Preliminary study: Leucine Supplementation Exacerbates Muscle Wasting Independent of the Ubiquitin-Proteasome System

Abstract

Cancer cachexia is the rapid, drastic loss of muscle mass associated with cancer and is not reversible by conventional nutritional means (Brown et al., 2018; Brown et al., 2017). It occurs in ~80% of cancer patients and is responsible for 20-40% of cancer-related deaths (Brown et al., 2018; Brown et al., 2017). This condition leaves patients with fatigue, functional impairment, reduced quality of life, and a decrease in survival rates. Cachexia occurs through an imbalance between protein degradation and protein synthesis (Brown et al., 2018), which is associated with inflammation and altered metabolic processes. Several studies have investigated the effects of leucine on cancer cachexia, as it is known for promoting muscle growth through the stimulation of anabolic signaling cascades while inhibiting catabolism. These studies have all been conducted for a short period of time and have shown promise for leucine as a treatment for cancer cachexia. However, one study found that long-term (6 weeks) leucine supplementation increased epididymal fat mass while decreasing muscle mass in rats fed a high-fat diet (Baum et al., 2016). In addition, Lee et al. (2019) demonstrated exacerbated atrophy in tumor-bearing mice after 28 days of low-dose leucine supplementation. Whether leucine is a viable long-term treatment for cancer cachexia requires further investigation. 10 C57BL/6 (WT) mice and 7 APCMin/+ (APC) mice were used in this study and given either tap water as a control or given 1.5% leucine-enriched water. Tissue harvest was conducted at ~24 weeks of age for genetic and western blot analysis. There was a main effect of genotype for decreased body and plantaris weight in APC mice compared to WT (p < 0.05), and a main effect of leucine for lower plantaris weight/tibia length in APC mice (p < 0.05), which appeared to be driven by the APC Min/+ genotype (p = 0.0841). Cyclin D1 mRNA abundance was ~2-fold greater in APC mice compared to WT, although no difference was found with treatment. No difference was found in MyoD or Myogenin mRNA abundance. Long-term leucine supplementation appears to exacerbate atrophy, which appeared to be independent of protein turnover or myogenesis disruption.