Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Eley, Helen L.; Russell, Steven T.; Tisdale, Michael J.

doi:10.1038/sj.bjc.6603704

Cited by 42 publications

(34 citation statements)

References 25 publications

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“…In addition, activation of PKR leads to an increased expression and activity of the ubiquitinproteasome pathway, through activation of NFB, either by direct interaction or through formation of ROS (66). The importance of this process to cancer cachexia is shown by the ability of a PKR inhibitor to attenuate skeletal muscle atrophy in a murine model of cachexia, through an increased protein synthesis and reduction of the increased protein degradation down to basal levels (63). Interestingly, inhibition of the activation of PKR also inhibited tumor growth.…”

Section: Apoptosis In Skeletal Musclementioning

confidence: 99%

Mechanisms of Cancer Cachexia

Tisdale

2009

Physiological Reviews

994

1,061

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Up to 50% of cancer patients suffer from a progressive atrophy of adipose tissue and skeletal muscle, called cachexia, resulting in weight loss, a reduced quality of life, and a shortened survival time. Anorexia often accompanies cachexia, but appears not to be responsible for the tissue loss, particularly lean body mass. An increased resting energy expenditure is seen, possibly arising from an increased thermogenesis in skeletal muscle due to an increased expression of uncoupling protein, and increased operation of the Cori cycle. Loss of adipose tissue is due to an increased lipolysis by tumor or host products. Loss of skeletal muscle in cachexia results from a depression in protein synthesis combined with an increase in protein degradation. The increase in protein degradation may include both increased activity of the ubiquitin-proteasome pathway and lysosomes. The decrease in protein synthesis is due to a reduced level of the initiation factor 4F, decreased elongation, and decreased binding of methionyl-tRNA to the 40S ribosomal subunit through increased phosphorylation of eIF2 on the α-subunit by activation of the dsRNA-dependent protein kinase, which also increases expression of the ubiquitin-proteasome pathway through activation of NFκB. Tumor factors such as proteolysis-inducing factor and host factors such as tumor necrosis factor-α, angiotensin II, and glucocorticoids can all induce muscle atrophy. Knowledge of the mechanisms of tissue destruction in cachexia should improve methods of treatment.

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Section: Apoptosis In Skeletal Musclementioning

confidence: 99%

Mechanisms of Cancer Cachexia

Tisdale

2009

Physiological Reviews

994

1,061

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“…A notable inflammatory stress mediator is the IFN-γ inducible dsRNA-dependent protein kinase (PKR), a critical negative regulator that when activated through phosphorylation blocks protein synthesis through phosphorylation of EIF-2α (Samuel, 2001), thereby promoting muscle atrophy (Eley et al, 2007; Eley and Tisdale, 2007; Tisdale, 2009). Recent studies dissecting the signaling pathways activated during muscle inflammatory stress also indicate that IFN–γ can potentiate TNF–α mediated atrophy by promoting increased mRNA instability in MyoD and Myogenin (Guttridge et al, 2000).…”

Section: Introductionmentioning

confidence: 99%

The RNA Editor Gene ADAR1 is Induced in Myoblasts by Inflammatory Ligands and Buffers Stress Response

Meltzer

Long

Nie

et al. 2010

Clinical Translational Sci

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Muscle atrophy remains a signifi cant concern in multiple infl ammatory conditions, including injury, sepsis, cachexia, and HIV-associated wasting. Herein, we show that infl ammatory stressors, including TNF-α, IFN-γ, or lipopolysaccharide, potently induced the novel expression of the RNA editor ADAR1, an observation not previously described in muscle cells. We also observed that cytokine stimulation suppressed muscle-associated microRNAs, an observation also not previously demonstrated. To map potential effects of ADAR1 induction in the muscle program, we conducted knockdown and overexpression studies in the mouse C2C12 muscle precursor cell (MPC) line and in primary human MPCs. We show that knockdown of stress-induced ADAR1 increased infl ammation-mediated declines in the muscle differentiation markers Myogenin and myosin heavy chain, and knockdown reduced levels of active phosphorylated Akt (phospho-Akt), but had no effect on microRNA transcript levels, suggesting a role for ADAR1 in buffering infl ammatory stress effects on myogenic transcription and protein synthesis pathways. In addition, overexpression of recombinant ADAR1 suppressed active phosphorylated double-stranded RNA (dsRNA)-dependent protein kinase (phospho-PKR), consistent with a role for ADAR1 in limiting infl ammationdriven catabolic atrophy pathways. Collectively, these data identify a novel regulatory role for ADAR1 activation under infl ammatory stress to both promote muscle protein synthesis pathways and limit atrophy pathways. Clin Trans Sci 2010; Volume 3: 73-80

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“…The significance of the convergence of these signaling pathways on NF-κB in cancerrelated muscle atrophy has been shown experimentally in a number of different ways. Both genetic or pharmacologic inhibition of NF-κB prevents muscle mass loss, improves strength, and increases muscle regeneration [2,9,16,28,31,36,46,48,57,70,75]. These numerous studies implicate NF-κB as having much potential as a therapeutic target in cancer-induced muscle loss.…”

Section: Introductionmentioning

confidence: 99%

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

Wysong¹,

Asher

Yin

et al. 2011

JCST

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Cancer cachexia is a severe wasting syndrome characterized by the progressive loss of lean body mass and systemic inflammation, which is seen in as many as 80% of patients with advanced malignancy. It accounts for an estimated 20-30% of all cancer-related deaths. The mechanism by which cancer induces skeletal muscle atrophy in cachexia involves tumor-derived cytokines, including TNFα, IL-1, and IL-6. Upon interaction with their unique receptors on skeletal muscle, these cytokines activate NF-kappaB, a transcription factor crucial for atrophy related sarcomere proteolysis to occur. The significance of NF-κB is highlighted in studies demonstrating that genetic inhibition of NF-κB ameliorates cancer-induced muscle loss in vivo. In the present study, we evaluate a selective NF-kappaB inhibitor (NBD peptide) which targets the IkappaB complex to prevent cancer-induced skeletal muscle atrophy in an established mouse model (C26 adenocarcinoma). We identified for the first time that NBD peptide can directly inhibit tumor-induced NFkappaB activation in skeletal muscle, resulting in a decrease loss of lean muscle. We also identified that NBD peptide reduces the expression of the tumor induced ubiquitin ligases MuRF-1 and MAFbx/Atrogin-1 necessary for atrophy. These findings highlight that NBD peptide may be a potential selective therapeutic agent for the treatment of cancer cachexia.

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Attenuation of muscle atrophy in a murine model of cachexia by inhibition of the dsRNA-dependent protein kinase

Cited by 42 publications

References 25 publications

Mechanisms of Cancer Cachexia

Mechanisms of Cancer Cachexia

The RNA Editor Gene ADAR1 is Induced in Myoblasts by Inflammatory Ligands and Buffers Stress Response

Selective Inhibition of NF-kappa-B with NBD Peptide Reduces Tumor- Induced Wasting in a Murine Model of Cancer Cachexia In vivo

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