Abstracts Division 2
33. Intramuscular lipid alterations in human pancreatic cancer cachexia
Min Deng1, Jianhua Cao3, Gregory van der Kroft1,2, Merel R. Aberle1, Andrej Grgic3, Ulf P. Neumann1,2, Georg Wiltberger2, Benjamin Balluff 3, Ron M. A. Heeren3, Frank G. Schaap1, Steven W.M. Olde Damink1,2, Sander S. Rensen1
1Department of Surgery and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, The Netherlands
2Department of General, Visceral- and Transplantation Surgery, RWTH Aachen University, Germany
3Division of Imaging Mass Spectrometry, Maastricht Multimodal Molecular Imaging (M4i) Institute, Maastricht University, Maastricht, The Netherlands
Background
Cancer cachexia is a multifactorial metabolic syndrome characterized by ongoing skeletal muscle loss resulting in weakness, poor quality of life, and decreased survival. Lipid accumulation in skeletal muscle is increasingly recognized as a defining cachexia feature that is promoted by inflammation and independently associated with muscle function and long-term survival. However, surprisingly little is known about the nature of the lipids that accumulate in skeletal muscle during cancer cachexia. We aimed to identify the types and distribution of intramuscular lipids in patients with cancer cachexia.
Methods
Rectus abdominis muscle biopsies were collected during surgery from pancreatic ductal adenocarcinoma patients (12 weight-stable, 24 with cachexia but without inflammation (CRP<10 mg/L), 12 with cachexia with inflammation (CRPâ„10 mg/mL). L3-CT scans were analyzed to assess body composition. Muscle sections were stained with Oil-RedO and H&E. Untargeted lipidomic analyses were performed on laser-microdissected lipid-rich muscle tissue areas using LC-MS/MS. Intramuscular lipid distribution was visualized by MALDI-MSImaging. Genes coding for enzymes involved in de novo ceramides synthesis were studied by qPCR.
Results
Muscle radiation attenuation was lower in cachectic patients with inflammation (median 24.3 HU, IQR 18.6-30.8) as compared to those without inflammation (34.2 HU, 29.3-38.7, p=0.033) or weight-stable patients (37.4 HU, 33.9-42.9, p=0.012). Accordingly, intramuscular lipid content was lower in weight-stable patients (1.8%, 1.5-2.0) as compared to those with cachexia with inflammation (5.5%, 4.5-7.3, p=0.005) or without inflammation (4.8%, 2.6-6.1, p=0.046). Compared to weight-stable patients, cachectic patients with inflammation displayed increases in several intramuscular sphingolipids (Cer(m10:0/16:0), Cer(d18:0/17:3), Cer(m10:0/18:0)), glycerolipids (TG(47:13), triglycerides (12:0/12:0/14:0, 45:14/16:3), and glycerophospholipids (PC(35:5)) that could be visualized by MS-imaging. Genes related to ceramide synthesis such as SPT1/2, KDSR, Cers1-6, and DEGS1 showed higher expression in cachectic patients with inflammation.
Conclusion
Patients with cachexia exhibit intramuscular accumulation of specific lipid species that may be partly related to elevated ceramide synthesis.
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