Interleukin‐4 administration improves muscle function, adult myogenesis, and lifespan of colon carcinoma‐bearing mice

Abstract

Background Anorexia, body wasting, inflammation, muscle, and adipose tissue loss are hallmarks of cancer cachexia, a syndrome that affects the majority of cancer patients, impairing their ability to endure chemotherapeutic therapies and reducing their lifespan. In the last 10 years, alterations of protein turnover and impairment of adult myogenesis have been proposed as major contributing factors. Methods Muscle stem cells, including satellite cells, mesoangioblasts, and fibroadipogenic progenitors, were isolated and characterized from C26 colon carcinoma‐bearing (C26) mice. Circulating levels of interleukin‐4/13 (IL4/IL13) were analysed by ELISA, and the effects of IL4 on muscle mass and function, protein synthesis, muscle regeneration, and myogenic progenitor cell number were analysed at both functional (treadmill and grip test) and molecular levels (qRT–PCR, immunofluorescence analysis, surface sensing of translation, and western blot). The Kaplan–Meier test was used to analyse the survival curve of IL4‐treated and IL4‐untreated C26 mice. Results The administration of IL4 to C26 mice rescued muscle mass by increasing protein synthesis. The IL4 treatment improved performances and prolonged survival of C26 mice. IL4 administration re‐established both number and function of satellite cells and fibroadipogenic progenitors without affecting mesoangioblasts in C26 mice, rescuing myogenesis. Upon IL4 treatment, a high number of cytotoxic lymphocytes and type II macrophages were observed with a subsequent increase in necrotic areas of C26 tumours. Conclusions The results here presented shed new light on IL4 signalling during muscle wasting and early stages of muscle regeneration that explain the beneficial effect observed in IL4‐treated C26 mice. These findings might aid to develop therapeutic approaches to improve mobility and quality of life in cachectic patients.

Muscle Microbiopsy to Delineate Stem Cell Involvement in Young Patients: A Novel Approach for Children With Cerebral Palsy

“…Once activated, SCs start to proliferate and either self-renew for maintaining the muscle stem cell pool or differentiate toward myoblasts and fuse with existing myofibers to increase fiber mass and length (Tidball, 2011). During chronic inflammation conditions, SC number can increase due to inflammatory stimuli, such as those in muscular dystrophies, where the number of SCs is eventually exhausted, or during cancer-induced muscle atrophy, where SCs accumulate in the interstitium (He et al, 2013;Costamagna et al, 2020). Despite their specific location, SCs can be identified by different molecular markers such as PAX7, CD56, and CD82 (Illa et al, 1992;Seale et al, 2000;Tedesco et al, 2017;Rotini et al, 2018;Tey et al, 2019).…”

The Impact of Immune Cells on the Skeletal Muscle Microenvironment During Cancer Cachexia

“…To date, few papers have directly investigated the changes to skeletal muscle monocytes or MΦs with cancer and/or cancer-associated wasting ( Inaba et al, 2018 ; Costamagna et al, 2020 ). Interleukin-4 (IL-4), a potent stimulator of M2-like MΦs, was shown to attenuate skeletal muscle wasting in the C26 mouse model of cachexia associated with reduced satellite cell accumulation and increased skeletal muscle CD206 protein expression ( Costamagna et al, 2020 ). Protein analysis showed no significant differences between control and C26-tumor bearing mice with F4/80, and CD206 (marker of M2-like MΦs) appears lower in C26 mice but did not achieve statistical significance.…”

“…Deficits in the capacity for myogenesis, which is needed for successful muscle regeneration, have been reported in skeletal muscle from preclinical cachexia models and cancer patients, and involve an inability of satellite cells to effectively differentiate to complete the regenerative process ( Penna et al, 2010 ; He et al, 2013 ). Due to the importance of the successful myogenic response in muscle regeneration, signaling pathways disrupting satellite cell activity have been actively investigated as potential therapeutic targets for cancer-induced muscle wasting ( Schwarzkopf et al, 2006 ; He et al, 2013 ; Cerquone Perpetuini et al, 2018 ; Costamagna et al, 2020 ; Schmidt et al, 2020 ). To this end, skeletal muscle satellite cell differentiation has been reported to be rescued in colon-26 induced cachexia in mice through the inhibition or ERK signaling ( Penna et al, 2010 ), and more recently IL-4 administration ( Costamagna et al, 2020 ).…”

“…Due to the importance of the successful myogenic response in muscle regeneration, signaling pathways disrupting satellite cell activity have been actively investigated as potential therapeutic targets for cancer-induced muscle wasting ( Schwarzkopf et al, 2006 ; He et al, 2013 ; Cerquone Perpetuini et al, 2018 ; Costamagna et al, 2020 ; Schmidt et al, 2020 ). To this end, skeletal muscle satellite cell differentiation has been reported to be rescued in colon-26 induced cachexia in mice through the inhibition or ERK signaling ( Penna et al, 2010 ), and more recently IL-4 administration ( Costamagna et al, 2020 ). Pax7 is a positive regulator of satellite cell proliferation, which has been reported to be disrupted in cachectic muscle from mice and cancer patients ( He et al, 2013 ); dysregulation of Pax7 in cachectic muscle was driven by aberrant NF-κΒ signaling induced by circulating tumor derived factors.…”

Advance in Drug Delivery for Ageing Skeletal Muscle

“…Costamagna, D et al found the IL-4 treatment would improve the performances and prolonged survival of colon carcinoma-bearing (C26) mice. IL-4 could rescue muscle mass by increasing protein synthesis and promote myogenesis (Costamagna et al, 2020). Du H et al investigated that overexpression of ADAMTS1 in macrophages could active satellite cell and promote muscle regeneration by reduces Notch signaling (Du et al, 2017).…”