bims-amsmem Biomed News
on AMPK signaling mechanism in energy metabolism
Issue of 2022‒10‒16
ten papers selected by
Dipsikha Biswas, Københavns Universitet
  1. The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.
  2. Obligatory Role of AMPK Activation and Antioxidant Defense Pathway in the Regulatory Effects of Metformin on Cellular Protection and Prevention of Lens Opacity.
  3. Protective Effect of Rutin on Triethylene Glycol Dimethacrylate-Induced Toxicity through the Inhibition of Caspase Activation and Reactive Oxygen Species Generation in Macrophages.
  4. Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway.
  5. Magnesium Supplementation Stimulates Autophagy to Reduce Lipid Accumulation in Hepatocytes via the AMPK/mTOR Pathway.
  6. Metformin attenuates an increase of calcium-dependent and ubiquitin-proteasome markers in unloaded muscle.
  7. Metformin Prevents or Delays the Development and Progression of Osteoarthritis: New Insight and Mechanism of Action.
  8. Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway.
  9. Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSC-EXO) regulate autophagy through AMPK-ULK1 signaling pathway to ameliorate diabetic cardiomyopathy.
  10. SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis.
  1. Nat Metab. 2022 Oct 10.
    The aldolase inhibitor aldometanib mimics glucose starvation to activate lysosomal AMPK.
    Chen-Song Zhang, Mengqi Li, Yu Wang, Xiaoyang Li, Yue Zong, Shating Long, Mingliang Zhang, Jin-Wei Feng, Xiaoyan Wei, Yan-Hui Liu, Baoding Zhang, Jianfeng Wu, Cixiong Zhang, Wenhua Lian, Teng Ma, Xiao Tian, Qi Qu, Yaxin Yu, Jinye Xiong, Dong-Tai Liu, Zhenhua Wu, Mingxia Zhu, Changchuan Xie, Yaying Wu, Zheni Xu, Chunyan Yang, Junjie Chen, Guohong Huang, Qingxia He, Xi Huang, Lei Zhang, Xiufeng Sun, Qingfeng Liu, Abdul Ghafoor, Fu Gui, Kaili Zheng, Wen Wang, Zhi-Chao Wang, Yong Yu, Qingliang Zhao, Shu-Yong Lin, Zhi-Xin Wang, Hai-Long Piao, Xianming Deng, Sheng-Cai Lin.
      The activity of 5'-adenosine monophosphate-activated protein kinase (AMPK) is inversely correlated with the cellular availability of glucose. When glucose levels are low, the glycolytic enzyme aldolase is not bound to fructose-1,6-bisphosphate (FBP) and, instead, signals to activate lysosomal AMPK. Here, we show that blocking FBP binding to aldolase with the small molecule aldometanib selectively activates the lysosomal pool of AMPK and has beneficial metabolic effects in rodents. We identify aldometanib in a screen for aldolase inhibitors and show that it prevents FBP from binding to v-ATPase-associated aldolase and activates lysosomal AMPK, thereby mimicking a cellular state of glucose starvation. In male mice, aldometanib elicits an insulin-independent glucose-lowering effect, without causing hypoglycaemia. Aldometanib also alleviates fatty liver and nonalcoholic steatohepatitis in obese male rodents. Moreover, aldometanib extends lifespan and healthspan in both Caenorhabditis elegans and mice. Taken together, aldometanib mimics and adopts the lysosomal AMPK activation pathway associated with glucose starvation to exert physiological roles, and might have potential as a therapeutic for metabolic disorders in humans.
    DOI:  https://doi.org/10.1038/s42255-022-00640-7
  2. Cells. 2022 Sep 27. pii: 3021. [Epub ahead of print]11(19):
    Obligatory Role of AMPK Activation and Antioxidant Defense Pathway in the Regulatory Effects of Metformin on Cellular Protection and Prevention of Lens Opacity.
    Bhavana Chhunchha, Eri Kubo, Dhirendra P Singh.
