiology

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The SCF-Fbxo40 Complex Induces IRS1 Ubiquitination in Skeletal Muscle, Limiting IGF1 Signaling

Cited by 127 publications

References 34 publications

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

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

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

Loss of muscle mass: Current developments in cachexia and sarcopenia focused on biomarkers and treatment

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