Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Eley, Helen L.; Skipworth, Richard J E; Deans, D A C; Fearon, Kenneth C. H.; Tisdale, Michael J.

doi:10.1038/sj.bjc.6604150

Cited by 46 publications

(44 citation statements)

References 33 publications

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“…There is no change in the total amount of PKR or eIF2␣. In weightlosing patients with esophagogastric cancer, levels of both phospho-PKR and phospho-eIF2␣ are also significantly enhanced, compared with healthy controls (65), and this is independent of the extent of weight loss. There is a linear relationship between phosphorylation of PKR and phosphorylation of eIF2␣, suggesting that phosphorylation of PKR led to phosphorylation of eIF2␣.…”

Section: A Control Of Protein Synthesis In Normal and Cachectic Statesmentioning

confidence: 83%

Mechanisms of Cancer Cachexia

Tisdale

2009

Physiological Reviews

977

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: A Control Of Protein Synthesis In Normal and Cachectic Statesmentioning

confidence: 83%

Mechanisms of Cancer Cachexia

Tisdale

2009

Physiological Reviews

977

1,061

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“…The regulation of protein synthesis in skeletal muscle is critically regulated at the translational initiation step, with a key role for the eukaryotic initiation factor - 2α (eIF-2α. In cachexia models for atrophy, there is an observed increase in phospho-eIF-2α in association with declines in myofibrillar proteins (Eley et al, 2008), suggesting that elevated phospho-eIF-2α levels contribute to net protein loss. A direct interaction of ADAR1 and PKR (both dsRNA binding proteins) has been recently described to result in PKR inhibition (Clerzius et al, 2009; Toth et al, 2009), consistent with results in this study.…”

Section: Discussionmentioning

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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“…Mice injected with MAC16 tumor cells exhibit increased phosphorylation of both the eIF2α kinase, PKR, and the α-subunit of eIF2 (Eley et al, 2007a; Tisdale, 2009). Elevated phosphorylation of both proteins is also observed in the skeletal muscle of cancer patients exhibiting cachexia (Eley et al, 2008). The increase in PKR phosphorylation is positively correlated with changes in eIF2α phosphorylation, suggesting that activation of PKR leads to eIF2 phosphorylation in human cachexia (Eley et al, 2008).…”

Section: Regulation Of Mrna Translation In Muscle Wasting Conditionsmentioning

confidence: 99%

“…Elevated phosphorylation of both proteins is also observed in the skeletal muscle of cancer patients exhibiting cachexia (Eley et al, 2008). The increase in PKR phosphorylation is positively correlated with changes in eIF2α phosphorylation, suggesting that activation of PKR leads to eIF2 phosphorylation in human cachexia (Eley et al, 2008). Lastly, an inverse relationship exists between muscle myosin content and levels of eIF2α phosphorylation, providing further support for the idea that reduced rates of protein synthesis during cachexia are directly attributable to PKR-mediated phosphorylation of eIF2 (Eley et al, 2008).…”

Section: Regulation Of Mrna Translation In Muscle Wasting Conditionsmentioning

confidence: 99%

“…The increase in PKR phosphorylation is positively correlated with changes in eIF2α phosphorylation, suggesting that activation of PKR leads to eIF2 phosphorylation in human cachexia (Eley et al, 2008). Lastly, an inverse relationship exists between muscle myosin content and levels of eIF2α phosphorylation, providing further support for the idea that reduced rates of protein synthesis during cachexia are directly attributable to PKR-mediated phosphorylation of eIF2 (Eley et al, 2008). Although untested, a possible mechanism that might account for the observed activation of PKR is inflammation, as this pathological feature is increased in both humans and in animal models of cancer and PKR has been shown to be activated in other disease models where inflammation is evident (Cao et al, 2012; McMillan et al, 1994; Puppa et al, 2012; White et al, 2011; White et al, 2012).…”

Section: Regulation Of Mrna Translation In Muscle Wasting Conditionsmentioning

confidence: 99%

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Regulation of muscle protein synthesis and the effects of catabolic states

Gordon

Kelleher

Kimball

2013

The International Journal of Biochemistry & Cell Biology

174

147

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Protein synthesis and degradation are dynamically regulated processes that act in concert to control the accretion or loss of muscle mass. The present article focuses on the mechanisms involved in the impairment of protein synthesis that are associated with skeletal muscle atrophy. The vast majority of mechanisms known to regulate protein synthesis involve modulation of the initiation phase of mRNA translation, which comprises a series of reactions that result in the binding of initiator methionyl-tRNAi and mRNA to the 40S ribosomal subunit. The function of the proteins involved in both events has been shown to be repressed under atrophic conditions such as sepsis, cachexia, chronic kidney disease, sarcopenia, and disuse atrophy. The basis for the inhibition of protein synthesis under such conditions is likely to be multifactorial and includes insulin/insulin-like growth factor 1 resistance, pro-inflammatory cytokine expression, malnutrition, corticosteroids, and/or physical inactivity. The present article provides an overview of the existing literature regarding mechanisms and signaling pathways involved in the regulation of mRNA translation as they apply to skeletal muscle wasting, as well as the efficacy of potential clinical interventions such as nutrition and exercise in the maintenance of skeletal muscle protein synthesis under atrophic conditions.

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Increased expression of phosphorylated forms of RNA-dependent protein kinase and eukaryotic initiation factor 2α may signal skeletal muscle atrophy in weight-losing cancer patients

Cited by 46 publications

References 33 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

Regulation of muscle protein synthesis and the effects of catabolic states

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