Abstract

1-16 Cancer cachexia induces iBAT thermogenesis in UCP1 / mice Magno A. Lopes, Jessica S. Santos, Marcela J.O.A. Carreira, Luis F. G. Valdivia, Luana G. Leal, Sydney B. Peres & Miguel L. BatistaJr Laboratory of Adipose Tissue Biology, Integrated Group of Biotechnology, University of Mogi das Cruzes, Mogi das Cruzes, Brazil, Department of Physiological Sciences, State University of Maringá, Maringá, Brazil Background: Cancer cachexia (CC) is a multifactorial syndrome with an unknown aetiology. The main symptom is the progressive body weight loss. During the development of the syndrome, there is an increase in uncoupling protein 1 (UCP1) in white adipose tissue (WAT) and intrascapular brown adipose tissue (iBAT), resulting in increased energy expenditure and heat generation. Recently, it was proposed that energy expenditure in CC does not depend on UCP1 but on an independent thermogenic pathway. In this sense, this study aimed to evaluate the thermogenic activity of UCP1 knockout mice during CC. Methods: Male C57BL/6 mice (8–10 week old) wild-type (WT) and knockout for UCP1 (UCP1 / ) were subcutaneously inoculated with 200 μL (3.5 × 10) of Lewis Lung Carcinoma Cell line (TB) and vehicle saline (CO). After 28 days, animals were submitted to thermal infrared measurements (T460, emissivity of 0.98, FLiR Systems). After analysing, animals were sacrificed, and the WAT subcutaneous (SC) and epididymal (EP), BAT, and gastrocnemius muscle (GA) were collected. Results: UCP1 TB presented higher maximum body temperature (10.4-fold, P = 0.0500) and tendency to increase the maximum temperature of BAT (P = 0.0750) when compared to UCP1 CO. In addition, UCP1 TB have preserved both the body weight loss (11.0-fold, P = 0.0101) and the values of the index of cachexia (45.4%, P = 0.0305) when compared to TB group. The adipose tissue atrophy (EP, 14.6-fold and BAT, 15.3-fold) was also attenuated in UCP1 TB group when compared to TB group. Conclusions: In general, the results showed that UCP1 animals presented attenuation in the main markers of CC. In addition, the BAT of these animals showed an increase in their thermogenic capacity, suggesting that its activation, at least in part, may be activated by an UCP1-independent pathway. 1-17 Lack of synergy between β-agonist treatment and a blockage of sarcoplasmic calcium flow in a rat cancer cachexia model Queralt Jové, Sílvia Busquets, Marta Castillejo, Baptiste Jude, Patricia Mejías, Francisco J. López-Soriano & Josep M. Argilés Cancer Research Group, Departament de Bioquímica i Biomedicina Molecular, Facultat de Biologia, Universitat de Barcelona, Barcelona, Spain, Institut de Biomedicina de la Universitat de Barcelona, Barcelona, Spain, Laboratoire de Physiologie, ORPHY, IBSAM, Université de Bretagne Occidentale, Brest, France Background: Accelerated muscle and adipose tissue loss are two of the main aspects of cancer cachexia. The use of β2agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in preclinical models. The aim if the present investigation was to study the effects on body weight loss in tumour-bearing animals of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1) involved in the sarcoplasmic reticulum calcium flow. Methods: Rats were divided into two groups, namely controls (C) and tumour-bearing (TB). TB group was further divided into four subgroups: untreated (saline as a vehicle), treated with formoterol (TF) (0.3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with formoterol (0.3 mg/kg body weight, subcutaneous (s.c.), daily) and dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). Seven days after tumour transplantation, muscle weights, grip force, and total physical activity were determined in all experimental groups. Results: While formoterol has, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle or any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the β2-agonist. Conclusions: It is concluded that in the preclinical cachectic model used, no synergy exists between β2-agonist treatment and the blockade of sarcoplasmic calcium flow. ABSTRACTS © 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders Journal of Cachexia, Sarcopenia and Muscle 2020; 11: 286–329 Published online in Wiley Online Library (wileyonlinelibrary.com) DOI: 10.1002/jcsm.12551 This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. 1-18 Chronic kidney disease induces muscle wasting via soluble pro-cachectic factors Francesca Solagna, Robert Mitchell, Charlotte Mayer, Saleh Omairi, Antonios Matsakas, Olli Ritvos, Arja Pasternak, E. Hoxha, Temel Kilic, Andrea Paolini, Nicola Wanner, Jan-Eric Turner, Julian Schulze zur Wiesch, Maja Lindenmeyer, Clemens D. Cohen, Oliver Kretz, Victor G. Puelles, Ketan Patel & Tobias B. Huber III. