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Minocycline promotes cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy to prevent sepsis-induced cardiac dysfunction by Akt/mTOR signaling

  • Erfei Zhang
  • Xiaoying Zhao
  • Li Zhang
  • Nan Li
  • Jinqi Yan
  • Ke Tu
  • Ruhu Yan
  • Jianqiang Hu
  • Mingming Zhang
  • Dongdong SunEmail author
  • Lichao HouEmail author


Myocardial damage is responsible for the high mortality of sepsis. However, the underlying mechanism is not well understood. Cardiomyocyte autophagy alleviates the cardiac injury caused by myocardial infarction. Enhanced cardiomyocyte autophagy also has protective effects against cardiomyocyte mitochondrial injury. Minocycline enhances autophagy in many types of cells under different types of pathological stress and can be easily taken up by cardiomyocytes. The present study investigated whether minocycline prevented myocardial injury caused by sepsis and whether cardiomyocyte autophagy participated in this process. The results indicated that minocycline enhanced cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy and improved myocardial mitochondrial and cardiac function. Minocycline upregulated protein kinase B (Akt) phosphorylation, inhibited mTORC1 expression and enhanced mTORC2 expression. In conclusion, minocycline enhanced cardiomyocyte mitochondrial autophagy and cardiomyocyte autophagy and improved cardiac function. The underlying mechanisms were associated with mTORC1 inhibition and mTORC2 activation. Thus, our findings suggest that minocycline may represent a potential approach for treating myocardial injury and provide novel insights into the underlying mechanisms of myocardial injury and dysfunction after sepsis.


Minocycline Sepsis Cardiomyocyte mitochondrial autophagy Cardiomyocyte autophagy Cardiac dysfunction 



This work was supported by the National Natural Science Foundation of China (Grant No. 81670204); National Natural Science Foundation of China (Grant No. 81171839); Funding of Xiamen University (Grant No. 20720170106).

Author Contributions

Dongdong Sun, Lichao Hou, Erfei Zhang, and Xiaoying Zhao designed the experiments, analyzed and interpreted the data and drafted the manuscript. Li Zhang, Nan Li, Jingqi Yan, Ke Tu, Ruhu Yan, Jianqiang Hu and Mingming Zhang, were involved in the data acquisition. All authors revised the manuscript critically and approved the final version to be published. Dongdong Sun and Lichao Hou are responsible for the integrity of the work as a whole.

Compliance with Ethical Standards

Conflict of interest

The authors declare that there is no duality of interest associated with this manuscript.

