DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy

Nowak, Marcel; Suenkel, Benjamin; Porras, Pablo; Migotti, Rebekka; Schmidt, Franziska; Kny, Melanie; Zhu, Xiaoxi; Wanker, Erich E.; Dittmar, Gunnar; Fielitz, Jens; Sommer, Thomas

doi:10.1242/jcs.233395

Cited by 21 publications

(22 citation statements)

References 53 publications

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“…Differential gene expression (log2FoldChange ±1.0, padj <0.01) analysis indicate 1,171 and 786 genes are increased and decreased in expression (mKO versus control), respectively ( Figure 5 A). Quantitative PCR validation of RNA sequencing (RNA-seq) analyses (data not shown) indicate a marked reduction in the expression of Myostatin, as well as a general repression of the E3 ubiquitin ligases and accessory proteins known to promote muscle atrophy ( Bodine et al., 2001 ; Nowak et al., 2019 ; Sartori et al., 2013 ). In addition, genes associated with increased energy expenditures and metabolic stress, including Sln , Asns , Fgf21 , Gdf15 , Psat1 , and Mthfd2 ( Balasubramanian et al., 2013 ; Chung et al., 2017 ; Fisher and Maratos-Flier, 2016 ; Maurya et al., 2018 ; Nilsson et al., 2014 ), are robustly induced in the muscles of Hnrnpu mutants ( Figure 5 B).…”

Section: Resultsmentioning

confidence: 99%

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

et al. 2020

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Summary Skeletal muscle has the remarkable ability to modulate its mass in response to changes in nutritional input, functional utilization, systemic disease, and age. This is achieved by the coordination of transcriptional and post-transcriptional networks and the signaling cascades balancing anabolic and catabolic processes with energy and nutrient availability. The extent to which alternative splicing regulates these signaling networks is uncertain. Here we investigate the role of the RNA-binding protein hnRNP-U on the expression and splicing of genes and the signaling processes regulating skeletal muscle hypertrophic growth. Muscle-specific Hnrnpu knockout (mKO) mice develop an adult-onset myopathy characterized by the selective atrophy of glycolytic muscle, the constitutive activation of Akt, increases in cellular and metabolic stress gene expression, and changes in the expression and splicing of metabolic and signal transduction genes. These findings link Hnrnpu with the balance between anabolic signaling, cellular and metabolic stress, and physiological growth.

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Section: Resultsmentioning

confidence: 99%

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

et al. 2020

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“…DCAF8 (WD repeat containing protein 42A, WDR42A) is a substrate receptor for cullin RING ligases (CRLs) belonging to the CRL4 complexes [171]. MuRF1 interacts with DCAF8 and immuno-precipitate with DCAF8 and DDB1, Cul4A, RBX1, that are members of CRL4 complexes [172]. The authors proposed that DCAF8 and MuRF1 may act synergistically to degrade MHC.…”

Section: Other Murf1 Interactors (Not or Not Yet Substrates)mentioning

confidence: 99%

MuRF1/TRIM63, Master Regulator of Muscle Mass

Peris-Moreno

Taillandier

Polge

2020

IJMS

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The E3 ubiquitin ligase MuRF1/TRIM63 was identified 20 years ago and suspected to play important roles during skeletal muscle atrophy. Since then, numerous studies have been conducted to decipher the roles, molecular mechanisms and regulation of this enzyme. This revealed that MuRF1 is an important player in the skeletal muscle atrophy process occurring during catabolic states, making MuRF1 a prime candidate for pharmacological treatments against muscle wasting. Indeed, muscle wasting is an associated event of several diseases (e.g., cancer, sepsis, diabetes, renal failure, etc.) and negatively impacts the prognosis of patients, which has stimulated the search for MuRF1 inhibitory molecules. However, studies on MuRF1 cardiac functions revealed that MuRF1 is also cardioprotective, revealing a yin and yang role of MuRF1, being detrimental in skeletal muscle and beneficial in the heart. This review discusses data obtained on MuRF1, both in skeletal and cardiac muscles, over the past 20 years, regarding the structure, the regulation, the location and the different functions identified, and the first inhibitors reported, and aim to draw the picture of what is known about MuRF1. The review also discusses important MuRF1 characteristics to consider for the design of future drugs to maintain skeletal muscle mass in patients with different pathologies.