      Increasing levels of oxidative-stress due to deterioration of the Nrf2 (NFE2-related factor)/ARE (antioxidant response element) pathway is found to be a primary cause of aging pathobiology. Metformin having anti-aging effects can delay/halt aging-related diseases. Herein, using lens epithelial cell lines (LECs) of human (h) or mouse (m) and aging h/m primary LECs along with lenses as model systems, we demonstrated that Metformin could correct deteriorated Bmal1/Nrf2/ARE pathway by reviving AMPK-activation, and transcriptional activities of Bmal1/Nrf2, resulting in increased antioxidants enzymatic activity and expression of Phase II enzymes. This ensued reactive oxygen species (ROS) mitigation with cytoprotection and prevention of lens opacity in response to aging/oxidative stress. It was intriguing to observe that Metformin internalized lens/LECs and upregulated OCTs (Organic Cation Transporters). Mechanistically, we found that Metformin evoked AMPK activation-dependent increase of Bmal1, Nrf2, and antioxidants transcription by promoting direct E-Box and ARE binding of Bmal1 and Nrf2 to the promoters. Loss-of-function and disruption of E-Box/ARE identified that Metformin acted by increasing Bmal1/Nrf2-mediated antioxidant expression. Data showed that AMPK-activation was a requisite for Bmal1/Nrf2-antioxidants-mediated defense, as pharmacologically inactivating AMPK impeded the Metformin's effect. Collectively, the results for the first-time shed light on the hitherto incompletely uncovered crosstalk between the AMPK and Bmal1/Nrf2/antioxidants mediated by Metformin for blunting oxidative/aging-linked pathobiology.
    Keywords:  Bmal1; Metformin; Nrf2; Peroxiredoxin 6; age-related diseases; aging; antioxidant response; antioxidants; oxidative stress
    DOI:  https://doi.org/10.3390/cells11193021
  3. Int J Mol Sci. 2022 Oct 04. pii: 11773. [Epub ahead of print]23(19):
    Protective Effect of Rutin on Triethylene Glycol Dimethacrylate-Induced Toxicity through the Inhibition of Caspase Activation and Reactive Oxygen Species Generation in Macrophages.
    Li-Chiu Yang, Yu-Chao Chang, Kun-Lin Yeh, Fu-Mei Huang, Ni-Yu Su, Yu-Hsiang Kuan.
      Rutin, also called quercetin-3-rhamnosyl glucoside, is a natural flavonol glycoside present in many plants. Rutin is used to treat various diseases, such as inflammation, diabetes, and cancer. For polymeric biomaterials, triethylene glycol dimethacrylate (TEGDMA) is the most commonly used monomer and serves as a restorative resin, a dentin bonding agent and sealant, and a bone cement component. Overall, TEGDMA induces various toxic effects in macrophages, including cytotoxicity, apoptosis, and genotoxicity. The aim of this study was to investigate the protective mechanism of rutin in alleviating TEGDMA-induced toxicity in RAW264.7 macrophages. After treatment with rutin, we assessed the cell viability and apoptosis of TEGDMA-induced RAW264.7 macrophages using an methylthiazol tetrazolium (MTT) assay and Annexin V-FITC/propidium iodide assay, respectively. Subsequently, we assessed the level of genotoxicity using comet and micronucleus assays, assessed the cysteinyla aspartate specific proteinases (caspases) and antioxidant enzyme (AOE) activity using commercial kits, and evaluated the generation of reactive oxygen species (ROS) using a dichlorodihydrofluorescein diacetate (DCFH-DA) assay. We evaluated the expression of heme oxygenase (HO)-1, the expression of nuclear factor erythroid 2 related factor (Nrf-2), and phosphorylation of AMP activated protein kinase (AMPK) using the Western blot assay. The results indicated that rutin substantially reduced the level of cytotoxicity, apoptosis, and genotoxicity of TEGDMA-induced RAW264.7 macrophages. Rutin also blocked the activity of caspase-3, caspase-8, and caspase-9 in TEGDMA-stimulated RAW264.7 macrophages. In addition, it decreased TEGDMA-induced ROS generation and AOE deactivation in macrophages. Finally, we found that TEGDMA-inhibited slightly the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation would be revered by rutin. In addition, the HO-1 expression, Nrf-2 expression, and AMPK phosphorylation was enhanced by rutin. These findings indicate that rutin suppresses TEGDMA-induced caspase-mediated toxic effects through ROS generation and antioxidative system deactivation through the Nrf-2/AMPK pathway. Therefore, rutin has the potential to serve as a novel antitoxicity agent for TEGDMA in RAW264.7 macrophages.
    Keywords:  TEGDMA; antioxidant system; apoptosis; cytotoxicity; genotoxicity; macrophage; reactive oxygen species; rutin
    DOI:  https://doi.org/10.3390/ijms231911773
  4. Sci Rep. 2022 Oct 12. 12(1): 17084
    Metformin alleviates neurocognitive impairment in aging via activation of AMPK/BDNF/PI3K pathway.
    Omnia Ameen, Rehab M Samaka, Reda A A Abo-Elsoud.
