Dual Energy X-ray Absorptiometry (DEXA) as a Longitudinal Outcome Measure of Cancer-Related Muscle Wasting in Mice

Abstract

300 out of 300 Words) 25 Introduction 26 Pancreatic ductal adenocarcinoma (PDAC) is notorious for its associated skeletal muscle wasting 27 (SMW) and mortality. Currently, the relationships between PDAC, SMW, and survival are poorly 28 understood. Thus, there is a great need for a faithful small animal model with a quantitative 29 longitudinal outcome measure that recapitulates clinical PDAC, to define SMW onset and assess 30 progression. Therefore, we aimed to validate dual energy X-ray absorptiometry (DEXA) as a 31 longitudinal outcome of lean body mass, and demonstrate its utility to quantify SMW in the KCKO 32 murine model of PDAC. 33 Methods 34In vivo body composition of: 1) untreated mice at 5, 8, 12, 18, and 22 weeks of age (n=4), and 2) a 35 cohort of mice with (n=20) and without PDAC (n=10), was determined via DEXA, and lean mass of the 36 lower hind limbs was predicted via a region of interest analysis by two independent observers. Total 37 body weight was determined. Tibialis anterior (TA) muscles were weighed and processed for 38 histomorphometry immediately post-mortem. Statistical differences between groups were assessed 39 using t-tests and ANOVA. Linear regression models and correlation analysis were used to measure the 40 association between TA and DEXA mass, and reproducibility of DEXA was quantified via the intraclass 41 correlation coefficient (ICC). 42 Results 43Lean mass in growing untreated mice determined by DEXA correlated with TA mass (r 2 = 0.94; p 44 <0.0001) and body weight (r 2 = 0.89; p <0.0001). DEXA measurements were highly reproducible 45 between observers (ICC = 0.95; 95% CI: 0.89-0.98). DEXA and TA mass also correlated in the PDAC 3 46 cohort (r 2 = 0.76; p <0.0001). Significant SMW in tumor-bearing mice was detected within 38 days of 47 implantation by DEXA, TA mass, and histomorphometry. 48 Conclusions 49 DEXA is a longitudinal outcome measure of lower limb lean mass in mice. The KCKO syngeneic 50 model is a bona fide model of PDAC-associated SMW that can be quantified with longitudinal DEXA. 51 4 52

Increased myocellular lipid and IGFBP‐3 expression in a pre‐clinical model of pancreatic cancer‐related skeletal muscle wasting

“…All experiments were approved by the University Committee on Animal Resources and were performed in compliance with the National Institutes of Health (NIH)‐approved and University of Rochester‐approved guidelines for the care and use of animals. We utilized the murine syngeneic‐orthotopic model of PDAC, as previously described 23 . Briefly, female C57BL/6J mice 6–8 weeks of age were used.…”

“…This technique was performed as previously described 23 . Briefly, body composition was assessed in all mice using a dual‐energy X‐ray absorptiometry (DEXA) scanner.…”

“…To our knowledge, this is the first model of its kind and incorporates clinically translatable outcome measures. Most recently, we developed longitudinal DEXA outcome measures to quantify lean mass in KCKO mice and demonstrated that this PDAC model faithfully recapitulates the pathophysiology of cancer‐related SMW 23 . Based on this advance, we aimed to determine the kinetics of SMW and its relationship to primary tumour size and mortality in the KCKO model.…”