The journal of nutrition, health & aging

, Volume 22, Issue 6, pp 710–717 | Cite as

Berberine Improves Cognitive Deficiency and Muscular Dysfunction via Activation of the AMPK/SIRT1/PGC-1a Pathway in Skeletal Muscle from Naturally Aging Rats

  • Y. Yu
  • Y. Zhao
  • F. Teng
  • J. Li
  • Y. Guan
  • J. Xu
  • X. Lv
  • F. Guan
  • Ming ZhangEmail author
  • L. Chen



The manifestations of aging include cognitive deficits and muscular dysfunction, which are closely linked to impairment of mitochondrial biogenesis. Berberine, an isoquinoline alkaloid, presents multiple anti-diabetic pharmacological effects. Evidence has indicated that insulin resistance and cognitive impairment share the same pathogenesis, and berberine could reverse glucose metabolism abnormalities and muscle mitochondrial dysfunction induced by a high-fat diet. This study was used to investigate whether berberine could be used as an anti-aging drug to prevent cognitive deficits and muscular dysfunction in natural aging.


Biochemical indicators and an intraperitoneal glucose tolerance test were tested in 5-monthold rats (5 mo group), 24-month-old rats (24 mo group) and 24-month-old rats that had undergone 6 months of berberine treatment (BBR group). A Morris water maze test was conducted to assess the cognitive ability of the rats. Insulin resistance in whole-body was evaluated by intraperitoneal glucose tolerance test (IPGTT). The morphology of the skeletal muscle tissue was observed by hematoxylin-eosin (HE) staining. The levels of total cholesterol, triglyceride, ATP and reactive oxygen species (ROS) were assessed with corresponding reagent kits. The protein expressions of GLUT4, AMPK, SIRT1 and PGC-1α in skeletal muscle were examined by Western blot.


The results showed that administration of berberine for 6 months significantly improved cognitive deficits and insulin resistance in naturally aging rats (p<0.01). Furthermore, berberine treatment helped normalize the disordered alignment and the decreased number of muscle fibers (p<0.01) in the skeletal muscle of 24 mo rats. Berberine decreased the levels of ROS in both the serum and the skeletal muscle of 24 mo rats (p<0.01). Berberine increased the protein expression of p-AMPK, SIRT1 and PGC-1α and increased the production of ATP in the skeletal muscle of aging rats (p<0.01).


Berberine markedly ameliorates aging-related reductions in cognitive ability and muscular function, and the activation of the AMPK/SIRT1/PGC-1α pathway in skeletal muscle may be the underlying protective mechanism of berberine on muscular function.

Key words

Berberine aging cognitive deficits skeletal muscle insulin resistance mitochondrial biogenesis 

