(P30-005-24) Effects of Dietary Linoleic Acid on Mitochondrial Function in Skeletal Muscles Isolated From a Mouse Model of Cancer Cachexia

Objectives: Cancer cachexia, characterized by depletion of muscle and adipose tissues, contributes to 20-30% of total cancer deaths. Underlying metabolic perturbation exhibits tissue specificity and alterations in muscle tissue phospholipid composition. Mitochondrial dysfunction has been reported in relation to metabolic perturbation in cancer cachexia. Linoleic acid (LA), an essential fatty acid, has been reported to restore metabolic performance in healthy and cancer animal models. This study aims to investigate and compare the effects of LA on two muscle types, type I (soleus and cardiac) and type II (gastrocnemius), in terms of mitochondrial function, phospholipid and fatty acid compositions, and gene transcription changes in a mouse model of cancer cachexia.

Methods: In this 2x2 study design, CD2F1 male mice will be randomized into 4 groups, either fed a control or an LA fortified diet for 2 weeks. Subsequently, mice will be inoculated with 0.5 million C26 adenocarcinoma cells or phosphate-buffered saline while continuing with their respective diets. Body weight, food intake, body composition, and grip strength will be measured during the progression of the disease. Mice will be euthanized when they exhibit a 10% loss of the maximum body weight and have a tumor size of ≥ 1 cm in diameter. Excised muscle tissue will be processed immediately for high-resolution respirometry analysis using Oroboros and flash-frozen for analyzing phospholipid and fatty acid composition using gas chromatography and gene expression using qRT-PCR. A 2-way ANOVA will be used to analyze the effects of diet and tumor.

Results: Hypothesis: Tumor-bearing mice fed the LA-fortified diet will exhibit higher index of oxidative phosphorylation and lower LEAK respiration across muscle types. Changes in phospholipids and fatty acid compositions will correlate with the respiratory indices. Gene expression data will reveal metabolic switches in cancer cachexia and how dietary LA modulates metabolic pathways to improve respiratory function in different types of muscle tissues.

Conclusions: This study will provide valuable insights into the effects of dietary LA on metabolism and mitochondrial function in different types of muscle tissue in of cancer cachexia.

Funding Sources: This project will be supported by the Ohio Agriculture Research and Development Center.