Abstract 3482: Cachexia has profound metabolic consequences in the heart and skeletal muscle

Abstract

Abstract Cachexia is an underexplored and yet devastating consequence of cancer that is the cause of 20% of all cancer related deaths [1]. Cachexia is associated with poor treatment outcome [3], fatigue, and extremely poor quality of life [2, 3]. Tissue wasting is one of the characteristics associated with cachexia syndrome. Here we have used 1H MRS to characterize the metabolic profile of skeletal muscle and heart muscle obtained from normal mice and noncachexia (Panc1) and cachexia inducing (Pa04C) human pancreatic cancer xenograft bearing mice to further understand this syndrome. Male severe combined immunodeficient (SCID) mice were inoculated in the right flank with cancer cells (2 × 106) and in the right hind leg muscle with cachexia reporter myoblasts (2×106) [4]. Mice were sacrificed once tumors were ~400 mm3, and the heart and skeletal muscle were harvested for dual phase solvent extraction. 1H magnetic resonance (MR) spectra of the water phase were acquired with a 750 MHz MR spectrometer. Quantitative changes in metabolite levels were obtained from 1H MR spectra. Leucine, creatine, lactate and glucose were significantly lower, and acetate and formate were significantly higher, in the muscle of cachectic mice compared to non-cachetic mice. Cachectic mice had significantly lower alanine, succinate, glycine, lipid and PUFA (poly unsaturated fatty acids), and significantly higher acetate, pyruvate, and formate compared to normal mice. Non-cachectic mice had significantly lower alanine, succinate, phosphocreatine, and glycine, and significantly higher leucine, isoleucine, valine, pyruvate, creatine, taurine and glucose compared to normal mice. In the heart, leucine, isoleucine, valine, aspartate, glucose, lipid and PUFA were significantly lower, and glutamine was significantly higher, in cachectic mice compared to non-cachetic mice. Cachectic mice had significantly lower leucine, isoleucine, valine, lactate, alanine, glutamate, and PUFA, and significantly higher glutamine and glucose compared to normal mice. Non-cachectic mice had significantly lower alanine, and significantly higher glucose and lipid compared to normal mice. These data highlight, for the first time, the profound metabolic changes that occur in skeletal muscle and the heart with cachexia, identifying potential in vivo 1H MRS indices to detect the onset of cachexia from changes in branched chain amino acids, glucose, and PUFAs. Our data also provide new insights into the effects of cachexia as well as noncachexia inducing tumors on skeletal muscle and heart metabolism that may lead to metabolic interventions in ‘metabolotheranostic' strategies to reduce the morbidity associated with cancer and cachexia. Supported by NIH R01CA193365, R35CA209960, and P30CA06973. Ref. 1. Argiles et al: Nat. Rev. Can 2014, 14(11):754 2. Fearon et al: HPB (Oxford) 2010, 12(5):323 3. Ozola et al: Pancreatology 2015, 15(1):19 4. Winnard et al: Can Res. 2016, 76(6):1441 Citation Format: Santosh Kumar Bharti, Paul Winnard, Yelena Mironchik, Marie-France Penet, Zaver M. Bhujwalla. Cachexia has profound metabolic consequences in the heart and skeletal muscle [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3482.