Skip to main content

Advertisement

SpringerLink
Log in

The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging

  • Published:
Stem Cell Reviews and Reports Aims and scope Submit manuscript

Summary

Age-related tendon disorders are closely linked with tendon stem/progenitor cell (TSPC) senescence. However, the underlying mechanisms of TSPC senescence and promising therapeutic strategies for rejuvenation of TSPC senescence remain unclear. In this study, the senescent state of TSPCs increased with age. It was also verified that the AMPK inhibition/mTOR activation is correlated with the senescent state of TSPCs. Furthermore, a low dose of metformin mitigated TSPC senescence and restored senescence-related functions, including proliferation, colony-forming ability, migration ability and tenogenic differentiation ability at the early stage of aging. The protective effects of metformin on TSPCs were regulated through the AMPK/mTOR axis. An in vivo study showed that metformin treatment postpones tendon aging and enhances AMPK phosphorylation but reduces mTOR phosphorylation in a natural aging rat model. Our study revealed new insight and mechanistic exploration of TSPC senescence and proposed a novel therapeutic treatment for age-related tendon disorders by targeting the AMPK/mTOR axis at the early stage of aging.

Graphical Abstract

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7

Similar content being viewed by others

Data Availability

All data and materials generated and analyzed during the present study are available from the corresponding author on reasonable request.

References

  1. Lui, P. P. Y., & Wong, C. M. (2019). Biology of Tendon Stem cells and Tendon in Aging. Frontiers In Genetics, 10, 1338.

    CAS  PubMed  Google Scholar 

  2. Dai, G., Li, Y., Liu, J., Zhang, C., Chen, M., Lu, P., & Rui, Y. (2020). Higher BMP expression in Tendon Stem/Progenitor cells contributes to the increased heterotopic ossification in Achilles Tendon with Aging. Front Cell Dev Biol, 8, 570605.

    PubMed  PubMed Central  Google Scholar 

  3. Li, Y., Dai, G., Shi, L., Lin, Y., Chen, M., Li, G., & Rui, Y. (2019). The potential roles of Tendon Stem/Progenitor cells in Tendon Aging. Curr Stem Cell Res Ther, 14, 34–42.

    CAS  PubMed  Google Scholar 

  4. Dai, G. C., Li, Y. J., Chen, M. H., Lu, P. P., & Rui, Y. F. (2019). Tendon stem/progenitor cell ageing: Modulation and rejuvenation. World J Stem Cells, 11, 677–692.

    PubMed  PubMed Central  Google Scholar 

  5. Rui, Y. F., Chen, M. H., Li, Y. J., Xiao, L. F., Geng, P., Wang, P., Xu, Z. Y., Zhang, X. P., & Dai, G. C. (2019). CTGF Attenuates Tendon-Derived Stem/Progenitor Cell Aging. Stem Cells Int 2019:6257537.

  6. Nie, D., Zhang, J., Zhou, Y., Sun, J., Wang, W., & Wang, J. H. (2021). Rapamycin Treatment of Tendon Stem/Progenitor Cells Reduces Cellular Senescence by Upregulating Autophagy. Stem Cells Int 2021:6638249.

  7. Han, W., Wang, B., Liu, J., & Chen, L. (2017). The p16/miR-217/EGR1 pathway modulates age-related tenogenic differentiation in tendon stem/progenitor cells. Acta Biochimica Et Biophysica Sinica (Shanghai), 49, 1015–1021.

    CAS  Google Scholar 

  8. Kiderlen, S., Polzer, C., Radler, J. O., Docheva, D., Clausen-Schaumann, H., & Sudhop, S. (2019). Age related changes in cell stiffness of tendon stem/progenitor cells and a rejuvenating effect of ROCK-inhibition. Biochemical And Biophysical Research Communications, 509, 839–844.

    CAS  PubMed  Google Scholar 

  9. Jiang, D., Xu, B., & Gao, P. (2018). Effects of young extracellular matrix on the biological characteristics of aged tendon stem cells. Adv Clin Exp Med, 27, 1625–1630.

    PubMed  Google Scholar 

  10. Lopez-Otin, C., Blasco, M. A., Partridge, L., Serrano, M., & Kroemer, G. (2023). Hallmarks of aging: An expanding universe. Cell, 186, 243–278.

