The Influence of Exercise During Weight Loss on Muscle Remodeling During Colon Cancer Induction In Mice

Abstract

Background: Diet and exercise have been recommended to reduce the risk of colorectal cancer (CRC) in individuals with obesity. However, the effects of these interventions on muscle remodeling during CRC initiation in individuals who were previously obese is unknown. Since CRC is associated with a high-risk of cachexia, it is important to understand how diet and exercise interventions can impact muscle remodeling in populations at risk of developing CRC-induced cachexia. Our aim was to investigate the effects of weight loss, with or without exercise, on markers of muscle remodeling in a mouse model of CRC. We hypothesized that exercise plus weight loss would increase muscle mass, reduce muscle fibro/fatty tissue, and increase muscle stem/progenitor cell content compared to weight loss alone. Methods: Mice consumed a high-fat diet (HFD) to induce obesity or a control (CON) diet. Subsequently, mice received injections of azoxymethane (AOM) to induce CRC. Then, weight loss was induced in HFD mice by placing them on the CON diet and those mice either remained sedentary (HFD-SED) or completed a treadmill exercise intervention (HFD-EX). Results: After 40 weeks, mice were sacrificed and analyzed for markers of muscle remodeling. HFD-SED and HFD-EX showed weight loss and a loss in percent fat mass when looking at changes between sacrifice and before AOM injections (p<0.05 vs. CON). HFD-SED and HFD-EX had increased lean mass (p<0.05 vs. CON), and HFD-EX had increased tibialis anterior (TA) weight (p<0.05 vs. CON). The proportion of medium-sized fibers increased (p<0.05 vs. HFD-SED and CON) in HFD-EX, but there were no differences in overall cross-sectional area, myonuclei per fiber, or myonuclear domain. HFD-SED had increased fibrosis (p<0.05 vs. HFD-EX and CON) and adiposity (p<0.05 vs. CON). The number of committed (Pax7+MyoD+) satellite cells (SCs) and FAPs was greater in HFD-EX (p<0.05 vs. CON). There were no differences in uncommitted (Pax7+MyoD-) or differentiated (Pax7-MyoD+) SCs. Additionally, nuclear p-NF-κB was reduced following exercise (p<0.05), specifically in the interstitium with a significant decrease in the number of interstitial p-NF-κB cells in the HFD-EX group (p<0.05 vs. CON and HFD-SED). Conclusions: Findings suggest that a HFD, followed by weight loss with exercise, can reduce fibrotic and fatty degeneration of the muscle and improve markers of muscle remodeling. These findings provide the rationale to further examine exercise interventions for maintaining muscle quality during weight loss interventions to reduce CRC-induced cachexia.