PMID- 28341633 OWN - NLM STAT- MEDLINE DCOM- 20170807 LR - 20210215 IS - 1522-1539 (Electronic) IS - 0363-6135 (Print) IS - 0363-6135 (Linking) VI - 312 IP - 6 DP - 2017 Jun 1 TI - Increased hypoxia-inducible factor-1alpha in striated muscle of tumor-bearing mice. PG - H1154-H1162 LID - 10.1152/ajpheart.00090.2016 [doi] AB - 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-1alpha (HIF-1alpha). 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-1alpha, such as glucose metabolic genes. M-mode echocardiography showed progressive decline in heart function by day 19, exhibited by significantly decreased ejection fraction and fractional shortening, along with posterior wall thickness. Using Western blot analysis, we confirmed that HIF-1alpha 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-1alpha, 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-1alpha in tumor-bearing mice, indicating a hypoxic response, not only in the heart, but also in skeletal muscle. These results indicate that HIF-1alpha may contribute, in part, to the metabolic changes that occur during cancer cachexia.NEW & NOTEWORTHY We 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-1alpha in the heart and skeletal muscle, suggesting a potential target for the therapeutic treatment of cancer cachexia. CI - Copyright (c) 2017 the American Physiological Society. FAU - Devine, Raymond D AU - Devine RD AD - Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio. AD - Molecular, Cellular and Developmental Biology Graduate Program, The Ohio State University, Columbus, Ohio. FAU - Bicer, Sabahattin AU - Bicer S AD - Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio. FAU - Reiser, Peter J AU - Reiser PJ AD - Division of Biosciences, College of Dentistry, The Ohio State University, Columbus, Ohio. FAU - Wold, Loren E AU - Wold LE AD - Dorothy M. Davis Heart and Lung Research Institute, The Ohio State University Wexner Medical Center, Columbus, Ohio; Loren.Wold@osumc.edu. AD - Department of Physiology and Cell Biology, The Ohio State University, Columbus, Ohio; and. AD - College of Nursing, The Ohio State University, Columbus, Ohio. LA - eng GR - R01 AG057046/AG/NIA NIH HHS/United States GR - R01 ES019923/ES/NIEHS NIH HHS/United States GR - R01 NR012618/NR/NINR NIH HHS/United States PT - Journal Article DEP - 20170324 PL - United States TA - Am J Physiol Heart Circ Physiol JT - American journal of physiology. Heart and circulatory physiology JID - 100901228 RN - 0 (Fabp4 protein, mouse) RN - 0 (Fatty Acid-Binding Proteins) RN - 0 (Hif1a protein, mouse) RN - 0 (Hypoxia-Inducible Factor 1, alpha Subunit) RN - EC 1.14.11.29 (Egln1 protein, mouse) RN - EC 1.14.11.29 (Hypoxia-Inducible Factor-Proline Dioxygenases) RN - EC 2.3.2.27 (Von Hippel-Lindau Tumor Suppressor Protein) RN - EC 2.7.10.1 (Proto-Oncogene Proteins c-kit) RN - EC 3.4.25.1 (Proteasome Endopeptidase Complex) RN - EC 6.3.2.- (VHL protein, mouse) RN - S88TT14065 (Oxygen) SB - IM MH - Adenocarcinoma/*complications MH - Animals MH - Cachexia/etiology/*metabolism/pathology/physiopathology MH - Cell Hypoxia MH - Colonic Neoplasms/*complications MH - Computational Biology MH - Diaphragm/*metabolism MH - Fatty Acid-Binding Proteins/metabolism MH - Female MH - Hydroxylation MH - Hypoxia-Inducible Factor 1, alpha Subunit/genetics/*metabolism MH - Hypoxia-Inducible Factor-Proline Dioxygenases/metabolism MH - Mice MH - Myocardial Contraction MH - Myocardium/*metabolism MH - Neoplasms, Experimental/*complications MH - Oxygen/blood MH - Proteasome Endopeptidase Complex/metabolism MH - Proteolysis MH - Proteomics/methods MH - Proto-Oncogene Proteins c-kit/metabolism MH - Stroke Volume MH - Time Factors MH - Ubiquitination MH - Up-Regulation MH - Von Hippel-Lindau Tumor Suppressor Protein/metabolism PMC - PMC5495928 OTO - NOTNLM OT - cancer cachexia OT - heart OT - hypoxia OT - hypoxia-inducible factor OT - proteomics OT - skeletal muscle EDAT- 2017/03/28 06:00 MHDA- 2017/08/08 06:00 PMCR- 2018/06/01 CRDT- 2017/03/26 06:00 PHST- 2016/01/27 00:00 [received] PHST- 2017/03/08 00:00 [revised] PHST- 2017/03/21 00:00 [accepted] PHST- 2017/03/28 06:00 [pubmed] PHST- 2017/08/08 06:00 [medline] PHST- 2017/03/26 06:00 [entrez] PHST- 2018/06/01 00:00 [pmc-release] AID - ajpheart.00090.2016 [pii] AID - H-00090-2016 [pii] AID - 10.1152/ajpheart.00090.2016 [doi] PST - ppublish SO - Am J Physiol Heart Circ Physiol. 2017 Jun 1;312(6):H1154-H1162. doi: 10.1152/ajpheart.00090.2016. Epub 2017 Mar 24.