Proceedings of The Physiological Society

Europhysiology 2018 (London, UK) (2018) Proc Physiol Soc 41, PCB192

Poster Communications

Dominant effect of experimental cancer over blocking activin receptor ligands on skeletal muscle metabolome

J. Lautaoja1, M. Lalowski2,3, T. A. Nissinen1, J. Hentilä1, S. Cheng4,5, O. Ritvos6, J. Hulmi1,6

1. Biology of Physical Activity, Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 2. Meilahti Clinical Proteomics Core Facility, University of Helsinki, Helsinki, Finland. 3. Faculty of Medicine, Biochemistry and Developmental biology, University of Helsinki, Helsinki, Finland. 4. Faculty of Sport and Health Sciences, University of Jyväskylä, Jyväskylä, Finland. 5. Exercise, Health and Technology center, Shanghai Jiao Tong University, Shanghai, China. 6. Department of Physiology, Faculty of Medicine, University of Helsinki, Helsinki, Finland.

Cancer cachexia is a life-threatening disease associated with skeletal muscle atrophy, decreased anti-cancer treatment tolerance and reduced survival1. We have shown that continued reversal of skeletal muscle loss by soluble activin receptor type IIB (sACVR2B-Fc) has improved survival in experimental cancer2. Currently, there is no clear explanation for mechanisms behind this phenomenon highlighting the complexity of cachexia. This study aimed to investigate whether the alternations in skeletal muscle metabolism could be associated with improved survival of the C26 tumour-bearing mice administered with sACVR2B-Fc. BALB/c mice were anaesthetized with a mixture of ketamine (60-70 mg/kg, i.p.) and xylazine (9 mg/kg, i.p.) and subcutaneously inoculated with C26 cancer cells (n = 33) or vehicle control (n = 15). Tumour-bearing mice were treated with vehicle (C26+PBS) or sACVR2B-Fc either only before (C26+ACVR/b) or both before and after (C26+ACVR/c) C26 tumour formation. Gastrocnemius (GA) muscles were collected 11 or 13 days post cancer cell inoculation depending on the experiment. Muscle metabolome was analysed by gas chromatography-mass spectrometry (GC-MS) and further bioinformatics searches were performed with Ingenuity software (IPA) after the false discovery rate (FDR) corrections. Statistical significance in metabolomics was set at FDR < 0.05 and fold change (FC) > 1.2, and in other analyses at P < 0.05. In total, 219 metabolites were detected from the skeletal muscle. In accordance with previous studies3, the most altered metabolites (42 in total) in cancer were distributed among: 1) amino acids, 2) energy sources, 3) glycolysis components and 4) nucleotide related intermediates. An increase in the aromatic amino acids in tumour-bearing mice indicates enhanced proteolysis while decrease in glycogenic amino acids supports their usage in the tricarboxylic acid (TCA) cycle. From nucleotide metabolism, a decrease in RNA yield was observed together with decreased ribosome biogenesis markers (n = 7-9 per group). Only a few metabolites tended to be reversed by continued sACVR2B-Fc treatment towards healthy control mice. Although blocking activin receptor ligands reverses cachexia in the skeletal muscle by increasing muscle size, the effect of experimental cancer on skeletal metabolome is more pronounced. The results suggest that changes in the skeletal muscle metabolome are not strongly associated with the improved survival in the sACVR2B group. The decreased protein synthesis capacity in tumour-bearing mice may in part explain our previous findings of decreased protein synthesis2.

Where applicable, experiments conform with Society ethical requirements