    CAS  PubMed  Google Scholar 

  11. Mico, V., Berninches, L., Tapia, J., & Daimiel, L. (2017). NutrimiRAging: Micromanaging Nutrient Sensing Pathways through Nutrition to Promote Healthy Aging. Int J Mol Sci18.

  12. Lopez, M., Nogueiras, R., Tena-Sempere, M., & Dieguez, C. (2016). Hypothalamic AMPK: A canonical regulator of whole-body energy balance. Nature Reviews. Endocrinology, 12, 421–432.

    CAS  PubMed  Google Scholar 

  13. Morsczeck, C. (2019). Cellular senescence in dental pulp stem cells. Archives Of Oral Biology, 99, 150–155.

    CAS  PubMed  Google Scholar 

  14. White, J. P., Billin, A. N., Campbell, M. E., Russell, A. J., Huffman, K. M., & Kraus, W. E. (2018). The AMPK/p27(Kip1) Axis regulates Autophagy/Apoptosis decisions in aged skeletal muscle stem cells. Stem Cell Reports, 11, 425–439.

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Kaeberlein, M., & Kapahi, P. (2009). Cell signaling. Aging is RSKy business. Science, 326, 55–56.

    CAS  PubMed  Google Scholar 

  16. Zhang, L., Zhou, F., Yu, X., Zhu, Y., Zhou, Y., Liu, J., Liu, Y., Ma, Q., Zhang, Y., Wang, W., & Chen, N. (2019). C/EBPalpha deficiency in podocytes aggravates podocyte senescence and kidney injury in aging mice. Cell Death And Disease, 10, 684.

    PubMed  PubMed Central  Google Scholar 

  17. Gonzalez, A., Hall, M. N., Lin, S. C., & Hardie, D. G. (2020). AMPK and TOR: The Yin and Yang of Cellular Nutrient Sensing and Growth Control. Cell Metab, 31, 472–492.

    CAS  PubMed  Google Scholar 

  18. Donato, A. J., Morgan, R. G., Walker, A. E., & Lesniewski, L. A. (2015). Cellular and molecular biology of aging endothelial cells. Journal Of Molecular And Cellular Cardiology, 89, 122–135.

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Iglesias, M., Felix, D. A., Gutierrez-Gutierrez, O., De Miguel-Bonet, M. D. M., Sahu, S., Fernandez-Varas, B., Perona, R., Aboobaker, A. A., Flores, I., & Gonzalez-Estevez, C. (2019). Downregulation of mTOR Signaling increases Stem Cell Population Telomere length during starvation of Immortal Planarians. Stem Cell Reports, 13, 405–418.

    CAS  PubMed  PubMed Central  Google Scholar 

  20. Zhang, D., Lu, H., Chen, Z., Wang, Y., Lin, J., Xu, S., Zhang, C., Wang, B., Yuan, Z., Feng, X., Jiang, X., & Pan, J. (2017). High glucose induces the aging of mesenchymal stem cells via Akt/mTOR signaling. Molecular Medicine Reports, 16, 1685–1690.

    CAS  PubMed  PubMed Central  Google Scholar 

  21. Zhang, S., Zhang, R., Qiao, P., Ma, X., Lu, R., Wang, F., Li, C., E L and, & Liu, H. (2021). Metformin-Induced MicroRNA-34a-3p Downregulation Alleviates Senescence in Human Dental Pulp Stem Cells by Targeting CAB39 through the AMPK/mTOR Signaling Pathway. Stem Cells Int 2021:6616240.

  22. Fang, J., Yang, J., Wu, X., Zhang, G., Li, T., Wang, X., Zhang, H., Wang, C. C., Liu, G. H., & Wang, L. (2018). Metformin alleviates human cellular aging by upregulating the endoplasmic reticulum glutathione peroxidase 7. Aging Cell, 17, e12765.

    PubMed  PubMed Central  Google Scholar 

  23. Barzilai, N., Crandall, J. P., Kritchevsky, S. B., & Espeland, M. A. (2016). Metformin as a Tool to target aging. Cell Metab, 23, 1060–1065.

