BackgroundCancer cachexia is a complex syndrome related to a negative energy balance resulting in muscle wasting. Implication of muscle mitochondrial bioenergetics alterations during cancer cachexia was suggested. Therefore, the aim of this study was to explore the efficiency of oxidative phosphorylation in skeletal muscle mitochondria in a preclinical model of cancer cachexia.MethodsBerlin–Druckrey IX rats with peritoneal carcinosis (PC) were used as a model of cancer cachexia with healthy pair-fed rats (PF) as control. Hindlimb muscle morphology and fibre type composition were analysed in parallel with ubiquitin ligases and UCP gene expression. Oxidative phosphorylation was investigated in isolated muscle mitochondria by measuring oxygen consumption and ATP synthesis rate.ResultsPC rats underwent significant muscle wasting affecting fast glycolytic muscles due to a reduction in fibre cross-sectional area. MuRF1 and MAFbx gene expression were significantly increased (9- and 3.5-fold, respectively) in the muscle of PC compared to PF rats. Oxygen consumption in non-phosphorylating state and the ATP/O were similar in both groups. Muscle UCP2 gene was overexpressed in PC rats. State III and the uncoupled state were significantly lower in muscle mitochondria from PC rats with a parallel reduction in complex IV activity (−30 %).ConclusionThis study demonstrated that there was neither alteration in ATP synthesis efficiency nor mitochondrial uncoupling in skeletal muscle of cachectic rats despite UCP2 gene overexpression. Muscle mitochondrial oxidative capacities were reduced due to a decrease in complex IV activity. This mitochondrial bioenergetics alteration could participate to insulin resistance, lipid droplet accumulation and lactate production.

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Purpose: To investigate whether dietary docosahexaenoic acid (DHA), a peroxidizable polyunsaturated N-3 fatty acids, sensitizes rat mammary tumors to anthracyclines and whether its action interferes with tumor vascularization, a critical determinant of tumor growth. Experimental Design: Female Sprague-Dawley rats were initiated by N-methylnitrosourea to develop mammary tumors and then assigned to a control group (n = 18), receiving a supplementation of palm oil, or to a DHA group (n = 54), supplemented with a microalgae-produced oil (DHASCO, 1.5 g/d). The DHA group was equally subdivided into three subgroups with addition of different amounts of a-tocopherol. Epirubicin was injected weekly during 6 weeks after the largest tumor reached 1.5 cm 2 , and subsequent changes in the tumor surface were evaluated. Tumor vascularization was assessed by power Doppler sonography before and during chemotherapy.Results: DHA and a-tocopherol were readily absorbed and incorporated into rat tissues. Epirubicin induced a 45% mammary tumor regression in the DHA-supplemented group, whereas no tumor regression was observed in the control group. In the DHA group, before chemotherapy was initiated, tumor vascular density was 43% lower than in the control group and remained lower during chemotherapy. Enhancement of epirubicin efficacy by DHA was abolished in a dosedependent manner by a-tocopherol, and the same trend was observed for DHA-induced reduction in tumor vascular density. Conclusions: Dietary DHA supplementation led to a reduction in tumor vascularization before the enhancement of any response to anthracyclines, suggesting that DHA chemosensitizes mammary tumors through an inhibition of the host vascular response to the tumor.