Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia

  • Authors:
    • Caterina Constantinou
    • Cibely Cristine Fontes de Oliveira
    • Dionyssios Mintzopoulos
    • Silvia Busquets
    • Jianxin He
    • Meenu Kesarwani
    • Michael Mindrinos
    • Laurence G. Rahme
    • Josep M. Argilés
    • A. Aria Tzika
  • View Affiliations

  • Published online on: November 10, 2010     https://doi.org/10.3892/ijmm.2010.557
  • Pages: 15-24
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Abstract

Cancer patients commonly suffer from cachexia, a syndrome in which tumors induce metabolic changes in the host that lead to massive loss in skeletal muscle mass. Using a preclinical mouse model of cancer cachexia, we tested the hypothesis that tumor inoculation causes a reduction in ATP synthesis and genome-wide aberrant expression in skeletal muscle. Mice implanted with Lewis lung carcinomas were examined by in vivo 31P nuclear magnetic resonance (NMR). We examined ATP synthesis rate and the expression of genes that play key-regulatory roles in skeletal muscle metabolism. Our in vivo NMR results showed reduced ATP synthesis rate in tumor-bearing (TB) mice relative to control (C) mice, and were cross-validated with whole genome transcriptome data showing atypical expression levels of skeletal muscle regulatory genes such as peroxisomal proliferator activator receptor γ coactivator 1 ß (PGC-1ß), a major regulator of mitochondrial biogenesis and, mitochondrial uncoupling protein 3 (UCP3). Aberrant pattern of gene expression was also associated with genes involved in inflammation and immune response, protein and lipid catabolism, mitochondrial biogenesis and uncoupling, and inadequate oxidative stress defenses, and these effects led to cachexia. Our findings suggest that reduced ATP synthesis is linked to mitochondrial dysfunction, ultimately leading to skeletal muscle wasting and thus advance our understanding of skeletal muscle dysfunction suffered by cancer patients. This study represents a new line of research that can support the development of novel therapeutics in the molecular medicine of skeletal muscle wasting. Such therapeutics would have wide-spread applications not only for cancer patients, but also for many individuals suffering from other chronic or endstage diseases that exhibit muscle wasting, a condition for which only marginally effective treatments are currently available.

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January 2011
Volume 27 Issue 1

Print ISSN: 1107-3756
Online ISSN:1791-244X

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Spandidos Publications style
Constantinou C, Fontes de Oliveira CC, Mintzopoulos D, Busquets S, He J, Kesarwani M, Mindrinos M, Rahme LG, Argilés JM, Tzika AA, Tzika AA, et al: Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia. Int J Mol Med 27: 15-24, 2011.
APA
Constantinou, C., Fontes de Oliveira, C.C., Mintzopoulos, D., Busquets, S., He, J., Kesarwani, M. ... Tzika, A.A. (2011). Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia. International Journal of Molecular Medicine, 27, 15-24. https://doi.org/10.3892/ijmm.2010.557
MLA
Constantinou, C., Fontes de Oliveira, C. C., Mintzopoulos, D., Busquets, S., He, J., Kesarwani, M., Mindrinos, M., Rahme, L. G., Argilés, J. M., Tzika, A. A."Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia". International Journal of Molecular Medicine 27.1 (2011): 15-24.
Chicago
Constantinou, C., Fontes de Oliveira, C. C., Mintzopoulos, D., Busquets, S., He, J., Kesarwani, M., Mindrinos, M., Rahme, L. G., Argilés, J. M., Tzika, A. A."Nuclear magnetic resonance in conjunction with functional genomics suggests mitochondrial dysfunction in a murine model of cancer cachexia". International Journal of Molecular Medicine 27, no. 1 (2011): 15-24. https://doi.org/10.3892/ijmm.2010.557