(P12-002-25) Using Linoleic Acid to Target Insulin Resistance and Prevent Muscle Atrophy in a Mouse Model of Cancer Cachexia

Objectives: Cancer cachexia (CCx), the involuntary loss of muscle and fat, affects 30-80% of patients with cancer patients. Insulin resistance plays a role in the progression of CCx. This study tests the hypothesis that linoleic acid (LA), an essential nutrient, reduces insulin resistance and preserves skeletal muscle in mice with CCx.

Methods: In this 2x2 study design, 36 CD2F1 male mice were randomized to a control (Con) or an LA fortified diet (LA). Two weeks later, mice were further randomized and inoculated with 0.5x10⁶ C26 adenocarcinoma cells (+) or phosphate-buffered saline (-). Body weight, food intake, grip strength, insulin resistance, and body composition were measured. Mice were euthanized when 10% weight loss from peak body weight and/or tumor size ≥ 1 cm were achieved. mRNA expression in muscle was quantified by qrt-PCR. A two-way ANOVA was carried out, with an alpha level of 0.05 considered significant.

Results: Body weight and weights of quadriceps and white adipose tissues were significantly lower while liver and spleen were significantly higher among tumor groups. Tumor weight (expressed as percentage of body weight) was significantly lower in LA+. From pre-inoculation to post-inoculation period, mean fasting glucose levels decreased significantly by 31% only among Con+. During pre-inoculation, LA groups had unexpectedly more insulin resistance than Con group, but there was no significant effect of diet in post-inoculation period. Tumor (vs. saline) significantly increased MuRF-1 (11.15 ± 3.0 vs. 0.97 ± 0.1), atrogin-1(10.12 ± 1.8 vs. 1.0 ± 0.2), Bnip3 (7.71 ± 2.0 vs. 0.89 ± 0.13), BAX (3.56 ± 1.0 vs. 0.92 ± 0.1), BID (3.47 ± 0.49 vs. 1.60 ± 0.24), and BCL2 (1.63 ± 0.1 vs. 1.01 ± 0.07) transcripts in quadriceps which was similar in gastrocnemius muscle. LA had no significant effects on assessed mRNA expression. Tumor had no significant effect on grip strength and body composition.

Conclusions: LA did not reduce pre- and post-inoculation periods fasting glucose levels nor improve insulin sensitivity. Diet had no effect on mRNA markers of ubiquitin proteases, mitophagy, or BCL2 proteins. Future studies will examine the effects of LA on cross-sectional area of different muscle fiber types, mitochondrial function, and apoptosis in CCx.

Funding Sources: This project was supported by the NIH (R01 AG080184).