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“…Specificity of the anti-MuRF1 antibody was tested by western blot analysis using tissue lysates of tibialis anterior muscle from wild type, Trim63/MuRF1 mutant and Trim54/MuRF3//Trim63/MuRF1 double mutant mice and of lysates from C2C12 cells following siRNA mediated knockdown of MuRF1 (data not shown). For more information, please refer to Nowak et al 47 GAPDH was used as loading control. abolishes IKK-dependent phosphorylation of p65 and of IκBα and subsequent degradation of IκBα and activation of NF-κ B.…”

Section: Serum Amyloid A1 Toll-like Receptors and Nf-κbmentioning

confidence: 99%

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

Hahn

Kny

Pablo‐Tortola

et al. 2019

J cachexia sarcopenia muscle

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Background Critically ill patients frequently develop muscle atrophy and weakness in the intensive‐care‐unit setting [intensive care unit‐acquired weakness (ICUAW)]. Sepsis, systemic inflammation, and acute‐phase response are major risk factors. We reported earlier that the acute‐phase protein serum amyloid A1 (SAA1) is increased and accumulates in muscle of ICUAW patients, but its relevance was unknown. Our objectives were to identify SAA1 receptors and their downstream signalling pathways in myocytes and skeletal muscle and to investigate the role of SAA1 in inflammation‐induced muscle atrophy. Methods We performed cell‐based in vitro and animal in vivo experiments. The atrophic effect of SAA1 on differentiated C2C12 myotubes was investigated by analysing gene expression, protein content, and the atrophy phenotype. We used the cecal ligation and puncture model to induce polymicrobial sepsis in wild type mice, which were treated with the IкB kinase inhibitor Bristol‐Myers Squibb (BMS)‐345541 or vehicle. Morphological and molecular analyses were used to investigate the phenotype of inflammation‐induced muscle atrophy and the effects of BMS‐345541 treatment. Results The SAA1 receptors Tlr2, Tlr4, Cd36, P2rx7, Vimp, and Scarb1 were all expressed in myocytes and skeletal muscle. Treatment of differentiated C2C12 myotubes with recombinant SAA1 caused myotube atrophy and increased interleukin 6 (Il6) gene expression. These effects were mediated by Toll‐like receptors (TLR) 2 and 4. SAA1 increased the phosphorylation and activity of the transcription factor nuclear factor ‘kappa‐light‐chain‐enhancer' of activated B‐cells (NF‐κB) p65 via TLR2 and TLR4 leading to an increased binding of NF‐κB to NF‐κB response elements in the promoter region of its target genes resulting in an increased expression of NF‐κB target genes. In polymicrobial sepsis, skeletal muscle mass, tissue morphology, gene expression, and protein content were associated with the atrophy response. Inhibition of NF‐κB signalling by BMS‐345541 increased survival (28.6% vs. 91.7%, P < 0.01). BMS‐345541 diminished inflammation‐induced atrophy as shown by a reduced weight loss of the gastrocnemius/plantaris (vehicle: −21.2% and BMS‐345541: −10.4%; P < 0.05), tibialis anterior (vehicle: −22.7% and BMS‐345541: −17.1%; P < 0.05) and soleus (vehicle: −21.1% and BMS‐345541: −11.3%; P < 0.05) in septic mice. Analysis of the fiber type specific myocyte cross‐sectional area showed that BMS‐345541 reduced inflammation‐induced atrophy of slow/type I and fast/type II myofibers compared with vehicle‐treated septic mice. BMS‐345541 reversed the inflammation‐induced atrophy program as indicated by a reduced expression of the atrogenes Trim63/MuRF1, Fbxo32/Atrogin1, and Fbxo30/MuSA1. Conclusions SAA1 activates the TLR2/TLR4//NF‐κB p65 signalling pathway to cause myocyte atrophy. Systemic inhibition of the NF‐κB pathway reduced muscle atrophy and increased survival of septic mice. The SAA1/TLR2/TLR4//NF‐κB p65 atrophy pathway could have utility in combatting ICUAW.

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DCAF8, a novel MuRF1 interaction partner, promotes muscle atrophy

Cited by 21 publications

References 53 publications

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

Adult-Onset Myopathy with Constitutive Activation of Akt following the Loss of hnRNP-U

MuRF1/TRIM63, Master Regulator of Muscle Mass

Serum amyloid A1 mediates myotube atrophy via Toll‐like receptors

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