A Ketogenic Diet Mitigates Pancreatic Cancer-Associated Cachexia in Mice

Abstract

Abstract Objectives Cancer cachexia is a multifactorial disorder characterized by involuntary and ongoing wasting of skeletal muscle. More than 80% of patients with pancreatic ductal adenocarcinoma (PDA) suffer from cachexia and up to 20% die directly from it. The ketogenic diet (KD) has been shown to improve health span in old mice. However, its effect in cancer remains elusive. Therefore, our objective was to determine whether a KD mitigates cachexia and/or increases survival in a clinically relevant genetically-engineered LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx1-Cre (KPC) model of PDA. Methods After confirming the presence of a pancreatic tumor by high resolution ultrasound imaging, male and female KPC mice were fed either a control diet (CD; %kcal: 14% protein, 70% carb, 16% fat), or a KD (%kcal: 14% protein, < 1% carb, 85% fat) until an endpoint related to PDA was met. Forelimb grip strength, body composition, and non-fasting glucose and ketone levels were evaluated at baseline, monthly and at time of euthanasia. Results After 1 month on the experimental diets, ketone levels were significantly higher in mice fed a KD compared to those fed a CD (p < 0.0001). After two months, KPC mice fed a KD significantly outperformed the KPC mice fed CD in the grip strength test, which assesses skeletal muscle function (p = 0.032). Moreover, the weight of the gastrocnemius muscle was significantly higher in KPC mice fed a KD compared to mice fed a CD (p = 0.024). However, the KD had no significant effect extending KPC survival (p = 0.527), or on the tumor/pancreas weight (p = 0.998). Conclusions A KD maximizes and preserves motor function strength during PDA progression. Additional studies are warranted to evaluate the mechanisms of how KD improves and preserves muscle strength in PDA. Funding Sources Startup funds and a University of California Comprehensive Cancer Center award to GGM. NEC is supported with a fellowship from UC-MEXUS.