Abstract 4796: Calorie restriction induces skeletal muscle wasting and a complex I defect while reducing mammary tumor growth in a mouse model of diet induced obesity

Purpose: Obesity is an independent risk factor for the development, morbidity, and mortality of breast cancer. Calorie restriction (CR) is the first line therapy for obesity management, with growing evidence and application in the treatment of breast cancer. In non-tumor bearing patients, ~20% of weight loss is attributed to reductions in skeletal muscle mass. However, little is known of how CR in a tumorigenic environment may influence muscle function and content. Methods: Obese C57BL/6J female mice were used to develop an allograft breast cancer model by orthotopically injecting the mammary fat pad with basal-like breast cancer (E0771 cells). Mice were randomized (1:1) by tumor size and body weight to high fat diet (HFD; 60% kcal from fat) or calorie restriction diet (CRD; ~40% restriction of HFD via an incremental reduction in food intake) for 2.5 weeks. Daily food intake, body weight and temperature, as well as twice weekly tumor measurements were obtained during treatment. Organ weights and size were obtained at the time of necropsy. Whole blood was collected for immunophenotyping and assessed via flow cytometry. Mitochondrial function was determined in tumor homogenates and permeabilized gastrocnemius fibers by high resolution respirometry (O2k). Results: CRD reduced body weight (HFD: 27.8±0.8 vs CRD: 22.9±0.5 g, P=0.0003) and tumor growth (HFD: 3.6±0.2 g vs. CRD: 2.7±0.3 g, P=0.03). There was no difference in the proportions of total NK cells, helper and cytotoxic T-cells between HFD and CRD (P>0.05). Respirometry studies of tumor mitochondria revealed diminished complex I uncoupled rate following CRD (HFD: 3.2±0.4 vs. CRD: 1.6±0.3 pmol/sec/mg, P= 0.02). Additionally, skeletal muscle mitochondria of CRD animals contained a defect in complex I oxidation (HFD: 49.2±6.5 vs. CRD: 28.6±4.0 pmol/sec/mg, P=0.03). Furthermore, soleus muscle mass was reduced (HFD: 7.7±0.8 mg vs. CRD: 4.5±1.1 mg, P=0.04). Conclusions: This study demonstrates that CRD induces complex I (CI) defects in tumor and skeletal muscle mitochondria. Suppression of CI was associated with a favorable reduction in tumor growth and unfavorable loss of skeletal muscle mass. Future studies formally evaluating skeletal muscle function and cachexia as well as muscle preserving therapies in combination with CR are warranted. Funding: Research was supported by NIGMS (GM104940 - JPK) and the Pennington Biomedical Research Foundation (LAG) Citation Format: Elizabeth R. Zunica, Christopher L. Axelrod, Gangarao Davuluri, Wagner S. Dantas, Guillaume Spielmann, Eunhan Cho, Brian A. Irving, John P. Kirwan, L. Anne Gilmore. Calorie restriction induces skeletal muscle wasting and a complex I defect while reducing mammary tumor growth in a mouse model of diet induced obesity [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4796.