List of abbreviations


proliferator-activated receptor γ coactivator 1-α


adenosine monophosphate-activated protein kinase


sirtuin type 1


fasting blood glucose


total cholesterol




bicinchoninic acid


Radiommunoprecipitation Assay


phenylmethanesulfonyl fluoride




intraperitoneal glucose tolerance test


Morris water maze


  1. 1.
    Harada CN, Natelson Love MC, Triebel KL: Normal cognitive aging. Clin Geriatr Med 2013, 29(4):737–752.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Fischer L, Baker J, Rienhoff R, Strauss B, Tirp J, Busch D, Schorer J: Perceptualcognitive expertise of handball coaches in their young and middle adult years. J Sports Sci 2016, 34(17):1637–1642.CrossRefPubMedGoogle Scholar
  3. 3.
    Nair KS: Aging muscle. Am J Clin Nutr 2005, 81(5):953–963.CrossRefPubMedGoogle Scholar
  4. 4.
    Purves-Smith FM, Sgarioto N, Hepple RT: Fiber typing in aging muscle. Exerc Sport Sci Rev 2014, 42(2):45–52.CrossRefPubMedGoogle Scholar
  5. 5.
    Scott D, Park MS, Kim TN, Ryu JY, Hong HC, Yoo HJ, Baik SH, Jones G, Choi KM: Associations of Low Muscle Mass and the Metabolic Syndrome in Caucasian and Asian Middle-aged and Older Adults. J Nutr Health Aging 2016, 20(3):248–255.CrossRefPubMedGoogle Scholar
  6. 6.
    Groen BB, Hamer HM, Snijders T, van Kranenburg J, Frijns D, Vink H, van Loon LJ: Skeletal muscle capillary density and microvascular function are compromised with aging and type 2 diabetes. J Appl Physiol (1985) 2014, 116(8):998–1005.CrossRefGoogle Scholar
  7. 7.
    Maddison LA, Joest KE, Kammeyer RM, Chen W: Skeletal muscle insulin resistance in zebrafish induces alterations in beta-cell number and glucose tolerance in an ageand diet-dependent manner. Am J Physiol Endocrinol Metab 2015, 308(8):E662–669.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Morris JK, Vidoni ED, Honea RA, Burns JM, Alzheimer’s Disease Neuroimaging I: Impaired glycemia increases disease progression in mild cognitive impairment. Neurobiol Aging 2014, 35(3):585–589.CrossRefPubMedGoogle Scholar
  9. 9.
    Kim TE, Lee DH, Kim YJ, Mok JO, Kim CH, Park JH, Lee TK, Yoo K, Jeong Y, Lee Y et al: The relationship between cognitive performance and insulin resistance in non-diabetic patients with mild cognitive impairment. Int J Geriatr Psychiatry 2015, 30(6):551–557.CrossRefPubMedGoogle Scholar
  10. 10.
    Chistiakov DA, Sobenin IA, Revin VV, Orekhov AN, Bobryshev YV: Mitochondrial aging and age-related dysfunction of mitochondria. Biomed Res Int 2014, 2014:238463.PubMedPubMedCentralGoogle Scholar
  11. 11.
    De Fronzo RA, Gunnarsson R, Bjorkman O, Olsson M, Wahren J: Effects of insulin on peripheral and splanchnic glucose metabolism in noninsulin-dependent (type II) diabetes mellitus. J Clin Invest 1985, 76(1):149–155.CrossRefGoogle Scholar
  12. 12.
    Sandri M, Lin J, Handschin C, Yang W, Arany ZP, Lecker SH, Goldberg AL, Spiegelman BM: PGC-1alpha protects skeletal muscle from atrophy by suppressing FoxO3 action and atrophy-specific gene transcription. Proc Natl Acad Sci U S A 2006, 103(44):16260–16265.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Loprinzi PD: Epidemiological investigation of muscle-strengthening activities and cognitive function among older adults. Chronic Illn 2016, 12(2):157–162.CrossRefPubMedGoogle Scholar
  14. 14.
