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.
"Several previous reports indicate that the myosin heavy chain isoform composition of skeletal muscle, a major determinant of muscle contractile properties, changes with tumor burden (Diffee et al., 2002; Taskin et al., 2014), whereas others reported no change in myosin heavy isoform composition or myosin-based fiber type composition (Johns et al., 2014; Schmitt et al., 2007). Consistent with no change in specific force generation, significant alterations in physical activity were observed in tumor-bearing mice, compared to control mice, without any detectable change in myosin isoform expression. "
"Cachexia is caused by complex interactions between pro-inflammatory cytokines, hypermetabolism, catabolism of muscle protein, neurohormonal changes, and proteolytic and lipolytic factors produced by the host and tumor [1-3]. Cancer cachexia is also associated with a decrease in protein synthesis that might be a consequence of, at least in part, alteration in the activation of the 5′ AMP-activated protein kinase, protein kinase B (Akt), and mammalian target of rapamycin (mTOR) signaling pathways [15, 16]. "
[Show abstract][Hide abstract] ABSTRACT: Cancer cachexia is defined as a multifactorial syndrome of involuntary weight loss characterized by an ongoing loss of skeletal muscle mass and progressive functional impairment. It is postulated that cardiac dysfunction/atrophy parallels skeletal muscle atrophy in cancer cachexia. Cardiotoxic chemotherapy may additionally result in cardiac dysfunction and heart failure in some cancer patients. Heart failure thus may be a consequence of either ongoing cachexia or chemotherapy-induced cardiotoxicity; at the same time, heart failure can result in cachexia, especially muscle wasting. Therefore, the subsequent heart failure and cardiac cachexia can exacerbate the existing cancer-induced cachexia. We discuss these bilateral effects between cancer cachexia and heart failure in cancer patients. Since cachectic patients are more susceptible to chemotherapy-induced toxicity overall, this may also include increased cardiotoxicity of antineoplastic agents. Patients with cachexia could thus be doubly unfortunate, with cachexia-related cardiac dysfunction/heart failure and increased susceptibility to cardiotoxicity during treatment. Cardiovascular risk factors as well as pre-existing heart failure seem to exacerbate cardiac susceptibility against cachexia and increase the rate of cardiac cachexia. Hence, chemotherapy-induced cardiotoxicity, cardiovascular risk factors, and pre-existing heart failure may accelerate the vicious cycle of cachexia-heart failure. The impact of cancer cachexia on cardiac dysfunction/heart failure in cancer patients has not been thoroughly studied. A combination of serial echocardiography for detection of cachexia-induced cardiac remodeling and computed tomography image analysis for detection of skeletal muscle wasting would appear a practical and non-invasive approach to develop an understanding of cardiac structural/functional alterations that are directly related to cachexia.
Journal of Cachexia, Sarcopenia and Muscle 03/2014; 5(2). DOI:10.1007/s13539-014-0137-y · 7.32 Impact Factor
"Our data also showed that treatment of AGE-MSA did not change the expression of total moesin protein in the mouse cerebrum, indicating that the increase of moesin phosphorylation is a rapid response, seemingly without the involvement of gene regulation. This result corresponds with the notion of moesin as a housekeeping protein (Schmitt et al., 2007). "
[Show abstract][Hide abstract] 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 · 2.84 Impact Factor
Adam M Gonzalez, Jay R Hoffman, Adam R Jajtner, Jeremy R Townsend, Carleigh H Boone, Kyle S Beyer, Kayla M Baker, Adam J Wells, David D Church, Gerald T Mangine, Leonardo P Oliveira, Jordan R Moon, David H Fukuda, Jeffrey R Stout
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