Combined Exercise Training Positively Affects Muscle Wasting in Tumor-Bearing Mice

Abstract

Introduction Cancer cachexia is characterized by loss of muscle mass and function. Increased protein catabolism, inflammation, impaired anabolism, and mitochondrial function markedly contribute to the pathogenesis of this syndrome. Physical activity has been suggested as a useful tool to prevent or at least delay the onset and progression of cancer-induced muscle wasting. Two main types of exercise can be adopted, namely, resistance and endurance training. The present study is aimed to investigate the effectiveness of a combined (resistance + endurance) exercise protocol in preventing/reverting cancer-induced muscle wasting. Methods Mice bearing the C26 colon carcinoma have been used as a model of cancer cachexia. They have been exposed to combined exercise training during 6 wk (4 before tumor implantation, 2 during tumor growth). Climbing a 1-m ladder inclined at 85° has been used for resistance training, while aerobic (endurance) exercise has been carried out on the same day using a motorized wheel. Results In C26-bearing mice, both muscle mass and strength are improved by combined training, while just the latter increased in exercised healthy animals. Such a pattern is associated with modulations of two markers of autophagy, namely, LC3B-I/II ratio, increased in sedentary tumor hosts and reduced in exercised C26-bearing mice, and p62, steadily increased in both sedentary and trained tumor-bearing animals. Finally, combined training is not able to modify PGC-1α protein levels, but it improves succinate dehydrogenase activity, both reduced in the muscle of the C26 hosts. Conclusion The data reported in the present study show that combined training improves muscle mass and function in the C26 hosts, likely modulating autophagy and improving mitochondrial function; these observations suggest that combined exercise might become part of a multimodal approach to treat cancer cachexia.

Moderate Exercise Improves Experimental Cancer Cachexia by Modulating the Redox Homeostasis

“…Indeed, endurance exercise results in different metabolic adaptations leading to increased mitochondrial mass, oxygen delivery, glucose uptake and antioxidant capacity, whereas resistance exercise mainly leads to increased muscle mass [37]. For these reasons, coupling endurance and resistance exercise could result in good outcomes in cancer hosts, as shown by different pre-clinical and clinical studies [38,39,40]. Consistently, the protocol used in the present study exerted beneficial effects on the C26-bearing mice, as demonstrated by the increase of muscle mass and strength in comparison with sedentary tumor hosts.…”

Musclin, A Myokine Induced by Aerobic Exercise, Retards Muscle Atrophy During Cancer Cachexia in Mice

“…This agrees with reports showing that especially aerobic activity can alleviate cancer cachexia [22,59], also because type I fibers are more resistant to atrophy than type II [15], while AKT overactivation was even found in cachectic muscles [23]. Interestingly, the drop in plasma concentration of musclin was fully recovered when C26-bearing mice were subjected to five days of uphill running sessions at moderate velocity, a condition that seems not to imply resistance exercise as others did [60], because FGF21 was not increased at mRNA level in these trained muscles. Notably, a well-known PGC1α-related myokine, FNDC5 (irisin) being downregulated in cachectic gastrocnemius (but not in TA)—although much less than musclin—is not reversed in gastrocnemius from treadmilled C26 mice, possibly excluding it among the mediators of the anti-atrophic effects of exercise in this model.…”

The Redox Balance: A Target for Interventions Against Muscle Wasting in Cancer Cachexia?

“…Notably, together with the reduction of markers of oxidative stress and increased antioxidant defenses, moderate exercise in C26-bearing mice increases PGC-1a levels and mitochondrial content (12). Similarly, PGC-1a expression increases in the C26 hosts upon combined exercise, including both aerobic and resistance training (107), and in chemotherapy-treated C26-bearing mice exposed to moderate endurance exercise (9). The increase of PGC-1a levels upon exercise training has been observed also in Apc Min/+ mice (148) and in C26 and LLC hosts, receiving also erythropoietin (EPO) or eicosapentaenoic acid (EPA), respectively (93,99).…”