Sex differences in skeletal muscle alterations in a model of colorectal cancer.

Angela C Greenman,Richard B Halberg,Dawn M Albrecht,Gary M Diffee

doi:10.14814/phy2.14391

Abstract

Cancer cachexia is the loss of lean muscle mass with or without loss of fat mass that is often highlighted by a progressive loss of skeletal muscle mass and function. The mechanisms behind the cachexia‐related loss of skeletal muscle are poorly understood, including cachexia‐related muscle functional impairments. Existing models have revealed some potential mechanisms, but appear limited to how the cancer develops and the type of tumors that form. We studied the C57BL6/J (B6) ApcMin/+ Tg::Fabp1‐Cre TG::PIK3ca* (CANCER) mouse. In this model, mice develop highly aggressive intestinal cancers. We tested whether CANCER mice develop cancer cachexia, if muscle function is altered and if sex differences are present. Both female and male mice, B6 (CONTROL) and CANCER mice, were analyzed to determine body weight, hindlimb muscle mass, protein concentration, specific force, and fatigability. Female CANCER mice had reduced body weight and hindlimb muscle mass compared with female CONTROL mice, but lacked changes in protein concentration and specific force. Male CANCER mice had reduced protein concentration and reduced specific force, but lacked altered body weight and muscle mass. There were no changes in fatigability in either group. Our study demonstrates that CANCER mice present an early stage of cachexia, have reduced specific force in male CANCER mice and develop a sex‐dependent cachexia phenotype. However, CANCER mice lack certain aspects of the syndrome seen in the human scenario and, therefore, using the CANCER mice as a preclinical model does not seem sufficient in order to maximize the translation of preclinical findings to humans.

Highlights

Cachexia is a progressive syndrome involving the loss of skeletal muscle mass, with or without the loss of adipose tissue, due to an underlying disease, such as cancer
Our study showed that the CANCER mice may present an early stage of cancer cachexia, had altered muscle function and developed sex differences
Female CANCER mice experienced reductions in body weight and muscle mass compared with female CONTROL mice, whereas male CANCER mice had reduced protein concentration and skeletal muscle function compared with male CONTROL mice

Summary

Introduction

Cachexia is a progressive syndrome involving the loss of skeletal muscle mass, with or without the loss of adipose tissue, due to an underlying disease, such as cancer. The severity of muscle mass loss, inflammation, loss of function and fatigue occurring in cancer cachexia is described as progressing through three stages of cancer cachexia: precachexia, Physiological Reports. The mechanisms underlying the development and progression of cancer cachexia are yet to be fully understood, but cancer-related systemic inflammation appears to negatively affect muscle mass (Argilés, Busquets, Toledo, & López-soriano, 2009; Tisdale, 2009; VanderVeen, Fix, & Carson, 2017a). Previous studies of cancer cachexia, in both clinical and preclinical settings, have focused primarily on the ongoing loss of muscle mass with little attention paid to changes in muscle functional properties despite the fact that reduced quality of life and increased risk of mortality, common outcomes of cancer cachexia, are due to increased muscle fatigue and functional impairments (Murphy & Lynch, 2009). Further determination of altered muscle functional properties accompanying the loss of muscle mass in cancer cachexia may lead to a more complete understanding of the cancer cachexia mechanism and lead to potential therapeutic targets

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