    Anderson R, Prolla T: PGC-1alpha in aging and anti-aging interventions. Biochim Biophys Acta 2009, 1790(10):1059–1066.CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Lan F, Cacicedo JM, Ruderman N, Ido Y: SIRT1 modulation of the acetylation status, cytosolic localization, and activity of LKB1. Possible role in AMP-activated protein kinase activation. J Biol Chem 2008, 283(41):27628–27635.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Gerhart-Hines Z, Rodgers JT, Bare O, Lerin C, Kim SH, Mostoslavsky R, Alt FW, Wu Z, Puigserver P: Metabolic control of muscle mitochondrial function and fatty acid oxidation through SIRT1/PGC-1alpha. EMBO J 2007, 26(7):1913–1923.CrossRefPubMedPubMedCentralGoogle Scholar
  17. 17.
    Lan J, Zhao Y, Dong F, Yan Z, Zheng W, Fan J, Sun G: Meta-analysis of the effect and safety of berberine in the treatment of type 2 diabetes mellitus, hyperlipemia and hypertension. J Ethnopharmacol 2015, 161: 69–81.CrossRefPubMedGoogle Scholar
  18. 18.
    Zhang Q, Li Y, Chen L: [Effect of berberine in treating type 2 diabetes mellitus and complications and its relevant mechanisms]. Zhongguo Zhong Yao Za Zhi 2015, 40(9):1660–1665.PubMedGoogle Scholar
  19. 19.
    Zhang Z, Li X, Li F, An L: Berberine alleviates postoperative cognitive dysfunction by suppressing neuroinflammation in aged mice. Int Immunopharmacol 2016, 38: 426–433.CrossRefPubMedGoogle Scholar
  20. 20.
    Durairajan SS, Liu LF, Lu JH, Chen LL, Yuan Q, Chung SK, Huang L, Li XS, Huang JD, Li M: Berberine ameliorates beta-amyloid pathology, gliosis, and cognitive impairment in an Alzheimer’s disease transgenic mouse model. Neurobiol Aging 2012, 33(12):2903–2919.CrossRefPubMedGoogle Scholar
  21. 21.
    Zhang M, Lv X, Li J, Meng Z, Wang Q, Chang W, Li W, Chen L, Liu Y: Sodium caprate augments the hypoglycemic effect of berberine via AMPK in inhibiting hepatic gluconeogenesis. Mol Cell Endocrinol 2012, 363(1-2):122–130.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Gomes AP, Duarte FV, Nunes P, Hubbard BP, Teodoro JS, Varela AT, Jones JG, Sinclair DA, Palmeira CM, Rolo AP: Berberine protects against high fat diet-induced dysfunction in muscle mitochondria by inducing SIRT1-dependent mitochondrial biogenesis. Biochim Biophys Acta 2012, 1822(2):185–195.CrossRefPubMedGoogle Scholar
  23. 23.
    Deibel SH, Zelinski EL, Keeley RJ, Kovalchuk O, McDonald RJ: Epigenetic alterations in the suprachiasmatic nucleus and hippocampus contribute to age-related cognitive decline. Oncotarget 2015, 6(27):23181–23203.CrossRefPubMedPubMedCentralGoogle Scholar
  24. 24.
    Lin CH, Wu RM: Biomarkers of cognitive decline in Parkinson’s disease. Parkinsonism Relat Disord 2015, 21(5):431–443.CrossRefPubMedGoogle Scholar
  25. 25.
    Lo RY, Jagust WJ, Alzheimer’s Disease Neuroimaging I: Effect of cognitive reserve markers on Alzheimer pathologic progression. Alzheimer Dis Assoc Disord 2013, 27(4):343–350.CrossRefPubMedGoogle Scholar
  26. 26.
    Kullmann S, Heni M, Hallschmid M, Fritsche A, Preissl H, Haring HU: Brain Insulin Resistance at the Crossroads of Metabolic and Cognitive Disorders in Humans. Physiol Rev 2016, 96(4):1169–1209.CrossRefPubMedGoogle Scholar
  27. 27.
    Capiotti KM, De Moraes DA, Menezes FP, Kist LW, Bogo MR, Da Silva RS: Hyperglycemia induces memory impairment linked to increased acetylcholinesterase activity in zebrafish (Danio rerio). Behav Brain Res 2014, 274: 319–325.CrossRefPubMedGoogle Scholar
  28. 28.
