Increased tumour burden alters skeletal muscle properties in the KPC mouse model of pancreatic cancer.

Abstract

Cancer cachexia is a multifactorial wasting syndrome that is characterized by the loss of skeletal muscle mass and weakness, which compromises physical function, reduces quality of life, and ultimately can lead to mortality. Experimental models of cancer cachexia have recapitulated this skeletal muscle atrophy and consequent decline in muscle force generating capacity. We address these issues in a novel transgenic mouse model Kras, Trp53 and Pdx-1-Cre (KPC) of pancreatic ductal adenocarcinoma (PDA) using multi-parametric magnetic resonance (mp-MR) measures. KPC mice (n = 10) were divided equally into two groups (n = 5/group) depending on the size of the tumor i.e. tumor size <250 mm3 and >250 mm3. Using mp-MR measures, we demonstrated the changes in the gastrocnemius muscle at the microstructural level. In addition, we evaluated skeletal muscle contractile function in KPC mice using an in vivo approach. Increase in tumor size resulted in decrease in gastrocnemius maximum cross sectional area, decrease in T2 relaxation time, increase in magnetization transfer ratio, decrease in mean diffusivity, and decrease in radial diffusivity of water across the muscle fibers. Finally, we detected significant decrease in absolute and specific force production of gastrocnemius muscle with increase in tumor size. Our findings indicate that increase in tumor size may cause alterations in structural and functional parameters of skeletal muscles and that MR parameters may be used as sensitive biomarkers to noninvasively detect structural changes in cachectic muscles.