Apelin-13 induces mitophagy in bone marrow mesenchymal stem cells to suppress intracellular oxidative stress and ameliorate osteoporosis by activation of AMPK signaling pathway

Chen, Liang; Shi, Xiang; Xie, Jun; Weng, She-Ji; Xie, Zhongjie; Tang, Jiahao; Yan, Daoguang; Wang, Bingzhang; Fang, Kang-Hao; Hong, Chen-Xuan; Wu, Zhiping; Yang, Lei

doi:10.1016/j.freeradbiomed.2020.12.235

Cited by 40 publications

(32 citation statements)

References 46 publications

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“…Forced Sirt3 expression preserves mitophagy and osteoporosis in SAMP6 mice, an in vivo model showing accelerated senescence [ 30 ]. The promotion of autophagy by mTOR/PI3K signaling inhibitor rapamycin increases the osteogenic activity of bone-marrow mesenchymal stem cells, whereas mitophagy repression by hydroxychloroquine accelerates the senescence program [ 31 ].…”

Section: The Role Of Mitochondrial Homeostasis In Bone-forming Cell Functionmentioning

confidence: 99%

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

Wang

Chen

et al. 2021

Antioxidants

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Bone-forming cells build mineralized microstructure and couple with bone-resorbing cells, harmonizing bone mineral acquisition, and remodeling to maintain bone mass homeostasis. Mitochondrial glycolysis and oxidative phosphorylation pathways together with ROS generation meet the energy requirement for bone-forming cell growth and differentiation, respectively. Moderate mechanical stimulations, such as weight loading, physical activity, ultrasound, vibration, and electromagnetic field stimulation, etc., are advantageous to bone-forming cell activity, promoting bone anabolism to compromise osteoporosis development. A plethora of molecules, including ion channels, integrins, focal adhesion kinases, and myokines, are mechanosensitive and transduce mechanical stimuli into intercellular signaling, regulating growth, mineralized extracellular matrix biosynthesis, and resorption. Mechanical stimulation changes mitochondrial respiration, biogenesis, dynamics, calcium influx, and redox, whereas mechanical disuse induces mitochondrial dysfunction and oxidative stress, which aggravates bone-forming cell apoptosis, senescence, and dysfunction. The control of the mitochondrial biogenesis activator PGC-1α by NAD+-dependent deacetylase sirtuins or myokine FNDC/irisin or repression of oxidative stress by mitochondrial antioxidant Nrf2 modulates the biophysical stimulation for the promotion of bone integrity. This review sheds light onto the roles of mechanosensitive signaling, mitochondrial dynamics, and antioxidants in mediating the anabolic effects of biophysical stimulation to bone tissue and highlights the remedial potential of mitochondrial biogenesis regulators for osteoporosis.

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Section: The Role Of Mitochondrial Homeostasis In Bone-forming Cell Functionmentioning

confidence: 99%

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

Wang

Chen

et al. 2021

Antioxidants

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“…The activated AMPK can produce ATP by promoting insulin sensitivity, fatty acid oxidation, and mitochondrial biosynthesis, thus reducing oxidative stress damage ( Herzig and Shaw, 2018 ). Previous studies have reported that activating the AMPK signaling pathway can induce mitochondrial autophagy of bone marrow mesenchymal stem cells to inhibit intracellular oxidative stress and improve osteoporosis ( Chen et al, 2021 ).…”

Section: Introductionmentioning

confidence: 99%

Folic Acid Attenuates High-Fat Diet-Induced Osteoporosis Through the AMPK Signaling Pathway

Zhang

Sun

et al. 2022

Front. Cell Dev. Biol.

