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

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 proliferatoractivated 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.

Baoyuan Jiedu decoction alleviating cancer cachexia–Induced muscle atrophy by regulating muscle mitochondrial function in ApcMin/+ mice

“…All herbs were purchased from Zhonglu Hospital (Shandong, China) and identified by the professors from the Department of Pharmacy, Shandong University of Traditional Chinese Medicine (Shandong, China). The method of preparing extracts of BJD was consistent with the study we published previously (Wang et al, 2020), as hot water extracts from the six crude herbs that concentrated to 1.15 g drug/ml.…”

“…C57BL/6 J mice were used as a blank control group (normal group). According to our previous study (Wang et al, 2020), the dose of the BJD group was 23 g/kgd by gavage. The MA group was intraperitoneally injected with 24 mg/kgd of megestrol acetate (Ape×Bio, United States, Cat# B1377).…”

“…Baoyuan Jiedu decoction (BJD) is a classic traditional Chinese herbal formula for treating cancer cachexia. Our prior studies have evaluated the efficacy of BJD in relieving muscle atrophy in Lewis lung carcinoma-induced cancer cachexia mice and C26 colorectal tumor-bearing mice by downregulating the expressions of atrogin-1 and MuRF-1 (Zhang et al, 2017;Wang et al, 2020). Furthermore, it has been proved that BJD could suppress the expressions of atrogin-1 and MuRF-1 via inhibiting the ubiquitin-proteasome pathway in the Lewis-conditioned medium (LCM)-induced C2C12 myotube atrophy model (Zhang et al, 2018).…”

“…Furthermore, it has been proved that BJD could suppress the expressions of atrogin-1 and MuRF-1 via inhibiting the ubiquitin-proteasome pathway in the Lewis-conditioned medium (LCM)-induced C2C12 myotube atrophy model (Zhang et al, 2018). In addition, we found that BJD could alleviate cancer-induced myotube atrophy by improving mitochondrial dynamics through the p38 MAPK/PGC-1α signaling pathway both in vivo and in vitro (Wang et al, 2020). Otherwise, we used the Apc Min/+ mouse model, a spontaneous intestinal tumorigenesis model, which likewise demonstrated that BJD could prevent muscle atrophy by downregulating the expressions of atrogin-1 and MuRF-1, and mitochondrial uncoupling was involved (Zong et al, 2019).…”

A Novel Formula Comprising Wolfberry, Figs, White Lentils, Raspberries, and Maca (WFWRM) Induced Antifatigue Effects in a Forced Exercise Mouse Model

“…In addition, peripheral inflammation and immune activation Meanwhile, palmitoylethanolamide is a fatty acid derivative that can antifatigue through inhibiting inflammation [ 36 ]. Notably, it has been reported that the treatment of Baoyuan Jiedu decoction involving indole-3-acrylic acid, isoliquiritigenin, formononetin, 18- β -glycyrrhetinic acid, and 9S,13R-12-oxophytodienoic acid prevented prominent myotube atrophy and regulated mitochondrial production [ 37 ]. Indeed, mitochondria and muscles are damaged with fatigue [ 38 ].…”