P192Cancer induced cardiac cachexia displays a shift of metabolic genes

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Abstract

Purpose

Patients suffering from heart failure or advanced cancer share several clinical features including limitation in exercise capacity, shortness of breath, early fatigue, and the development of cachexia. One of the major factors in both populations that reduces quality of life and is associated with an unfavorable prognosis is cachexia. The underlying mechanisms of cancer-mediated cardiac cachexia are poorly understood. To investigate putative metabolic alterations, we evaluated the expression of genes involved in fatty acid oxidation in a mouse cancer model associated with cardiac cachexia.

Methods and Results

A solid peritoneal tumor was induced through intraperitoneal implantation of melanoma cells (106 B16-F10 cells). Tumor bearing mice revealed markedly reduced heart weight/body weight (HW/BW: Cntr.: 5.1 ± 0.2, vs. Tumor: 3.7 ± 0.2 mg/g; p < 0.001) and heart weight/tibia length ratio as compared to control mice (HW/TL: Cntr: 12.6 vs. Tumor: 5.0mg/cm; p < 0.001) three weeks after cell implantation. Echocardiographic analysis showed reduced systolic function of tumor bearing mice as measured byfractional shortening (FS: Cntr: 38.9 ± 10.4%, n=12 vs. Tumor: 23.1 ± 5.1%, n=9;p < 0.001) and overall thinning of the wall thickness. This was associated with a high mortality in cancer animals (66%, n=25, vs. 0% in control, n=17;p < 0.001). QRT-PCR revealed increased mRNA expression of three peroxisome proliferator-activated receptor isoforms (PPARa, d and g) and their co-factor PGC1a (PPARa: + 71.4 ± 19.2 %, p=0.02; PPARd: + 17.3 ± 10.1%, p < 0.04; PPARg: + 70 ± 20.6%,p=0.04; PGC1a: + 36.1 ± 23.1%,p=0.01). Western blot analysis of subcellular fragments revealed reduced cytoplasmic protein levels and enhanced nuclear levels of PPARin the cachectic myocardium, indicative of enhanced nuclear translocation. Moreover, the mRNA level of carnitine palmitoyltransferase-1, the rate-limiting enzyme that acts in β-oxidation, was significantly increased (CPT1a: + 114.2 ± 29.4%,p < 0.001; CPT1b: + 164.8 ± 21.9%, p=0.03).

Conclusion

These findings demonstrate that cancer-induced cachexia is associated with up-regulation of components of the PPAR pathway involved in muscle fatty acid oxidative gene transcription. This observation suggests that cancer-mediated cardiac cachexia differs at the molecular and potentially also at the metabolic level from cardiac cachexia in end-stage heart failure where this pathway has been reported to be down-regulated.

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