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Objective: Obesity caused by a high-fat diet (HFD) will expand adipose tissue and cause chronic low-grade systemic inflammation, leading to osteoporosis. Folic acid (FA) is a water-soluble vitamin that plays an essential role in regulating blood lipids and antioxidants. However, the effects and underlying mechanisms of FA in osteoporosis induced by an HFD remain poorly understood. This study aimed to investigate the effect of FA on bone health by using HFD-induced osteoporosis mice.Materials and Methods: Mice were fed a normal diet, HFD or an HFD supplemented with FA (20 μg/ml in drinking water) for 16 weeks. Throughout the 16 weeks study period, the rats were weighed once every week. GTT, ITT and lipid indexes were detected to evaluate the effects of FA on lipid metabolism in the HFD-fed mice. Morphological and structural changes of the femur and tibial bone were observed using micro-CT, HE staining and bone conversion parameters. The expression of MDA, SOD and inflammatory factors were detected to evaluate the effects of FA on oxidative stress and inflammatory response in the HFD-fed mice. Quantitative real-time PCR and Western blot (WB) were used to investigate the AMPK signaling pathway.Results: After the intervention of FA, the body fat rate of obese mice was reduced, and related metabolic disorders such as insulin resistance, hyperlipidemia, and systemic inflammation were alleviated. In correlation with those modifications, FA attenuated bone loss and improved bone microarchitecture, accompanied the number of osteoclasts and adipocytes decreased. Furthermore, FA promoted the phosphorylation of AMPK, thereby promoting the expression of Carnitine palmitoyltransferase 1 (CPT1), nuclear factor erythroid-2 related factor 2 (Nrf2) and antioxidant enzymes.Conclusion: These findings suggest that FA may modulate lipid metabolism and oxidative stress responses activating the AMPK signaling pathway, thereby alleviating HFD-induced osteoporosis. The results from our study provide experimental evidence to prevent HFD-induced osteoporosis.

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“…It has several isoforms of which Apelin-13 is the most active one, binding to the APJ receptor. It is well documented that Apelin plays an essential role in regulating the biological properties of MSCs [ 14 , 15 ]. In a mouse model of hindlimb ischemia, Apelin treatment increased the viability of adipose-derived MSCs by promoting autophagy during hypoxia via activation of the Akt signaling pathway, leading to a better therapeutic efficacy [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival

Chen

Liang

Han

et al. 2022

Stem Cells International

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Although mesenchymal stem cell- (MSC-) based therapy has shown promising results for myocardial infarction (MI), low cell survival heavily limits its beneficial effects. Apelin plays an essential regulatory role in cell proliferation. This study was aimed at determining whether Apelin-13 pretreatment could improve the survival of MSCs in the ischemic heart and enhance their cardioprotective efficacy against MI. MSCs were pretreated with or without Apelin-13 for 24 hours and then exposed to serum deprivation and hypoxia (SD/H) for 48 hours. The mitochondrial morphology of MSCs was assessed by MitoTracker staining. The apoptosis of MSCs was determined by TUNEL staining. The level of mitochondrial reactive oxygen species (ROS) of MSCs was detected by Mito-Sox staining. MSCs and Apelin-13-pretreated MSCs were transplanted into the peri-infarct region in a mouse MI model. Apelin-13 pretreatment protected MSCs against SD/H-induced mitochondrial fragmentation and apoptosis. Apelin-13 pretreatment reduced ROS generation induced by SD/H in MSCs. Furthermore, Apelin-13 pretreatment enhanced the angiogenesis of MSCs under SD/H conditions. Mechanistically, Apelin-13 pretreatment inhibited SD/H-induced MSC apoptosis by downregulating mitochondrial fission via activation of the ERK pathway, and these effects were partially abrogated by ERK inhibitor U0126. Apelin-13 pretreatment promoted the survival of MSCs in the ischemic heart. Moreover, transplantation with Apelin-13-pretreated MSCs improved heart function and increased angiogenesis accompanied by decreased fibrosis compared with MSC transplantation at 28 days following MI. These findings reveal that pretreatment with Apelin-13 improves MSCs survival and enhances their therapeutic efficacy for MI. Our study provides a novel approach to improve MSC-based therapy for cardiovascular disease.

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Apelin-13 induces mitophagy in bone marrow mesenchymal stem cells to suppress intracellular oxidative stress and ameliorate osteoporosis by activation of AMPK signaling pathway

Cited by 40 publications

References 46 publications

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

Biophysical Modulation of the Mitochondrial Metabolism and Redox in Bone Homeostasis and Osteoporosis: How Biophysics Converts into Bioenergetics

Folic Acid Attenuates High-Fat Diet-Induced Osteoporosis Through the AMPK Signaling Pathway

Apelin-13 Pretreatment Promotes the Cardioprotective Effect of Mesenchymal Stem Cells against Myocardial Infarction by Improving Their Survival

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