    Perez-Rubio KG, Gonzalez-Ortiz M, Martinez-Abundis E, Robles-Cervantes JA, Espinel-Bermudez MC: Effect of berberine administration on metabolic syndrome, insulin sensitivity, and insulin secretion. Metab Syndr Relat Disord 2013, 11(5):366–369.CrossRefPubMedGoogle Scholar
  29. 29.
    Chen Q, Mo R, Wu N, Zou X, Shi C, Gong J, Li J, Fang K, Wang D, Yang D et al: Berberine Ameliorates Diabetes-Associated Cognitive Decline through Modulation of Aberrant Inflammation Response and Insulin Signaling Pathway in DM Rats. Front Pharmacol 2017, 8:334.CrossRefPubMedPubMedCentralGoogle Scholar
  30. 30.
    Xue H, Ji Y, Wei S, Yu Y, Yan X, Liu S, Zhang M, Yao F, Lan X, Chen L: HGSD attenuates neuronal apoptosis through enhancing neuronal autophagy in the brain of diabetic mice: The role of AMP-activated protein kinase. Life Sci 2016, 153: 23–34.CrossRefPubMedGoogle Scholar
  31. 31.
    Calvo-Ochoa E, Arias C: Cellular and metabolic alterations in the hippocampus caused by insulin signalling dysfunction and its association with cognitive impairment during aging and Alzheimer’s disease: studies in animal models. Diabetes Metab Res Rev 2015, 31(1):1–13.CrossRefPubMedGoogle Scholar
  32. 32.
    Kim B, Feldman EL: Insulin resistance as a key link for the increased risk of cognitive impairment in the metabolic syndrome. Exp Mol Med 2015, 47:e149.CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Yin Q, Ma Y, Hong Y, Hou X, Chen J, Shen C, Sun M, Shang Y, Dong S, Zeng Z et al: Lycopene attenuates insulin signaling deficits, oxidative stress, neuroinflammation, and cognitive impairment in fructose-drinking insulin resistant rats. Neuropharmacology 2014, 86: 389–396.CrossRefPubMedGoogle Scholar
  34. 34.
    Gao N, Zhao TY, Li XJ: The protective effect of berberine on beta-cell lipoapoptosis. J Endocrinol Invest 2011, 34(2):124–130.CrossRefPubMedGoogle Scholar
  35. 35.
    Yang TC, Chao HF, Shi LS, Chang TC, Lin HC, Chang WL: Alkaloids from Coptis chinensis root promote glucose uptake in C2C12 myotubes. Fitoterapia 2014, 93: 239–244.CrossRefPubMedGoogle Scholar
  36. 36.
    Xia X, Yan J, Shen Y, Tang K, Yin J, Zhang Y, Yang D, Liang H, Ye J, Weng J: Berberine improves glucose metabolism in diabetic rats by inhibition of hepatic gluconeogenesis. PLoS One 2011, 6(2):e16556.CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Pirillo A, Catapano AL: Berberine, a plant alkaloid with lipid- and glucoselowering properties: From in vitro evidence to clinical studies. Atherosclerosis 2015, 243(2):449–461.CrossRefPubMedGoogle Scholar
  38. 38.
    Potes Y, de Luxan-Delgado B, Rodriguez-Gonzalez S, Guimaraes MRM, Solano JJ, Fernandez-Fernandez M, Bermudez M, Boga JA, Vega-Naredo I, Coto-Montes A: Overweight in elderly people induces impaired autophagy in skeletal muscle. Free Radic Biol Med 2017, 110: 31–41.CrossRefPubMedGoogle Scholar
  39. 39.
    Kenny HC, Rudwill F, Breen L, Salanova M, Blottner D, Heise T, Heer M, Blanc S, O’Gorman DJ: Bed rest and resistive vibration exercise unveil novel links between skeletal muscle mitochondrial function and insulin resistance. Diabetologia 2017.Google Scholar
  40. 40.
    Zhang N, Valentine JM, Zhou Y, Li ME, Zhang Y, Bhattacharya A, Walsh ME, Fischer KE, Austad SN, Osmulski P et al: Sustained NFkappaB inhibition improves insulin sensitivity but is detrimental to muscle health. Aging Cell 2017.Google Scholar
  41. 41.