    CAS  PubMed  PubMed Central  Google Scholar 

  24. Martin-Montalvo, A., Mercken, E. M., Mitchell, S. J., Palacios, H. H., Mote, P. L., Scheibye-Knudsen, M., Gomes, A. P., Ward, T. M., Minor, R. K., Blouin, M. J., Schwab, M., Pollak, M., Zhang, Y., Yu, Y., Becker, K. G., Bohr, V. A., Ingram, D. K., Sinclair, D. A., Wolf, N. S., Spindler, S. R., Bernier, M., & de Cabo, R. (2013). Metformin improves healthspan and lifespan in mice. Nature Communications, 4, 2192.

    PubMed  Google Scholar 

  25. Green, C. L., Lamming, D. W., & Fontana, L. (2022). Molecular mechanisms of dietary restriction promoting health and longevity. Nature Reviews Molecular Cell Biology, 23, 56–73.

    CAS  PubMed  Google Scholar 

  26. Carmona, J. J., & Michan, S. (2016). Biology of healthy aging and longevity. Revista De Investigacion Clinica, 68, 7–16.

    CAS  PubMed  Google Scholar 

  27. Ala, M., & Ala, M. (2021). Metformin for Cardiovascular Protection, Inflammatory Bowel Disease, osteoporosis, Periodontitis, Polycystic Ovarian Syndrome, Neurodegeneration, Cancer, inflammation and senescence: What is next? ACS Pharmacol Transl Sci, 4, 1747–1770.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Darzynkiewicz, Z., Zhao, H., Halicka, H. D., Li, J., Lee, Y. S., Hsieh, T. C., & Wu, J. M. (2014). In search of antiaging modalities: Evaluation of mTOR- and ROS/DNA damage-signaling by cytometry. Cytometry. Part A, 85, 386–399.

    Google Scholar 

  29. Dong, D., Cai, G. Y., Ning, Y. C., Wang, J. C., Lv, Y., Hong, Q., Cui, S. Y., Fu, B., Guo, Y. N., & Chen, X. M. (2017). Alleviation of senescence and epithelial-mesenchymal transition in aging kidney by short-term caloric restriction and caloric restriction mimetics via modulation of AMPK/mTOR signaling. Oncotarget, 8, 16109–16121.

    PubMed  PubMed Central  Google Scholar 

  30. Feng, X., Pan, J., Li, J., Zeng, C., Qi, W., Shao, Y., Liu, X., Liu, L., Xiao, G., Zhang, H., Bai, X., & Cai, D. (2020). Metformin attenuates cartilage degeneration in an experimental osteoarthritis model by regulating AMPK/mTOR. Aging (Albany NY), 12, 1087–1103.

    CAS  PubMed  Google Scholar 

  31. Jang, S. G., Lee, J., Hong, S. M., Kwok, S. K., Cho, M. L., & Park, S. H. (2020). Metformin enhances the immunomodulatory potential of adipose-derived mesenchymal stem cells through STAT1 in an animal model of lupus. Rheumatology (Oxford), 59, 1426–1438.

    CAS  PubMed  Google Scholar 

  32. Yang, Z., Gao, X., Zhou, M., Kuang, Y., Xiang, M., Li, J., & Song, J. (2019). Effect of metformin on human periodontal ligament stem cells cultured with polydopamine-templated hydroxyapatite. European Journal Of Oral Sciences, 127, 210–221.

    CAS  PubMed  Google Scholar 

  33. Rui, Y. F., Lui, P. P., Li, G., Fu, S. C., Lee, Y. W., & Chan, K. M. (2010). Isolation and characterization of multipotent rat tendon-derived stem cells. Tissue Engineering Part A, 16, 1549–1558.

    CAS  PubMed  Google Scholar 

  34. Chen, J., Zhang, W., Liu, Z., Zhu, T., Shen, W., Ran, J., Tang, Q., Gong, X., Backman, L. J., Chen, X., Chen, X., Wen, F., & Ouyang, H. (2016). Characterization and comparison of post-natal rat Achilles tendon-derived stem cells at different development stages. Scientific Reports, 6, 22946.

