Eicosapentaenoic and Docosahexaenoic Fatty Acids Modify Skeletal Muscle Fat Infiltration in an Animal Model of Colorectal Cancer Receiving Chemotherapy

  • Author / Creator
    Almasud,Alaa A
  • Background: Myosteatosis is defined as low skeletal muscle radio-density with elevated amounts of intermuscular adipose tissue, assessed using computed tomography. Myosteatosis has been recently observed to be associated with mortality in people with cancer. Previous work from our lab reported that deposition of intermuscular fat occurs as patients progress through chemotherapy. However, when patients supplemented their daily intake with eicosapentaenoic acid (20:5n-3; EPA) and docosahexaenoic acid (22:6n-3; DHA), a reduction in intermuscular adipose tissue was observed. Mechanisms underlying myosteatosis in cancer have not been explored and no preclinical model of cancer associated with myosteatosis has been developed. Therefore, this study aimed to first establish a preclinical model of cancer and chemotherapy treatment associated with myosteatosis, and then assess if feeding a diet containing fish oil was efficacious in reducing tumor- and chemotherapy-associated fat accumulation within skeletal muscle. Methods: Fischer 344 rats were fed either a control diet for the entire study (control), or switched to a diet containing fish oil (2.3 g /100 g of diet) one week prior to tumor implantation (long term fish oil) or at the start of chemotherapy (adjuvant fish oil). Chemotherapy (irinotecan plus 5-fluorouracil) was initiated 2 weeks after tumor implantation (cycle-1) and 1 week thereafter (cycle-2). Reference animals received no tumor or treatment and consumed the control diet. Gastrocnemius and tibialis anterior muscles were frozen in melting isopentane cooled in liquid nitrogen (-156°C), and stored at -80°C until subsequent analyses. To assess myosteatosis, lipids were revealed histologically by Oil Red O staining and triglyceride fatty acids were quantified by gas chromatography. Expression of adipogenic transcription factors and mitochondrial density were assessed at the mRNA level by real-time RT-PCR. Mitochondrial enzymatic activities were assessed using spectrophotometry. Myosin Heavy Chain isoforms were identified by immunofluorescence. Results: Feeding a diet containing fish oil reduced tumor- and subsequent chemotherapy-associated increases in muscle neutral lipid content, triglyceride fatty acid levels, and expression of adipogenic transcriptional factors that occurred in control diet fed animals. Lower neutral lipid content within the muscle following chemotherapy treatment in rats fed fish oil diet was associated with higher mitochondrial oxidative capacity. The adjuvant fish oil diet was as effective as the long term fish oil diet in mitigating chemotherapy-associated muscle fat content. Conclusion: Long term and adjuvant fish oil diets are both efficacious in reducing chemotherapy-associated myosteatosis by reducing expression of transcriptional factors involved in adipogenesis/lipogenesis, and improving mitochondrial oxidative capacity and density. The data we have assembled suggests that myosteatosis, an independent prognostic factor in cancer, is modifiable through dietary intake of EPA and DHA.

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  • Degree
    Doctor of Philosophy
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