PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia

Fabrizio Pin, Leah J. Novinger, Joshua R. Huot, Robert Harris, Marion E. Couch, Thomas M. O'Connell, Andrea Bonetto

Research output: Contribution to journalArticle

2 Citations (Scopus)

Abstract

Cachexia is frequently accompanied by severe metabolic derangements, although the mechanisms responsible for this debilitating condition remain unclear. Pyruvate dehydrogenase kinase (PDK)4, a critical regulator of cellular energetic metabolism, was found elevated in experimental models of cancer, starvation, diabetes, and sepsis. Here we aimed to investigate the link between PDK4 and the changes in muscle size in cancer cachexia. High PDK4 and abnormal energetic metabolism were found in the skeletal muscle of colon-26 tumor hosts, as well as in mice fed a diet enriched in Pirinixic acid, previously shown to increase PDK4 levels. Viral-mediated PDK4 overexpression in myotube cultures was sufficient to promote myofiber shrinkage, consistent with enhanced protein catabolism and mitochondrial abnormalities. On the contrary, blockade of PDK4 was sufficient to restore myotube size in C2C12 cultures exposed to tumor media. Our data support, for the first time, a direct role for PDK4 in promoting cancer-associated muscle metabolic alterations and skeletal muscle atrophy.-Pin, F., Novinger, L. J., Huot, J. R., Harris, R. A., Couch, M. E., O'Connell, T. M., Bonetto, A. PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia.

Original languageEnglish (US)
Pages (from-to)7778-7790
Number of pages13
JournalFASEB journal : official publication of the Federation of American Societies for Experimental Biology
Volume33
Issue number6
DOIs
StatePublished - Jun 1 2019

Fingerprint

Cachexia
Muscular Atrophy
Muscle
Skeletal Muscle Fibers
Neoplasms
Metabolism
Tumors
Skeletal Muscle
Muscle Neoplasms
Mitochondrial Proteins
Nutrition
Medical problems
Starvation
Sepsis
Colon
Theoretical Models
Diet
Muscles
Proteins

Keywords

  • C2C12 myotubes
  • chemotherapy
  • energy metabolism
  • mitochondria
  • skeletal muscle atrophy

ASJC Scopus subject areas

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

Cite this

PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. / Pin, Fabrizio; Novinger, Leah J.; Huot, Joshua R.; Harris, Robert; Couch, Marion E.; O'Connell, Thomas M.; Bonetto, Andrea.

In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology, Vol. 33, No. 6, 01.06.2019, p. 7778-7790.

Research output: Contribution to journalArticle

Pin, Fabrizio ; Novinger, Leah J. ; Huot, Joshua R. ; Harris, Robert ; Couch, Marion E. ; O'Connell, Thomas M. ; Bonetto, Andrea. / PDK4 drives metabolic alterations and muscle atrophy in cancer cachexia. In: FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019 ; Vol. 33, No. 6. pp. 7778-7790.
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