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Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia

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A Publisher´s Erratum to this article was published on 22 May 2007

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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Abbreviations

IR:

insulin receptor

IRS1:

insulin receptor substrate 1

MyHC:

myosin heavy chain

PAA:

polyacrylamide

PI3-K:

phosphatidylinositol 3-kinase

SDS:

sodium dodecyl sulphate

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Acknowledgements

We appreciate the technical assistance of Mrs. A. Ott-Hartmann and N. Erbe.

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Authors and Affiliations

  1. Division of Immunochemistry (D020), German Cancer Research Center, Im Neuenheimer Feld 280, 69120, Heidelberg, Germany

    Thomas L. Schmitt & Wulf Hildebrandt

  2. Department of General Surgery, University of Heidelberg, Heidelberg, Germany

    Marcus E. Martignoni, Jeannine Bachmann & Helmut Friess

  3. Department of Radiology, University of Heidelberg, Heidelberg, Germany

    Kerstin Fechtner

  4. Anatomy and Developmental Biology, Medizinische Fakultät Mannheim, University of Heidelberg, Heidelberg, Germany

    Ralf Kinscherf

Authors
  1. Thomas L. Schmitt
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  2. Marcus E. Martignoni
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Correspondence to Thomas L. Schmitt.

Additional information

Thomas L. Schmitt and Marcus E. Martignoni contributed equally to the paper.

An erratum to this article can be found at http://dx.doi.org/10.1007/s00109-007-0206-1

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Schmitt, T.L., Martignoni, M.E., Bachmann, J. et al. Activity of the Akt-dependent anabolic and catabolic pathways in muscle and liver samples in cancer-related cachexia. J Mol Med 85, 647–654 (2007). https://doi.org/10.1007/s00109-007-0177-2

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  • DOI: https://doi.org/10.1007/s00109-007-0177-2

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