Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia
ABSTRACT In animal models of cachexia, alterations in the phosphatidylinositol 3-kinase (PI3-K)/Akt pathway have been demonstrated in atrophying skeletal muscles. Therefore, we assessed the activity of proteins in this pathway in muscle and liver biopsies from 16 patients undergoing pancreatectomy for suspect of carcinoma. Patients were divided in a non-cachectic or cachectic group according to their weight loss before operation. Extracts of skeletal muscle and liver tissue from eight cachectic patients with pancreas carcinoma and eight non-cachectic patients were analysed by Western blotting using pan- and phospho-specific antibodies directed against eight important signal transduction proteins of the PI3-K/Akt pathway. Muscle samples from cachectic patients revealed significantly decreased levels of myosin heavy chain (-45%) and actin (-18%) in comparison to non-cachectic samples. Akt protein level was decreased by -55%. The abundance and/or phosphorylation of the transcription factors Foxo1 and Foxo3a were reduced by up to fourfold in muscle biopsies from cachectic patients. Various decreases of the phosphorylated forms of the protein kinases mTOR (-82%) and p70S6K (-39%) were found. In contrast to skeletal muscle, cachexia is associated with a significant increase in phosphorylated Akt level in the liver samples with a general activation of the PI3-K/Akt cascade. Our study demonstrates a cachexia-associated loss of Akt-dependent signalling in human skeletal muscle with decreased activity of regulators of protein synthesis and a disinhibition of protein degradation.
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ABSTRACT: Cancer patients frequently suffer from fatigue, a complex syndrome associated with tiredness and depressed mood. Cancer-related fatigue (CRF) can be present at the time of diagnosis, escalates during treatment, and can persist for years after treatment. CRF negatively influences quality of life, limits functional independence, and is associated with decreased survival in patients with incurable disease. We have previously shown that increased pro-inflammatory cytokine expression in the brain contributes to depressive- and fatigue- like behaviors in a mouse model of CRF. Inflammatory cytokines increase activity of indoleamine 2,3-dioxygenase (IDO) and kynurenine 3-monooxygenase (KMO), which competitively reduce serotonin synthesis. Reduced serotonin availability in the brain and increased production of alternative neuroactive metabolites of tryptophan are thought to contribute to the development of depression and fatigue. The purpose of this study was to determine the effects of fluoxetine, a selective serotonin reuptake inhibitor (SSRI), on brain cytokines and behavioral measures of fatigue and depression in tumor-bearing mice. Here we show that tumor growth increased brain expression of pro-inflammatory cytokines and KMO. Treatment with fluoxetine had no effect on tumor growth, muscle wasting, fatigue behavior, or cytokine expression in the brain. Fluoxetine, however, reduced depressive-like behaviors in tumor bearing mice. In conclusion, our data confirm that increased brain expression of pro-inflammatory cytokines is associated with tumor-induced fatigue and depressive-like behavior. However, it is possible to separate the effects of tumor growth on mood and fatigue-like behaviors using SSRI's such as fluoxetine. Copyright © 2014. Published by Elsevier Inc.Physiology & Behavior 12/2014; 140. DOI:10.1016/j.physbeh.2014.12.045 · 3.03 Impact Factor
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ABSTRACT: Advanced glycation end products (AGEs) have been found to play an important role in the development of diabetes, and AGE levels are correlated with the severity of diabetic complications. We have demonstrated that moesin, a protein linker between actin filaments and the plasma membrane, undergoes phosphorylation of its threonine 558 residue by AGE stimulation in human dermal microvascular endothelial cells through activation of p38 and Rho kinase (ROCK) pathways. In this study, we observed in situ whether AGEs caused phosphorylation of vascular endothelial cells in the brains of AGE-stimulated mice. The animals were injected with AGE-modified mouse serum albumin (AGE-MSA) for 7 consecutive days. Immunohistochemistry was conducted to assess the phosphorylation of moesin in brain vessels. The level of moesin protein phosphorylation was also assessed in cerebral microvessels by western blotting. The effects of p38 and ROCK activation were determined by application of a p38 inhibitor (SB203580) and a ROCK inhibitor (Y27632) at 30 min before each AGE administration. The results showed specific expression of moesin in murine brain vascular endothelial cells. AGE treatment induced a significant increase of threonine 558 phosphorylation in moesin, while inhibition of p38 and ROCK remarkably attenuated the phosphorylation of moesin. The level of moesin protein phosphorylation was also increased in cerebral microvessels, along with an increased permeability of the blood-brain barrier, while inhibition of the p38 and ROCK attenuated these responses. These results demonstrate that AGEs cause the phosphorylation of moesin in murine brain microvascular endothelial cells, with p38 and ROCK being involved in this process.Brain research 02/2011; 1373:1-10. DOI:10.1016/j.brainres.2010.12.032 · 2.83 Impact Factor