      Slowing down age-related neurocognitive impairment has been a challenge. We evaluated the therapeutic effects of metformin in D-galactose-induced aging. Additionally, we studied the potential molecular mechanisms that could be responsible for metformin's anti-aging effects. Thirty male rats were equally divided into: 1-control group, which received saline solution, 2-D-galactose (D-gal) group, which received D-galactose (100 mg/kg/day) by gastric lavage for eight weeks, and 3-D-galactose + Metformin (D-gal + Met) treated group, which received D-galactose + metformin (200 mg/kg/day) by gastric lavage for eight weeks. Neurocognitive assessment was done. Measurement of inflammatory, oxidative stress, and BDNF biomarkers was performed. AMPK and PI3K genes expression were assessed. Hippocampal tissues were dissected for histopathological and immunohistochemical studies. D-gal resulted in neurocognitive impairments, elevation of inflammatory biomarkers, altered oxidative stress markers, decreased BDNF, decreased expression of synaptophysin and Bcl2 with increased expression of Caspase-3, and down-regulation of AMPK and PI3K genes. Neurodegenerative changes were present in the hippocampus. Metformin restored significantly D-gal induced neurodegenerative changes. We concluded that metformin could alleviate age-induced neurocognitive deficit via amelioration of neuroinflammation, attenuation of oxidative stress, reduction of apoptosis, as well as promotion of synaptic plasticity. These mechanisms could be mediated via the activation of the AMPK/BDNF/PI3K pathway.
    DOI:  https://doi.org/10.1038/s41598-022-20945-7
  5. Biol Trace Elem Res. 2022 Oct 13.
    Magnesium Supplementation Stimulates Autophagy to Reduce Lipid Accumulation in Hepatocytes via the AMPK/mTOR Pathway.
    Shiyan Chen, Shunkui Luo, Baojia Zou, Jianhui Xie, Jian Li, Yingjuan Zeng.
      Metabolic-associated fatty liver disease (MAFLD) (previously known as nonalcoholic fatty liver disease (NAFLD)) is a disease with high worldwide prevalence, but with limited available therapeutic interventions. Autophagy is a cell survival mechanism for clearing excess lipids in hepatocytes and affects the occurrence and development of MAFLD. In addition, some studies have shown that magnesium deficiency is common in patients with obesity and metabolic syndrome. Magnesium supplementation can effectively improve metabolism-related diseases such as obesity and fatty liver. Our study successfully constructed a cellular model of MAFLD by 1 mM free fatty acid (FFA) intervention in LO2 cells for 24 h, and there was an increase in lipid accumulation in hepatocytes after FFA intervention. Magnesium supplementation was shown to reduce lipid deposition in hepatocytes induced by FFA, and Western blotting (WB) analysis showed that magnesium supplementation could downregulate the expression of Fasn and SREBP1 and increase the expression of LPL, suggesting that magnesium can reduce lipid accumulation by reducing lipid synthesis and increasing lipid oxidation. Magnesium supplementation could affect cellular lipid metabolism by activating the AMPK/mTOR pathway to stimulate autophagy. Our results identified a relationship between magnesium and lipid accumulation in hepatocytes and showed that magnesium supplementation reduced lipid deposition in hepatocytes by activating autophagy by activating the AMPK-mTOR pathway.
    Keywords:  Autophagy; Lipid metabolism; Magnesium; Metabolic-associated fatty liver disease
    DOI:  https://doi.org/10.1007/s12011-022-03438-6
  6. J Appl Physiol (1985). 2022 Oct 13.
    Metformin attenuates an increase of calcium-dependent and ubiquitin-proteasome markers in unloaded muscle.
    Svetlana P Belova, Ksenia Zaripova, Kristina Sharlo, Tatiana Y Kostrominova, Boris S Shenkman, Tatiana L Nemirovskaya.
      Current study tested a hypothesis that during skeletal muscle unloading, calcium-dependent signaling pathways, markers of protein synthesis and expression of E3 ubiquitin ligases can be regulated by metformin. Thirty-two male Wistar rats were randomly assigned into one of four groups: non-treated control (3C), control rats treated with metformin (3CM), 3 days of unloading/hindlimb suspension with placebo (3HS), and 3 days of unloading treated with metformin (3HSM). In soleus muscle of HS group level of phospho-AMPK (p-AMPK) was decreased by 46% while ATP content was increased by 49% when compared with the control group. There was an increase of the level of phospho-CaMK II (483%) and an up-regulation of CaN, SERCA2a, and Calpain-1 mRNA expression (87%, 41% and 62%, respectively, p<0.05) in the HS group relative to the control. HS group also had increased mRNA expression of MuRF1, MAFbx, and ubiquitin (167%, 146% and 191%, respectively, p<0.05) when compared to the control soleus muscle. Metformin treatment impeded unloading-induced changes in soleus muscle. Conclusions: metformin treatment during three days of soleus muscle unloading: 1) prevented the decrease of p-AMPK and increase of ATP content; 2) affected regulation of calcium-dependent signaling pathways via level of CaMK II phosphorylation or CaMK II, CaN, SERCA2a, and Calpain-1 mRNA expression; 3) attenuated an increase in the expression of critical markers of ubiquitin-proteasome pathways MuRF1, MAFbx, and ubiquitin while not affecting the unloading-induced increase of ULK-1 marker of autophagic/lysosomal pathway.
