Resistance Training’s Ability to Prevent Cancer-induced Muscle Atrophy Extends Anabolic Stimulus

Abstract

Purpose: This study aimed to determine the role of mammalian target of rapamycin (mTORC1) activation and catabolic markers in resistance training's (RT) antiatrophy effect during cachexia-induced muscle loss. Methods: Myofiber atrophy was induced by injecting Walker 256 tumor cells into rats exposed or not exposed to the RT protocol of ladder climbing. The role of RT-induced anabolic stimulation was investigated in tumor-bearing rats with the mTORC1 inhibitor rapamycin, and cross-sectional areas of skeletal muscle were evaluated to identify atrophy or hypertrophy. Components of the mTORC1 and ubiquitin-proteasome pathways were assessed by real-time polymerase chain reaction or immunoblotting. Results: Although RT prevented myofiber atrophy and impaired the strength of tumor-bearing rats, in healthy rats, it promoted activated mTORC1, as demonstrated by p70S6K's increased phosphorylation and myofiber's enlarged cross-sectional area. However, RT promoted no changes in the ratio of p70S6K to phospho-p70S6K protein expression while prevented myofiber atrophy in tumor-bearing rats. Beyond that, treatment with rapamycin did not preclude RT's preventive effect on myofiber atrophy in tumor-bearing rats. Thus, RT's ability to prevent cancer-induced myofiber atrophy seems to be independent of mTORC1's and p70S6K's activation. Indeed, RT's preventive effect on cancer-induced myofiber atrophy was associated with its capacity to attenuate elevated tumor necrosis factor α and interleukin 6 as well as to prevent oxidative damage in muscles and an elevated abundance of atrogin-1. Conclusions: By inducing attenuated myofiber atrophy independent of mTORC1's signaling activation, RT prevents muscle atrophy during cancer by reducing inflammation, oxidative damage, and atrogin-1 expression.

Resistance Training Attenuates Activation of STAT3 and Muscle Atrophy in Tumor-Bearing Mice

“…STAT3-phosphorylated protein content was markedly elevated in the skeletal muscle of tumor-bearing mice compared to the controls (Figure 4A). In agreement with previous studies using different cancer cachexia models (5,6,18), Ehrlich tumor development presented characteristics of pro-inflammatory scenario, as demonstrated by significant (P <.05) elevated TNFa and IL-6 in plasma of tumor-bearing mice compared to the control group (Figures 4B, C). Tumor-bearing mice also presented skeletal muscle oxidative damage, as demonstrated by elevated levels (P <.05) of the lipid peroxidation evaluated by TBARS, protein oxidation evaluated by AOPP, and redox imbalance demonstrated by elevated skeletal muscle GSSG concentration and reduced GSH/GSSG ratio (Figures 4D-F).…”

“…RT was performed as previously described in a ladder-climbing protocol for rats (5,6,19) adapted to mice. RT consisted of a set of ladder-climbing (0.5m, 0.01m grid, 900 incline) projected so it favored 8-12 dynamic movements per climb.…”

“…In this scenario, resistance exercise training (RT) emerges as an anti-cachexia strategy. Recent pre-clinical studies have demonstrated that RT counteracted muscle wasting and functional decline (4)(5)(6). However, the mechanism by which RT protects against cancer-induced muscle wasting and strength loss is still debated.…”

High-Intensity Aerobic Exercise Suppresses Cancer Growth by Regulating Skeletal Muscle-Derived Oncogenes and Tumor Suppressors

“…Our previous ( Jee et al, 2016a ) and current studies also showed the cancer-suppressive effect of high-intensity aerobic exercise. Other studies demonstrated that resistant exercise on the animal cancer model mitigates tumor growth, tumor grade, viable tumor area, tumor cell proliferation, and myofiber atrophy-causing cancer cachexia via attenuating some key markers such as TNF-α, IL-6, Atrogin1, and oxidative damage ( Padilha et al, 2019 ; Padilha et al, 2021 ). In addition, we also found an effect of exercise on cancer cachexia.…”

“…For example, a recent microarray-based study on the effect of low-intensity resistance training on human subjects showed that the accurate mode and extent of exercise resulted in the upregulation of microRNAs, such as miR-630 and miR-5703, and myokines (fractalkine/CX3CL1) among 42 pathways and 12 cytokines/myokines, which subsequently suppressed tumor growth by inducing tumor-specific cytotoxic T cells ( Hashida et al, 2021 ). In addition, the ladder climbing resistant training exercise on preclinical tumor-bearing animals also mitigated muscle atrophy, tumor growth, and cancer malignancy ( Padilha et al, 2019 ; Padilha et al, 2021 ). However, the molecular mechanisms underlying the anticancer effects of exercise remain largely unknown.…”