Increased hypoxia-inducible factor-1α in striated muscle of tumor-bearing mice.
Cancer cachexia is a progressive wasting disease resulting in significant effects on the quality of life and high mortality. Most studies on cancer cachexia have focused on skeletal muscle; however, the heart is now recognized as a major site of cachexia-related effects. To elucidate possible mechanisms, a proteomic study was performed on the left ventricles of colon-26 (C26) adenocarcinoma tumor-bearing mice. The results revealed several changes in proteins involved in metabolism. An integrated pathway analysis of the results revealed a common mediator in hypoxia-inducible factor-1α (HIF-1α). Work by other laboratories has shown that extensive metabolic restructuring in the C26 mouse model causes changes in gene expression that may be affected directly by HIF-1α, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function byday 19, exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1α is significantly upregulated in the heart, whereas there were no changes in its regulatory proteins, prolyl hydroxylase domain-containing protein 2 (PHD2) and von Hippel-Lindau protein (VHL). PHD2 requires both oxygen and iron as cofactors for the hydroxylation of HIF-1α, marking it for ubiquination via VHL and subsequent destruction by the proteasome complex. We examined venous blood gas values in the tumor-bearing mice and found significantly lower oxygen concentration compared with control animals in the third week after tumor inoculation. We also examined select skeletal muscles to determine whether they are similarly affected. In the diaphragm, extensor digitorum longus, and soleus, we found significantly increased HIF-1α in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1α may contribute, in part, to the metabolic changes that occur during cancer cachexia.NEW & NOTEWORTHYWe used proteomics and metadata analysis software to identify contributors to metabolic changes in striated muscle during cancer cachexia. We found increased expression of hypoxia-inducible factor-1α in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia.
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio.|Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio.
Raymond D
RD
Devine
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio.
Sabahattin
S
Bicer
Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio.
Peter J
PJ
Reiser
Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Loren.Wold@osumc.edu.|Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio; and.|College of Nursing, The Ohio State University, Columbus, Ohio.
Loren E
LE
Wold
D000230:Adenocarcinoma / Q000150:complications*; D000818:Animals; D002100:Cachexia / Q000209:etiology / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D015687:Cell Hypoxia; D003110:Colonic Neoplasms / Q000150:complications*; D019295:Computational Biology; D003964:Diaphragm / Q000378:metabolism*; D050556:Fatty Acid-Binding Proteins / Q000378:metabolism; D005260:Female; D006900:Hydroxylation; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000378:metabolism*; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases / Q000378:metabolism; D051379:Mice; D009200:Myocardial Contraction; D009206:Myocardium / Q000378:metabolism*; D009374:Neoplasms, Experimental / Q000150:complications*; D010100:Oxygen / Q000097:blood; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D059748:Proteolysis; D040901:Proteomics / Q000379:methods; D019009:Proto-Oncogene Proteins c-kit / Q000378:metabolism; D013318:Stroke Volume; D013997:Time Factors; D054875:Ubiquitination; D015854:Up-Regulation; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000378:metabolism
C493411:Fabp4 protein, mouse; D050556:Fatty Acid-Binding Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C490189:Egln1 protein, mouse; D064799:Hypoxia-Inducible Factor-Proline Dioxygenases; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D019009:Proto-Oncogene Proteins c-kit; D046988:Proteasome Endopeptidase Complex; C494469:VHL protein, mouse; D010100:Oxygen
cancer cachexia; heart; hypoxia; hypoxia-inducible factor; proteomics; skeletal muscle