    Keywords:  AMPK; MAFbx; MuRF1; metformin; muscle unloading
    DOI:  https://doi.org/10.1152/japplphysiol.00415.2022
  7. Cells. 2022 Sep 27. pii: 3012. [Epub ahead of print]11(19):
    Metformin Prevents or Delays the Development and Progression of Osteoarthritis: New Insight and Mechanism of Action.
    Miao He, Bangbao Lu, Michael Opoku, Liang Zhang, Wenqing Xie, Hongfu Jin, Siyu Chen, Yusheng Li, Zhenhan Deng.
      For over 60 years, metformin has been widely prescribed by physicians to treat type 2 diabetes. Along with more in-depth research on metformin and its molecular mechanism in recent decades, metformin has also been proposed as an effective drug to prevent or delay musculoskeletal disorders, including osteoarthritis (OA). The occurrence and development of OA are deemed to be associated with the impaired mitochondrial functions of articular chondrocytes. Metformin can activate the pathways and expressions of both AMPK and SIRT1 so as to protect the mitochondrial function of chondrocytes, thereby promoting osteoblast production. Moreover, the clinical significance of the metformin combination therapy in preventing OA has also been demonstrated. This review aimed to comprehensively summarize the current research progress on metformin as a proposed drug for OA prevention or treatment.
    Keywords:  AMPK; SIRT1; metformin; osteoarthritis; type 2 diabetes
    DOI:  https://doi.org/10.3390/cells11193012
  8. Cardiovasc Diabetol. 2022 Oct 11. 21(1): 205
    Neuregulin-4 attenuates diabetic cardiomyopathy by regulating autophagy via the AMPK/mTOR signalling pathway.
    Hongchao Wang, Lijie Wang, Fuli Hu, Pengfei Wang, Yanan Xie, Fang Li, Bingyan Guo.
      BACKGROUND: Diabetic cardiomyopathy is characterized by left ventricle dysfunction, cardiomyocyte apoptosis, and interstitial fibrosis and is a serious complication of diabetes mellitus (DM). Autophagy is a mechanism that is essential for maintaining normal heart morphology and function, and its dysregulation can produce pathological effects on diabetic hearts. Neuregulin-4 (Nrg4) is an adipokine that exerts protective effects against metabolic disorders and insulin resistance. The aim of this study was to explore whether Nrg4 could ameliorate DM-induced myocardial injury by regulating autophagy.METHODS: Four weeks after the establishment of a model of type 1 diabetes in mice, the mice received Nrg4 treatment (with or without an autophagy inhibitor) for another 4 weeks. The cardiac functions, histological structures and cardiomyocyte apoptosis were investigated. Autophagy-related protein levels along with related signalling pathways that regulate autophagy were evaluated. In addition, the effects of Nrg4 on autophagy were also determined in cultured primary cardiomyocytes.
    RESULTS: Nrg4 alleviated myocardial injury both in vivo and in vitro. The autophagy level was decreased in type 1 diabetic mice, and Nrg4 intervention reactivated autophagy. Furthermore, Nrg4 intervention was found to activate autophagy via the AMPK/mTOR signalling pathway. Moreover, when autophagy was suppressed or the AMPK/mTOR pathway was inhibited, the beneficial effects of Nrg4 were diminished.
    CONCLUSION: Nrg4 intervention attenuated diabetic cardiomyopathy by promoting autophagy in type 1 diabetic mice. Additionally, Nrg4 induced autophagy via the AMPK/mTOR signalling pathway.
    Keywords:  Autophagy; Diabetic cardiomyopathy; Neuregulin-4; Signalling pathway
    DOI:  https://doi.org/10.1186/s12933-022-01643-0
  9. Biochem Biophys Res Commun. 2022 Oct 04. pii: S0006-291X(22)01386-9. [Epub ahead of print]632 195-203
    Exosomes derived from human umbilical cord mesenchymal stem cells (HUCMSC-EXO) regulate autophagy through AMPK-ULK1 signaling pathway to ameliorate diabetic cardiomyopathy.