    CAS  PubMed  PubMed Central  Google Scholar 

  35. Zhang, B., Luo, Q., Deng, B., Morita, Y., Ju, Y., & Song, G. (2018). Construction of tendon replacement tissue based on collagen sponge and mesenchymal stem cells by coupled mechano-chemical induction and evaluation of its tendon repair abilities. Acta Biomaterialia, 74, 247–259.

    CAS  PubMed  Google Scholar 

  36. Mihaylova, M. M., & Shaw, R. J. (2011). The AMPK signalling pathway coordinates cell growth, autophagy and metabolism. Nature Cell Biology, 13, 1016–1023.

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Saxton, R. A., & Sabatini, D. M. (2017). mTOR Signaling in Growth, Metabolism, and Disease. Cell, 168, 960–976.

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Xu, J., Ji, J., & Yan, X. H. (2012). Cross-talk between AMPK and mTOR in regulating energy balance. Critical Reviews In Food Science And Nutrition, 52, 373–381.

    CAS  PubMed  Google Scholar 

  39. Anisimov, V. N., Berstein, L. M., Popovich, I. G., Zabezhinski, M. A., Egormin, P. A., Piskunova, T. S., Semenchenko, A. V., Tyndyk, M. L., Yurova, M. N., Kovalenko, I. G., & Poroshina, T. E. (2011). If started early in life, metformin treatment increases life span and postpones tumors in female SHR mice. Aging (Albany NY), 3, 148–157.

    CAS  PubMed  Google Scholar 

  40. Karnewar, S., Neeli, P. K., Panuganti, D., Kotagiri, S., Mallappa, S., Jain, N., Jerald, M. K., & Kotamraju, S. (2018). Metformin regulates mitochondrial biogenesis and senescence through AMPK mediated H3K79 methylation: Relevance in age-associated vascular dysfunction. Biochim Biophys Acta Mol Basis Dis, 1864, 1115–1128.

    CAS  PubMed  Google Scholar 

  41. Fu, J., Zhang, J., Jiang, T., Ao, X., Li, P., Lian, Z., Li, C., Zhang, X., Liu, J., Huang, M., Zhang, Z., & Wang, L. (2022). mTORC1 coordinates NF-kappaB signaling pathway to promote chondrogenic differentiation of tendon cells in heterotopic ossification. Bone, 163, 116507.

    CAS  PubMed  Google Scholar 

  42. He, X., Yao, M. W., Zhu, M., Liang, D. L., Guo, W., Yang, Y., Zhao, R. S., Ren, T. T., Ao, X., Wang, W., Zeng, C. Y., Liang, H. P., Jiang, D. P., Yu, J., & Xu, X. (2018). Metformin induces apoptosis in mesenchymal stromal cells and dampens their therapeutic efficacy in infarcted myocardium. Stem Cell Research & Therapy, 9, 306.

    CAS  Google Scholar 

  43. Chen, M., Li, Y., Xiao, L., Dai, G., Lu, P., Wang, Y., & Rui, Y. (2020). AQP1 modulates tendon stem/progenitor cells senescence during tendon aging. Cell Death And Disease, 11, 193.

    PubMed  PubMed Central  Google Scholar 

  44. Kohler, J., Popov, C., Klotz, B., Alberton, P., Prall, W. C., Haasters, F., Muller-Deubert, S., Ebert, R., Klein-Hitpass, L., Jakob, F., Schieker, M., & Docheva, D. (2013). Uncovering the cellular and molecular changes in tendon stem/progenitor cells attributed to tendon aging and degeneration. Aging Cell, 12, 988–999.

    CAS  PubMed  Google Scholar 

  45. Tan, Q., Lui, P. P., & Rui, Y. F. (2012). Effect of in vitro passaging on the stem cell-related properties of tendon-derived stem cells-implications in tissue engineering. Stem Cells And Development, 21, 790–800.

    CAS  PubMed  Google Scholar 

  46. Ruzzini, L., Abbruzzese, F., Rainer, A., Longo, U. G., Trombetta, M., Maffulli, N., & Denaro, V. (2014). Characterization of age-related changes of tendon stem cells from adult human tendons. Knee Surgery, Sports Traumatology, Arthroscopy, 22, 2856–2866.

