Baoyuan Jiedu Decoction Alleviates Cancer-Induced Myotube Atrophy by Regulating Mitochondrial Dynamics Through p38 MAPK/PGC-1α Signaling Pathway

Delong Wang; Weiqiao Chen; Qianyu Bi; Xin Zong; Jiazhao Ruan; Xiangjun Yin; Jixin Wang; Honghua Zhang; Xuming Ji

doi:10.3389/fonc.2020.523577

Baoyuan Jiedu Decoction Alleviates Cancer-Induced Myotube Atrophy by Regulating Mitochondrial Dynamics Through p38 MAPK/PGC-1α Signaling Pathway

Front Oncol. 2020 Sep 30:10:523577. doi: 10.3389/fonc.2020.523577. eCollection 2020.

Authors

Delong Wang¹, Weiqiao Chen¹, Qianyu Bi², Xin Zong², Jiazhao Ruan¹, Xiangjun Yin¹, Jixin Wang³, Honghua Zhang⁴, Xuming Ji¹

Affiliations

¹ School of Basic Medical Science, Zhejiang Chinese Medical University, Zhejiang, China.
² College of Traditional Chinese Medicine, Shandong University of Traditional Chinese Medicine, Shandong, China.
³ Zhejiang University-University of Edinburgh Institute, Zhejiang University, Zhejiang, China.
⁴ Medical College, Hangzhou Normal University, Zhejiang, China.

Abstract

Cancer cachexia is a multifactorial syndrome characterized by continuous body wasting and loss of skeletal muscle. Impaired mitochondria function is closely associated with muscle atrophy in cancer cachexia. Our previous study confirmed the effectiveness of Baoyuan Jiedu decoction (BJD) in inhibiting cancer-induced muscle atrophy in an in vivo model. However, little is known about its mechanisms in regulating mitochondria dysfunction. In this study, we evaluated the therapeutic effect and action mechanisms of BJD against atrophy both in the Lewis-conditioned medium induced C2C12 myotube atrophy model and in a BALB/c mice xenograft model using mouse colon cancer C26 cells. The mitochondrial content was tested by 10-Non-ylacridine orange staining. Expressions of related proteins and mRNAs were detected by western blotting (WB) and qPCR, respectively. As a result, 18 major components were identified in BJD by ultra-high performance liquid chromatography-quadrupole (UHPLC-Q) Exactive analysis. As shown in the in vitro results, BJD treatment prevented prominent myotube atrophy and increased the myotube diameter of C2C12 cells. Besides, BJD treatment increased mitochondrial content and ATPase activity. Furthermore, the protein and mRNA expressions that were related to mitochondrial functions and generation such as cytochrome-c oxidase IV, Cytochrome C, nuclear respiratory factor 1, and mitochondrial transcription factor A were significantly increased in BJD treatment compared to the control group. The in vivo results showed that BJD treatment prevented body weight loss and improved the gastrocnemius index in cachexia mice. Moreover, the expressions of Atrogin-1 and muscle RING-finger protein-1 were decreased by BJD treatment. Mechanically, BJD increased the expression of peroxisome proliferator-activated receptor-gamma coactivator 1, and consistently, inhibited the expression of p38 MAPK and its phosphorylation both in vivo and in vitro. Taken together, this study identified that BJD effectively relieved cancer-induced myotube atrophy and provided a potential mechanism for BJD in regulating mitochondrial dynamics through p38 MAPK/PGC-1α signaling pathway.

Keywords: Baoyuan Jiedu decoction (BJD); cancer cachexia; in vitro; in vivo; mitochondrial dynamics; p38 MAPK/PGC-1α pathway; traditional Chinese medicine.