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Abstract
Skeletal muscle atrophy, the most prominent phenotypic feature of cancer cachexia, is often observed in cancer patients undergoing chemotherapy. Magnolol (M) extracted from Magnolia officinalis exhibits several pharmacological effects including anti-inflammatory and anticancer activities. In this study, we investigated whether magnolol supplementation protects against the development of cachexia symptoms in bladder cancer-bearing mice undergoing chemotherapy. Combined treatment of magnolol with chemotherapeutic drugs, such as gemcitabine and cisplatin (TGCM) or gemcitabine (TGM), markedly attenuates the body weight loss and skeletal muscle atrophy compared with conventional chemotherapy (TGC). The antiatrophic effect of magnolol may be associated with inhibition of myostatin and activin A formation, as well as FoxO3 transcriptional activity resulting from Akt activation, thereby suppressing ubiquitin ligases MuRF-1 and MAFbx/atrogin-1 expression, as well as proteasomal enzyme activity. Notably, magnolol-induced insulin-like growth factor 1 (IGF-1) production and related protein synthesis may also contribute to its protective effects. The decreased food intake, and intestinal injury and dysfunction observed in the mice of TGC group were significantly improved in the TGCM and TGM groups. Moreover, the increased inflammatory responses evidenced by elevation of proinflammatory cytokine formation and NF-κB activation occurred in the atrophying muscle of TGC group were markedly inhibited in mice of combined treatment with magnolol. In summary, these findings support that magnolol is a promising chemopreventive supplement for preventing chemotherapy-induced skeletal muscle atrophy associated with cancer cachexia by suppressing muscle protein degradation, and inflammatory responses, as well as increasing IGF-1-mediated protein synthesis.
Highlights
Cancer cachexia has been considered a complex metabolic syndrome that is characterized by anorexia, body weight loss, skeletal muscle atrophy, inflammation, and impaired metabolic functions [1]
It is known that overproduction of myostatin and activins, nuclear factor-κB (NF-κB)-evoked inflammatory responses, and impaired insulin-like growth factor 1 (IGF-1)-dependent protein synthesis are closely related to the pathogenesis of muscle atrophy [10, 11]
The anticancer effect on the TGM group was greater than that in the treated with gemcitabine and cisplatin (TGC) group. These results indicated that magnolol supplementation improved cachexia symptoms and enhanced the anticancer effect of the chemotherapeutic drugs
Summary
Cancer cachexia has been considered a complex metabolic syndrome that is characterized by anorexia, body weight loss, skeletal muscle atrophy, inflammation, and impaired metabolic functions [1]. The forkhead box O (FoxO) is a key transcription factor accounting for the transcription of muscle-specific E3 ligase, F-box (MAFbx)/atrogin-1, and muscle ring finger 1 (MuRF-1), which are responsible for muscle protein ubiquitination and degradation by the proteasome [6, 7]. It is known that overproduction of myostatin and activins, nuclear factor-κB (NF-κB)-evoked inflammatory responses, and impaired insulin-like growth factor 1 (IGF-1)-dependent protein synthesis are closely related to the pathogenesis of muscle atrophy [10, 11]. Regulating these muscle atrophy-related pathways may be a potential strategy for alleviating the muscle mass loss associated with cancer cachexia
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