    PubMed  Google Scholar 

  47. Menendez, J. A., Joven, J., Aragones, G., Barrajon-Catalan, E., Beltran-Debon, R., Borras-Linares, I., Camps, J., Corominas-Faja, B., Cufi, S., Fernandez-Arroyo, S., Garcia-Heredia, A., Hernandez-Aguilera, A., Herranz-Lopez, M., Jimenez-Sanchez, C., Lopez-Bonet, E., Lozano-Sanchez, J., Luciano-Mateo, F., Martin-Castillo, B., Martin-Paredero, V., Perez-Sanchez, A., Oliveras-Ferraros, C., Riera-Borrull, M., Rodriguez-Gallego, E., Quirantes-Pine, R., Rull, A., Tomas-Menor, L., Vazquez-Martin, A., Alonso-Villaverde, C., Micol, V., & Segura-Carretero, A. (2013). Xenohormetic and anti-aging activity of secoiridoid polyphenols present in extra virgin olive oil: A new family of gerosuppressant agents. Cell Cycle, 12, 555–578.

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Zhang, J., Lin, Y., Dai, X., Fang, W., Wu, X., & Chen, X. (2019). Metformin treatment improves the spatial memory of aged mice in an APOE genotype-dependent manner. The Faseb Journal, 33, 7748–7757.

    CAS  PubMed  Google Scholar 

  49. Bahrambeigi, S., Yousefi, B., Rahimi, M., & Shafiei-Irannejad, V. (2019). Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomedicine & Pharmacotherapy, 109, 1593–1601.

    CAS  Google Scholar 

  50. Smith, D. L. Jr., Elam, C. F. Jr., Mattison, J. A., Lane, M. A., Roth, G. S., Ingram, D. K., & Allison, D. B. (2010). Metformin supplementation and life span in Fischer-344 rats. Journals Of Gerontology. Series A, Biological Sciences And Medical Sciences, 65, 468–474.

    PubMed  Google Scholar 

  51. Noren Hooten, N., Martin-Montalvo, A., Dluzen, D. F., Zhang, Y., Bernier, M., Zonderman, A. B., Becker, K. G., Gorospe, M., de Cabo, R., & Evans, M. K. (2016). Metformin-mediated increase in DICER1 regulates microRNA expression and cellular senescence. Aging Cell, 15, 572–581.

    CAS  PubMed  PubMed Central  Google Scholar 

  52. Menendez, J. A., Cufi, S., Oliveras-Ferraros, C., Martin-Castillo, B., Joven, J., Vellon, L., & Vazquez-Martin, A. (2011). Metformin and the ATM DNA damage response (DDR): Accelerating the onset of stress-induced senescence to boost protection against cancer. Aging (Albany NY), 3, 1063–1077.

    CAS  PubMed  Google Scholar 

  53. Martin-Castillo, B., Vazquez-Martin, A., Oliveras-Ferraros, C., & Menendez, J. A. (2010). Metformin and cancer: Doses, mechanisms and the dandelion and hormetic phenomena. Cell Cycle, 9, 1057–1064.

    CAS  PubMed  Google Scholar 

  54. Owen, M. R., Doran, E., & Halestrap, A. P. (2000). Evidence that metformin exerts its anti-diabetic effects through inhibition of complex 1 of the mitochondrial respiratory chain. Biochem J 348 Pt, 3, 607–614.

    Google Scholar 

  55. Chen, C., Zhou, M., Ge, Y., & Wang, X. (2020). SIRT1 and aging related signaling pathways. Mechanisms Of Ageing And Development, 187, 111215.

    CAS  PubMed  Google Scholar 

  56. Li, P., Zhao, M., Parris, A. B., Feng, X., & Yang, X. (2015). p53 is required for metformin-induced growth inhibition, senescence and apoptosis in breast cancer cells. Biochemical And Biophysical Research Communications, 464, 1267–1274.

    CAS  PubMed  Google Scholar 

  57. Moiseeva, O., Deschenes-Simard, X., St-Germain, E., Igelmann, S., Huot, G., Cadar, A. E., Bourdeau, V., Pollak, M. N., & Ferbeyre, G. (2013). Metformin inhibits the senescence-associated secretory phenotype by interfering with IKK/NF-kappaB activation. Aging Cell, 12, 489–498.