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, School of Biological Sciences, University of Reading, Reading, UK, Department of Neuroanatomy, Institute of Anatomy, Medical Faculty, University Freiburg, Freiburg, Germany, Department of Medicine, Renal Division, University Medical Centre Freiburg, Freiburg, Germany, Molecular Physiology Laboratory, Centre for Atherothrombosis and Metabolic Disease, Hull York Medical School, Hull, UK, Department of Bacteriology and Immunology, University of Helsinki, Helsinki, Finland, Freiburg Institute for Advanced Studies and Center for Biological System Analysis, Freiburg, Germany, I. Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany, Nephrological Center, Medical Clinic and Policlinic IV, University of Munich, Munich, Germany, Department of Nephrology and Centre of Inflammatory Diseases, Monash University, Melbourne, Australia Chronic kidney disease (CKD) represents the progressive and permanent loss of kidney function. While muscle wasting is a prominent feature of CKD and significantly increases morbidity and mortality, this interorgan signalling network remains poorly understood. Here, we identified muscle wasting in a mouse model of CKD (KIf3a deficiency), where we discovered an increased renal production of soluble pro-cachectic factors (i.e. Activin A) as shown by both transcriptional regulation and increases in plasma levels, an observation that was also confirmed in patients at different stages of CKD. Furthermore, pharmacological blockade of the identified procachectic factor in mice prevented muscle wasting and progression to CKD by reducing its levels in the plasma—both a direct neutralization and recovery of kidney function. Together, this study uncovers a previously unrecognized crosstalk between kidney and muscle and provides a potential therapeutic strategy for muscle wasting in patients with CKD. 2-09 Interleukin-6 controls microRNA-regulated networks in skeletal muscle cells Paula P. Freire, Jianming Liu, Sarah S. Cury, Letícia Oliveira, Grasieli de Oliveira, Diogo de Moraes, Geysson J. Fernandez, Maeli Dal-Pai-Silva, Da-Zhi Wang & Robson F. Carvalho Department of Morphology, Institute of Biosciences, São Paulo State University, UNESP, Botucatu, Brazil, Department of Cardiology, Boston Children’s Hospital, Harvard Medical School, Boston, MA, USA, Faculty of Medicine, University of Antioquia, UdeA, Medellín, Colombia, Harvard Stem Cell Institute, Harvard University, Cambridge, MA, USA Systemic inflammation contributes to the development of cachexia, and the pro-inflammatory cytokine interleukin-6 (IL-6) has emerged as a critical factor related to muscle wasting during disease. Regulation of gene expression by microRNAs (miRNAs) in skeletal muscles integrates regulatory networks, which are predicted to involve thousands of transcripts through different mechanisms. Our objective was to analyse the global miRNA expression profile of skeletal muscle cells atrophy induced by IL-6 to uncover potential miRNAs involved with this catabolic condition. Genome-wide gene expression profiles of miRNAs were performed by using TaqMan Low-Density Arrays in C2C12 myotubes treated with IL-6, followed by in silico predictions for miRNA targets. High concentrations of IL-6 induced myotube atrophy and decreased the levels of Myh7 and e-MHC. Moreover, we identified 20 differentially expressed miRNAs in C2C12 myotubes in response to IL-6 (five upregulated, and 15 downregulated). Gene Ontology analysis of the predicted targets of these miRNAs revealed potential posttranscriptional regulation of genes involved in cell differentiation, apoptosis, migration, and catabolic processes. Interestingly, the miR-497 was suppressed by the treatment with IL-6, and it was found in the literature to be downregulated in other muscle catabolic conditions. Thus, we used miR-497 mimics and inhibitors to explore the function of this miRNA. The miR-497 changed cell cycle target genes, such as Ccnd2 and Ccne1, but did not alter myoblast proliferation, as assessed by the EdU assay. Also, miR-497 mimic induced myotubes atrophy. The miR-497 inhibitor did not change myotubes diameters but resulted in overexpression of the miR-497 target genes Insr and Igf1r. These genes are involved with the insulin-like growth factor pathway and are overexpressed in muscle samples of cachexia models (GSE48363, GSE63032, GSE24111, and GSE51931). Our miRNA analysis identified miRNA-regulated networks and suggests that miR-497 is involved in a compensatory