    Ou YC, Chuang HH, Li WC, Tzeng IS, Chen JY: Gender difference in the association between lower muscle mass and metabolic syndrome independent of insulin resistance in a middle-aged and elderly Taiwanese population. Arch Gerontol Geriatr 2017, 72: 12–18.CrossRefPubMedGoogle Scholar
  42. 42.
    Brown M, Ross TP, Holloszy JO: Effects of ageing and exercise on soleus and extensor digitorum longus muscles of female rats. Mech Ageing Dev 1992, 63(1):69–77.CrossRefPubMedGoogle Scholar
  43. 43.
    Crescenzo R, Bianco F, Mazzoli A, Giacco A, Liverini G, Iossa S: Skeletal muscle mitochondrial energetic efficiency and aging. Int J Mol Sci 2015, 16(5):10674–10685.CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Javadov S, Jang S, Rodriguez-Reyes N, Rodriguez-Zayas AE, Soto Hernandez J, Krainz T, Wipf P, Frontera W: Mitochondria-targeted antioxidant preserves contractile properties and mitochondrial function of skeletal muscle in aged rats. Oncotarget 2015, 6(37):39469–39481.CrossRefPubMedPubMedCentralGoogle Scholar
  45. 45.
    Yamamori T, Yasui H, Yamazumi M, Wada Y, Nakamura Y, Nakamura H, Inanami O: Ionizing radiation induces mitochondrial reactive oxygen species production accompanied by upregulation of mitochondrial electron transport chain function and mitochondrial content under control of the cell cycle checkpoint. Free Radic Biol Med 2012, 53(2):260–270.CrossRefPubMedGoogle Scholar
  46. 46.
    Bagkos G, Koufopoulos K, Piperi C: ATP synthesis revisited: new avenues for the management of mitochondrial diseases. Curr Pharm Des 2014, 20(28):4570–4579.CrossRefPubMedGoogle Scholar
  47. 47.
    Russ DW, Acksel C, McCorkle KW, Edens NK, Garvey SM: Effects of Running Wheel Activity and Dietary HMB and beta-alanine Co-Supplementation on Muscle Quality in Aged Male Rats. J Nutr Health Aging 2017, 21(5):554–561.CrossRefPubMedGoogle Scholar
  48. 48.
    Gurd BJ: Deacetylation of PGC-1alpha by SIRT1: importance for skeletal muscle function and exercise-induced mitochondrial biogenesis. Appl Physiol Nutr Metab 2011, 36(5):589–597.CrossRefPubMedGoogle Scholar
  49. 49.
    Park SJ, Ahmad F, Philp A, Baar K, Williams T, Luo H, Ke H, Rehmann H, Taussig R, Brown AL et al: Resveratrol ameliorates aging-related metabolic phenotypes by inhibiting cAMP phosphodiesterases. Cell 2012, 148(3):421–433.CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Jager S, Handschin C, St-Pierre J, Spiegelman BM: AMP-activated protein kinase (AMPK) action in skeletal muscle via direct phosphorylation of PGC-1alpha. Proc Natl Acad Sci U S A 2007, 104(29):12017–12022.CrossRefPubMedPubMedCentralGoogle Scholar
  51. 51.
    Iwabu M, Yamauchi T, Okada-Iwabu M, Sato K, Nakagawa T, Funata M, Yamaguchi M, Namiki S, Nakayama R, Tabata M et al: Adiponectin and AdipoR1 regulate PGC-1alpha and mitochondria by Ca(2+) and AMPK/SIRT1. Nature 2010, 464(7293):1313–1319.CrossRefPubMedGoogle Scholar

Copyright information

© Serdi and Springer-Verlag France SAS, part of Springer Nature 2018

Authors and Affiliations

  • Y. Yu
    • 1
  • Y. Zhao
    • 1
  • F. Teng
    • 1
  • J. Li
    • 1
  • Y. Guan
    • 1
  • J. Xu
    • 1
  • X. Lv
    • 2
  • F. Guan
    • 1
  • Ming Zhang
    • 1
    Email author
  • L. Chen
    • 1
  1. 1.Department of Pharmacology, College of Basic Medical Sciences, School of NursingJilin UniversityChangchun, JilinChina
  2. 2.The Second HospitalJilin UniversityChangchunChina

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