    CAS  PubMed  Google Scholar 

  58. Zhang, J., & Wang, J. H. (2010). Characterization of differential properties of rabbit tendon stem cells and tenocytes. Bmc Musculoskeletal Disorders, 11, 10.

    PubMed  PubMed Central  Google Scholar 

  59. Chen, L., Liu, J., Tao, X., Wang, G., Wang, Q., & Liu, X. (2015). The role of Pin1 protein in aging of human tendon stem/progenitor cells. Biochemical And Biophysical Research Communications, 464, 487–492.

    CAS  PubMed  Google Scholar 

  60. Xu, H., & Liu, F. (2018). Downregulation of FOXP1 correlates with tendon stem/progenitor cells aging. Biochemical And Biophysical Research Communications, 504, 96–102.

    CAS  PubMed  Google Scholar 

  61. Menendez, J. A., & Vazquez-Martin, A. (2012). Rejuvenating regeneration: Metformin activates endogenous adult stem cells. Cell Cycle, 11, 3521–3522.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Houshmand, B., Tabibzadeh, Z., Motamedian, S. R., & Kouhestani, F. (2018). Effect of metformin on dental pulp stem cells attachment, proliferation and differentiation cultured on biphasic bone substitutes. Archives Of Oral Biology, 95, 44–50.

    CAS  PubMed  Google Scholar 

  63. Shi, Z., Wang, Q., & Jiang, D. (2021). Ascorbic acid mitigates the deleterious effects of nicotine on tendon stem cells. Connective Tissue Research, 62, 183–193.

    CAS  PubMed  Google Scholar 

  64. Zhang, R., Liang, Q., Kang, W., & Ge, S. (2019). Metformin facilitates the proliferation, migration, and osteogenic differentiation of periodontal ligament stem cells in vitro. Cell Biol Int.

  65. Chen, D., Xia, D., Pan, Z., Xu, D., Zhou, Y., Wu, Y., Cai, N., Tang, Q., Wang, C., Yan, M., Zhang, J. J., Zhou, K., Wang, Q., Feng, Y., Wang, X., Xu, H., Zhang, X., & Tian, N. (2016). Metformin protects against apoptosis and senescence in nucleus pulposus cells and ameliorates disc degeneration in vivo. Cell Death And Disease, 7, e2441.

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Anisimov, V. N., Berstein, L. M., Egormin, P. A., Piskunova, T. S., Popovich, I. G., Zabezhinski, M. A., Kovalenko, I. G., Poroshina, T. E., Semenchenko, A. V., Provinciali, M., Re, F., & Franceschi, C. (2005). Effect of metformin on life span and on the development of spontaneous mammary tumors in HER-2/neu transgenic mice. Experimental Gerontology, 40, 685–693.

    CAS  PubMed  Google Scholar 

  67. Zhang, J., Li, F., Nie, D., Onishi, K., Hogan, M. V., & Wang, J. H. (2020). Effect of Metformin on Development of Tendinopathy due to mechanical overloading in an animal model. Foot And Ankle International, 41, 1455–1465.

    PubMed  Google Scholar 

  68. Zheng, W., Song, J., Zhang, Y., Chen, S., Ruan, H., & Fan, C. (2017). Metformin prevents peritendinous fibrosis by inhibiting transforming growth factor-beta signaling. Oncotarget, 8, 101784–101794.

    PubMed  PubMed Central  Google Scholar 

  69. Mary, A., Hartemann, A., Liabeuf, S., Aubert, C. E., Kemel, S., Salem, J. E., Cluzel, P., Lenglet, A., Massy, Z. A., Lalau, J. D., Mentaverri, R., Bourron, O., & Kamel, S. (2017). Association between metformin use and below-the-knee arterial calcification score in type 2 diabetic patients. Cardiovasc Diabetol, 16, 24.

    PubMed  PubMed Central  Google Scholar 

  70. Lee, J., Hong, S. W., Kim, M. J., Kwon, H., Park, S. E., Rhee, E. J., & Lee, W. Y. (2020). Metformin, resveratrol, and exendin-4 inhibit high phosphate-induced vascular calcification via AMPK-RANKL signaling. Biochemical And Biophysical Research Communications, 530, 374–380.