    Zhiqiang Zhang, Lei Chen, Xueheng Chen, Yiran Qin, Chao Tian, Xuening Dai, Runqi Meng, Yuanyuan Zhong, Wenyan Liang, Cheng Shen, Jinguo Zhang, Bin Zhang, Xiqing Wei.
      One of the main causes of severe diabetic heart failure and mortality is diabetic cardiomyopathy (DCM), a cardiovascular condition attributable to diabetes with a high incidence, a complicated and unexplained pathophysiology, and poor treatment results. Current findings have demonstrated that the onset of diabetic cardiomyopathy involves autophagy, inflammation, and mitochondrial damage. Myocardial autophagy behaves differently in different states,and one of the targets for the detection and treatment of cardiovascular illnesses like diabetic cardiomyopathy may be the control of autophagy. The role of human umbilical cord Mesenchymal stem cells-derived exosomes (HUCMSC-EXO) as a non-cellular system in the repair of cardiomyocytes, the evolution of diabetic cardiomyopathy and their cardioprotective effects are gradually being recognized. This study's objectives were to assess the therapeutic benefits of HUCMSC-EXO for diabetic cardiomyopathy and to look into their potential mechanisms of action. High-speed centrifugation was used to extract HUCMSC-EXO, and the shape of the exosomes was examined using transmission electron microscopy. Immunoblotting was used to determine the expression of CD9, CD63, and TSG101 molecules on the surface of the exosomes. A high-fat, high-sugar diet mixed with streptozotocin was used to build a rat model of type 2 diabetic cardiomyopathy. Cardiac function, ventricular wall thickness and cardiac histological changes were examined by cardiac ultrasound, serum BNP and histology. In cardiac myocytes, HUCMSC-EXO reduced the levels of autophagy-related protein expression. Additionally, immunoblotting supported our suspicion that this mechanism is strongly tied to the activation of the AMPK-ULK1 signaling pathway. So, we propose that it would be a good strategy to follow for treating diabetic cardiomyopathy. These findings offer both fresh concepts for building a model of diabetic cardiomyopathy and a creative theoretical framework for using HUCMSC-EXO to treat diabetic cardiomyopathy in a clinical setting.
    Keywords:  AMPK-ULK1; Autophagy; Diabetic cardiomyopathy; HUCMSC-Derived exosomes
    DOI:  https://doi.org/10.1016/j.bbrc.2022.10.001
  10. Mol Metab. 2022 Oct 11. pii: S2212-8778(22)00182-X. [Epub ahead of print] 101613
    SGLT2i reduces renal injury by improving mitochondrial metabolism and biogenesis.
    Xiaojie Peng, Shuze Chen, Ying Wang, Ming Jin, Fen Mei, Yun Bao, Xixian Liao, Ye Chen, Wei Gong.
      OBJECTIVES: Despite advances in treatment, an effective therapeutic strategy for acute kidney injury (AKI) is still lacking. Considering the widely reported clinical benefits of canagliflozin in the kidneys, we assessed the effects of canagliflozin on AKI.METHODS: Lipopolysaccharide was used to induce AKI in the presence of canagliflozin.
    RESULTS: Canagliflozin treatment reduced blood urea nitrogen and serum creatinine levels and improved the renal tubular structure in mice with lipopolysaccharide-induced septic AKI. Canagliflozin also suppressed the inflammatory response, oxidative stress and tubular cell death in the kidneys during septic AKI. In vitro, canagliflozin supplementation maintained mitochondrial function in lipopolysaccharide-treated HK-2 cells by restoring the mitochondrial membrane potential, inhibiting mitochondrial reactive oxygen species production and normalizing mitochondrial respiratory complex activity. In HK-2 cells, canagliflozin stimulated the adenosine monophosphate-activated protein kinase catalytic subunit alpha 1 (AMPKα1)/peroxisome proliferator-activated receptor-gamma coactivator 1 alpha (PGC1α)/nuclear respiratory factor 1 (NRF1) pathway, thus elevating the number of live and healthy mitochondria following lipopolysaccharide treatment. Inhibition of the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway abolished the protective effects of canagliflozin on renal cell mitochondria and tubular viability. Similarly, the protective effects of canagliflozin on kidney function and tubular structure were abrogated in AMPKα1-knockout mice.
    CONCLUSION: Canagliflozin could be used to treat septic AKI by activating the AMPKα1/PGC1α/NRF1/mitochondrial biogenesis pathway.
    Keywords:  AMPKα1/PGC1α/NRF1 pathway; Canagliflozin; mitochondria; mitochondrial biogenesis pathways; septic AKI
    DOI:  https://doi.org/10.1016/j.molmet.2022.101613
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