Supplementary material

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  1. 1.
    Seymour CW, Liu VX, Iwashyna TJ et al (2016) Assessment of clinical criteria for sepsis: for the third international consensus definitions for sepsis and septic shock (Sepsis-3). JAMA 315(8):762–774Google Scholar
  2. 2.
    Zhou J, Qian C, Zhao M et al (2014) Epidemiology and outcome of severe sepsis and septic shock in intensive care units in mainland china. PLoS ONE 9(9):e107181Google Scholar
  3. 3.
    Vieillard-Baron A, Caille V, Charron C et al (2008) Actual incidence of global left ventricular hypokinesia in adult septic shock. Crit Care Med 36(6):1701–1706Google Scholar
  4. 4.
    Frencken JF, Donker DW, Spitoni C et al (2018) Myocardial injury in patients with sepsis and its association with long-term outcome. Circ Cardiovasc Qual Outcomes 11(2):e004040Google Scholar
  5. 5.
    Han D, Li X, Li S et al (2017) Reduced silent information regulator 1 signaling exacerbates sepsis-induced myocardial injury and mitigates the protective effect of a liver X receptor agonist. Free Radic Biol Med 113:291–303Google Scholar
  6. 6.
    Martin L, Peters C, Heinbockel L et al (2016) The synthetic antimicrobial peptide 19–2.5 attenuates mitochondrial dysfunction in cardiomyocytes stimulated with human sepsis serum. Innate Immun 22(8):612–619Google Scholar
  7. 7.
    Shirakabe A, Zhai P, Ikeda Y et al (2016) Drp1-dependent mitochondrial autophagy plays a protective role against pressure overload-induced mitochondrial dysfunction and heart failure. Circulation 133(13):1249–1263Google Scholar
  8. 8.
    Zhang L, Huang P, Chen H et al (2017) The inhibitory effect of minocycline on radiation-induced neuronal apoptosis via AMPKalpha1 signaling-mediated autophagy. Sci Rep 7(1):16373Google Scholar
  9. 9.
    Dong W, Xiao S, Cheng M et al (2016) Minocycline induces protective autophagy in vascular endothelial cells exposed to an in vitro model of ischemia/reperfusion-induced injury. Biomed Rep 4(2):173–177Google Scholar
  10. 10.
    Romero-Perez D, Fricovsky E, Yamasaki KG et al (2008) Cardiac uptake of minocycline and mechanisms for in vivo cardioprotection. J Am Coll Cardiol 52(13):1086–1094Google Scholar
  11. 11.
    Boutouja F, Stiehm CM, Platta HW (2019) mTOR: a cellular regulator interface in health and disease. Cells 8(1):1–23Google Scholar
  12. 12.
    Ataie-Kachoie P, Pourgholami MH, Bahrami BF et al (2015) Minocycline attenuates hypoxia-inducible factor-1alpha expression correlated with modulation of p53 and AKT/mTOR/p70S6K/4E-BP1 pathway in ovarian cancer: in vitro and in vivo studies. Am J Cancer Res 5(2):575–588Google Scholar
  13. 13.
    Zhang EF, Hou ZX, Shao T et al (2017) Combined administration of a sedative dose sevoflurane and 60% oxygen reduces inflammatory responses to sepsis in animals and in human PMBCs. Am J Transl Res 9(6):3105–3119Google Scholar
  14. 14.
    Hu J, Man W, Shen M et al (2016) Luteolin alleviates post-infarction cardiac dysfunction by up-regulating autophagy through Mst1 inhibition. J Cell Mol Med 20(1):147–156Google Scholar
  15. 15.
    Cheng NT, Meng H, Ma LF et al (2017) Role of autophagy in the progression of osteoarthritis: the autophagy inhibitor, 3-methyladenine, aggravates the severity of experimental osteoarthritis. Int J Mol Med 39(5):1224–1232Google Scholar
  16. 16.
    Zhang M, Zhang L, Hu J et al (2016) MST1 coordinately regulates autophagy and apoptosis in diabetic cardiomyopathy in mice. Diabetologia 59(11):2435–2447Google Scholar
  17. 17.
    Wang T, Zhang L, Hu J et al (2016) Mst1 participates in the atherosclerosis progression through macrophage autophagy inhibition and macrophage apoptosis enhancement. J Mol Cell Cardiol 98:108–116Google Scholar
  18. 18.
    Vives-Bauza C, Starkov A, Garcia-Arumi E (2007) Measurements of the antioxidant enzyme activities of superoxide dismutase, catalase, and glutathione peroxidase. Methods Cell Biol 80:379–393Google Scholar
  19. 19.
    Sun D, Li S, Wu H et al (2015) Oncostatin M (OSM) protects against cardiac ischaemia/reperfusion injury in diabetic mice by regulating apoptosis, mitochondrial biogenesis and insulin sensitivity. J Cell Mol Med 19(6):1296–1307Google Scholar
  20. 20.
    Yamashita SI, Kanki T (2017) How autophagy eats large mitochondria: autophagosome formation coupled with mitochondrial fragmentation. Autophagy 13(5):980–981Google Scholar
  21. 21.
    Saxton RA, Sabatini DM (2017) mTOR Signaling in growth, metabolism, and disease. Cell 168(6):960–976Google Scholar
  22. 22.
    Chen D, Lin X, Zhang C et al (2018) Dual PI3K/mTOR inhibitor BEZ235 as a promising therapeutic strategy against paclitaxel-resistant gastric cancer via targeting PI3K/Akt/mTOR pathway. Cell Death Dis 9(2):123Google Scholar