    CAS  PubMed  Google Scholar 

  71. Eisenreich, A., & Leppert, U. (2017). Update on the Protective Renal Effects of Metformin in Diabetic Nephropathy. Current Medicinal Chemistry, 24, 3397–3412.

    CAS  PubMed  Google Scholar 

  72. Liu, Y., Li, J., Li, H., Shang, Y., Guo, Y., Li, Z., & Liu, Z. (2019). AMP-Activated Protein Kinase Activation in Dorsal Root Ganglion Suppresses mTOR/p70S6K Signaling and Alleviates Painful Radiculopathies in Lumbar Disc Herniation Rat Model. Spine (Phila Pa 1976) 44:E865-E872.

Download references

Acknowledgements

The authors acknowledge Figdraw (www.figdraw.com) that have provided help for drawing model picture in this manuscript.

Funding

This work was supported by the National Natural Science Foundation of China (81871812 and 81572187); the Natural Science Foundation of Jiangsu Province (BK20221462); the Natural Science Foundation of Jiangsu Province for Young Scholars (BK2012334); the Jiangsu Provincial Medical Talent; The Project of Invigorating Health Care through Science, Technology and Education (ZDRCA2016083); and The Six Projects Sponsoring Talent Summits of Jiangsu Province, China (LGY2017099).

Author information

Authors and Affiliations

  1. Department of Orthopaedics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, 210009, Nanjing, Jiangsu, PR China

    Guangchun Dai, Ming Zhang, Panpan Lu, Yuanwei Zhang, Hao Wang, Liu Shi, Mumin Cao, Renwang Shen & Yunfeng Rui

  2. School of Medicine, Southeast University, N0.87 Ding Jia Qiao, 210009, Nanjing, PR China

    Guangchun Dai, Ming Zhang, Panpan Lu, Yuanwei Zhang, Hao Wang, Mumin Cao & Renwang Shen

  3. Department of Geriatrics, School of Medicine, Zhongda Hospital, Southeast University, NO.87 Ding Jia Qiao, Nanjing, PR China

    Yingjuan Li

  4. Trauma Center, Zhongda Hospital, Southeast University, 210009, Nanjing, Jiangsu, PR China

    Guangchun Dai, Ming Zhang, Panpan Lu, Yuanwei Zhang, Hao Wang, Liu Shi, Mumin Cao, Renwang Shen & Yunfeng Rui

  5. Orthopaedic Trauma Institute (OTI), Southeast University, 210009, Nanjing, Jiangsu, PR China

    Guangchun Dai, Ming Zhang, Panpan Lu, Yuanwei Zhang, Hao Wang, Liu Shi, Mumin Cao, Renwang Shen & Yunfeng Rui

  6. China Orthopedic Regenerative Medicine Group, 310000, Hangzhou, Zhejiang, PR China

    Yunfeng Rui

Authors
  1. Guangchun Dai
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingjuan Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ming Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Panpan Lu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Yuanwei Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Hao Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Liu Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mumin Cao
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Renwang Shen
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Yunfeng Rui
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

GCD and YFR designed the project. GCD, MZ, PPL and YWZ performed the experiments. LS, MMC and RWS analyzed the data. GCD, YJL, MZ and HW wrote the manuscript. YFR revised and proofread the paper.

Corresponding author

Correspondence to Yunfeng Rui.

Ethics declarations

Ethics approval and consent to participate

Animal experiments were approved by the Institutional Animal Care and Use Committee (IACUC) of the Southeast University School of Medicine.

Consent for publication

Not applicable.

Competing Interests

The authors declare that they have no competing interest.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Electronic Supplementary Material

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Dai, G., Li, Y., Zhang, M. et al. The Regulation of the AMPK/mTOR Axis Mitigates Tendon Stem/Progenitor Cell Senescence and Delays Tendon Aging. Stem Cell Rev and Rep 19, 1492–1506 (2023). https://doi.org/10.1007/s12015-023-10526-0

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s12015-023-10526-0

Keywords

Search

Navigation