Journal of Molecular Medicine

, Volume 85, Issue 6, pp 647–654

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

  • Thomas L. Schmitt
  • Marcus E. Martignoni
  • Jeannine Bachmann
  • Kerstin Fechtner
  • Helmut Friess
  • Ralf Kinscherf
  • Wulf Hildebrandt
Original Article

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.

Keywords

Cachexia Pancreatic cancer Skeletal muscle Liver Phosphatidylinositol 3-kinase Signal transduction 

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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Copyright information

© Springer-Verlag 2007

Authors and Affiliations

  • Thomas L. Schmitt
    • 1
  • Marcus E. Martignoni
    • 2
  • Jeannine Bachmann
    • 2
  • Kerstin Fechtner
    • 3
  • Helmut Friess
    • 2
  • Ralf Kinscherf
    • 4
  • Wulf Hildebrandt
    • 1
  1. 1.Division of Immunochemistry (D020)German Cancer Research CenterHeidelbergGermany
  2. 2.Department of General SurgeryUniversity of HeidelbergHeidelbergGermany
  3. 3.Department of RadiologyUniversity of HeidelbergHeidelbergGermany
  4. 4.Anatomy and Developmental Biology, Medizinische Fakultät MannheimUniversity of HeidelbergHeidelbergGermany

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