  23. 23.
    Kundu M (2014) Too sweet for autophagy: hexokinase inhibition of mTORC1 activates autophagy. Mol Cell 53(4):517–518Google Scholar
  24. 24.
    Lampada A, O’Prey J, Szabadkai G et al (2017) mTORC1-independent autophagy regulates receptor tyrosine kinase phosphorylation in colorectal cancer cells via an mTORC2-mediated mechanism. Cell Death Differ 24(6):1045–1062Google Scholar
  25. 25.
    Lin YC, Kuo HC, Wang JS et al (2012) Regulation of inflammatory response by 3-methyladenine involves the coordinative actions on Akt and glycogen synthase kinase 3beta rather than autophagy. J Immunol 189(8):4154–4164Google Scholar
  26. 26.
    Huang CH, Tsai MS, Chiang CY et al (2015) Activation of mitochondrial STAT-3 and reduced mitochondria damage during hypothermia treatment for post-cardiac arrest myocardial dysfunction. Basic Res Cardiol 110(6):59Google Scholar
  27. 27.
    Doerrier C, Garcia JA, Volt H et al (2016) Permeabilized myocardial fibers as model to detect mitochondrial dysfunction during sepsis and melatonin effects without disruption of mitochondrial network. Mitochondrion 27:56–63Google Scholar
  28. 28.
    Soriano FG, Nogueira AC, Caldini EG et al (2006) Potential role of poly(adenosine 5′-diphosphate-ribose) polymerase activation in the pathogenesis of myocardial contractile dysfunction associated with human septic shock. Crit Care Med 34(4):1073–1079Google Scholar
  29. 29.
    Barile L, Lionetti V, Cervio E et al (2014) Extracellular vesicles from human cardiac progenitor cells inhibit cardiomyocyte apoptosis and improve cardiac function after myocardial infarction. Cardiovasc Res 103(4):530–541Google Scholar
  30. 30.
    Thomas HE, Zhang Y, Stefely JA et al (2018) Mitochondrial complex I activity is required for maximal autophagy. Cell Rep 24(9):2404–2417.e2408Google Scholar
  31. 31.
    Liu Z, Liang Y, Wang H et al (2017) LncRNA expression in the spinal cord modulated by minocycline in a mouse model of spared nerve injury. J Pain Res 10:2503–2514Google Scholar
  32. 32.
    Liu WT, Lin CH, Hsiao M et al (2011) Minocycline inhibits the growth of glioma by inducing autophagy. Autophagy 7(2):166–175Google Scholar
  33. 33.
    Zhang J, He Z, Xiao W et al (2016) Overexpression of BAG3 attenuates hypoxia-induced cardiomyocyte apoptosis by inducing autophagy. Cell Physiol Biochem 39(2):491–500Google Scholar
  34. 34.
    Wang L, Li Y, Ning N et al (2018) Decreased autophagy induced by beta1-adrenoceptor autoantibodies contributes to cardiomyocyte apoptosis. Cell Death Dis 9(3):406Google Scholar
  35. 35.
    Guichard JL, Rogowski M, Agnetti G et al (2017) Desmin loss and mitochondrial damage precede left ventricular systolic failure in volume overload heart failure. Am J Physiol Heart Circ Physiol 313(1):H32–Hh45Google Scholar
  36. 36.
    Ma LL, Ma X, Kong FJ et al (2018) Mammalian target of rapamycin inhibition attenuates myocardial ischaemia-reperfusion injury in hypertrophic heart. J Cell Mol Med 22(3):1708–1719Google Scholar
  37. 37.
    Schiattarella GG, Hill JA (2016) Therapeutic targeting of autophagy in cardiovascular disease. J Mol Cell Cardiol 95:86–93Google Scholar
  38. 38.
    Song HP, Chu ZG, Zhang DX et al (2018) PI3K-AKT pathway protects cardiomyocytes against hypoxia-induced apoptosis by MitoKATP-mediated mitochondrial translocation of pAKT. Cell Physiol Biochem 49(2):717–727Google Scholar
  39. 39.
    Lawlor MA, Alessi DR (2001) PKB/Akt: a key mediator of cell proliferation, survival and insulin responses? J Cell Sci 114(Pt 16):2903–2910Google Scholar
  40. 40.
    Zhang D, Contu R, Latronico MV et al (2010) MTORC1 regulates cardiac function and myocyte survival through 4E-BP1 inhibition in mice. J Clin Invest 120(8):2805–2816Google Scholar
  41. 41.
    Bulley SJ, Droubi A, Clarke JH et al (2016) In B cells, phosphatidylinositol 5-phosphate 4-kinase-alpha synthesizes PI(4,5)P2 to impact mTORC2 and Akt signaling. Proc Natl Acad Sci USA 113(38):10571–10576Google Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Department of Anesthesiology and Critical Care Medicine, Xijing HospitalThe Fourth Military Medical UniversityXi’anPeople’s Republic of China
  2. 2.Department of AnesthesiologyThe Affiliated Hospital of Yan’an UniversityYan’anPeople’s Republic of China
  3. 3.Department of AnesthesiologySecond Hospital of Shanxi Medical UniversityTaiyuanPeople’s Republic of China
  4. 4.Department of CardiologyXijing Hospital, Fourth Military Medical UniversityXi’anPeople’s Republic of China
  5. 5.Department of CardiologyTangdu Hospital, Fourth Military Medical UniversityXi’anPeople’s Republic of China
  6. 6.Xiang’an Hospital of Xiamen UniversityXiamenPeople’s Republic of China

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