Exercise Reduces the Resumption of Tumor Growth and Proteolytic Pathways in the Skeletal Muscle of Mice Following Chemotherapy

Abstract

The pathogenesis of muscle atrophy plays a central role in cancer cachexia, and chemotherapy contributes to this condition. Therefore, the present study aimed to evaluate the effects of endurance exercise on time-dependent muscle atrophy caused by doxorubicin. For this, C57 BL/6 mice were subcutaneously inoculated with Lewis lung carcinoma cells (LLC group). One week after the tumor establishment, a group of these animals initiated the doxorubicin chemotherapy alone (LLC + DOX group) or combined with endurance exercise (LLC + DOX + EXER group). One group of animals was euthanized after the chemotherapy cycle, whereas the remaining animals were euthanized one week after the last administration of doxorubicin. The practice of exercise combined with chemotherapy showed beneficial effects such as a decrease in tumor growth rate after chemotherapy interruption and amelioration of premature death due to doxorubicin toxicity. Moreover, the protein degradation levels in mice undergoing exercise returned to basal levels after chemotherapy; in contrast, the mice treated with doxorubicin alone experienced an increase in the mRNA expression levels of the proteolytic pathways in gastrocnemius muscle (Trim63, Fbxo32, Myostatin, FoxO). Collectively, our results suggest that endurance exercise could be utilized during and after chemotherapy for mitigating muscle atrophy promoted by doxorubicin and avoid the resumption of tumor growth.

Chemotherapy-Induced Myopathy: The Dark Side of the Cachexia Sphere

“…Nevertheless, these data highlight inconsistency with data derived from chemotherapy treated, cancer-free mouse models, which demonstrate protective efficacy from exercise (see Table 1 ) [ 78 , 142 ]. Perhaps even more interesting, and consistent with the clinical data, is that exercise did not alter skeletal muscle mass or CSA in two tumour-burdened mouse models treated with chemotherapy [ 89 , 143 ]. Thus, tumour factors appear to be most influential in dictating whether skeletal muscle can be modulated by exercise.…”

“…This makes it difficult to form a consensus sufficient to facilitate clinical exercise prescription based upon pre-clinical data. For example, some studies employed a maximal treadmill running test to exhaustion [ 141 , 143 ]. This is a low-cost alternative to incorporating the use of metabolic studies that enable the quantification of peak/maximum oxygen consumption (VO 2 peak/max), which can be used to identify a relative exercise intensity [ 144 ].…”

“…The utility of metronomic delivery regimens in experimental models of chemotherapy cachexia still require a balance between retaining a clinically compatible cumulative dose and maintaining survival of the animals, so that exercise training interventions can be implemented. Going forward, future studies should refer to current gold standard models published in both de Lima et al [ 143 ] and Ballaro et al [ 89 ], which evaluate the effect of exercise during the synergistic-induction of cachectic myopathy from both chemotherapy and cancer-related factors. If possible, a chemotherapy control group should be included alongside a cancer control group when models are being optimised.…”

“…Thus, tumour factors appear to be most influential in dictating whether skeletal muscle can be modulated by exercise. While mass may not necessarily be modifiable by exercise therapy, de Lima et al importantly demonstrated that exercise training improved skeletal muscle recovery after the cessation of chemotherapy, a paradigm yet to be explored in clinical studies [ 143 ]. Considering that current exercise interventions only elicit modest protective efficacy against chemotherapy and cancer-induced cachectic myopathy at best, there is an emphasis to explore multi-modal therapeutic strategies that involve exercise prescription programs alongside pharmacological interventions for synergistic benefits.…”

Metabolic Remodeling in Skeletal Muscle Atrophy as a Therapeutic Target

“…Among them, agonists of P PARδ or of AMPK, molecules able to activate SIRT1 or to reduce fatty acid oxidation, have given promising results to modulate lipid metabolism, mitochondrial function, and fiber-type determination in different muscle-wasting diseases, and cachexia as well [ 248 , 249 ]. Importantly, as part of a combined approach, exercise showed beneficial effects after chemotherapy in terms of reducing tumor growth rate, protein degradation and doxorubicin-induced toxicity in tumor-bearing mice [ 250 ].…”