Magnolol inhibits myotube atrophy induced by cancer cachexia through myostatin signaling pathway in vitro
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ORIGINAL PAPER
Magnolol inhibits myotube atrophy induced by cancer cachexia through myostatin signaling pathway in vitro Zhijuan Ge1 · Dong Liu1 · Yue Shang1 · Yi Li1 · Shu‑zhen Chen1 Received: 9 March 2020 / Accepted: 22 June 2020 © The Japanese Society of Pharmacognosy 2020
Abstract Cancer cachexia is a complex and multifactorial syndrome that influences about 50–80% of cancer patients and may lead to 20% of cancer deaths and muscle atrophy is the key characteristic of the syndrome. Recent researches have shown that myostatin is a negative regulator in the growth and differentiation of skeletal muscle. Herein, C2C12 cancer cachexia model was established with C26 conditioned culture medium (CCM), then treated with magnolol to evaluate the pharmacological activity of magnolol in myotube atrophy. Our results demonstrated that magnolol inhibited the activity of myostatin promotor and the myostatin signaling pathway. In C2C12 cancer cachexia model, magnolol decreased myostatin expression, inhibited the phosphorylation of SMAD2/3 activated by C26 conditioned culture medium (CCM), and elevated the phosphorylation of FOXO3a lowered by CCM. Myosin heavy chain (MyHC), myogenin (MyoG), and myogenic differentiation (MyoD), as three common myotube markers in C2C12 myotube, were decreased by CCM, which could be effectively reversed by magnolol via activation of AKT/mTOR-regulated protein synthesis and inhibition of ubiquitin-mediated proteolysis. This study reveals that magnolol inhibits myotube atrophy induced by CCM by increasing protein synthesis and decreasing ubiquitin-mediated proteolysis, so that magnolol is a promising leading compound in treating muscle atrophy induced by cancer cachexia. Keywords Magnolol · Cancer cachexia · Muscle atrophy · Myostatin · C2C12
Introduction Cancer cachexia is considered as a complex and multifactorial syndrome that is characterized by a continuing skeletal muscle mass loss (with or without fat mass loss) that cannot be entirely recovered by conventional nutritional support [1]. The adverse outcomes of cancer-associated cachexia include poor survival, complications from cancer surgery and increased chemotherapy toxicity [2]. Cancer cachexia happens in about 50–80% of cancer patients and contributes to 20% of cancer deaths [3]. Depletion of skeletal muscle is the key characteristic of cancer-associated cachexia [1]. Abnormalities in protein degradation and synthesis are responsible for muscle wasting [4]. The process of muscle wasting seems to be mostly associated with accelerated proteolysis that is regulated by the ubiquitin-dependent proteasome pathway * Shu‑zhen Chen [email protected] 1
Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, 1# Tiantan Xili, Dongcheng District, Beijing 100050, China
[5]. Muscle-specific E3 ligases (Ub-protein ligases) are key enzymes which regulate synthesis and degradation of structural muscle proteins in skeletal muscle atrophy. In experimental animals of muscle atrophy, E3 ligase mu
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