Anti‑aging effects of melatonin on the myocardial mitochondria of rats and associated mechanisms

Guo,Xin‑Hong; Li,Yan‑Hua; Zhao,Yu‑Sheng; Zhai,Yong‑Zhi; Zhang,Li‑Cheng

doi:10.3892/mmr.2016.6002

Anti‑aging effects of melatonin on the myocardial mitochondria of rats and associated mechanisms

Authors:
- Xin‑Hong Guo
- Yan‑Hua Li
- Yu‑Sheng Zhao
- Yong‑Zhi Zhai
- Li‑Cheng Zhang
View Affiliations

Affiliations: Department of Cardiology, Institute of Geriatric Cardiology, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Emergency Department, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China, Department of Orthopedics, Institute of Orthopedics, Chinese People's Liberation Army General Hospital, Beijing 100853, P.R. China
Published online on: December 7, 2016 https://doi.org/10.3892/mmr.2016.6002
Pages: 403-410

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

The present study investigated the anti-aging effects of melatonin on the myocardial mitochondria of D-galactose-aged rats and associated mechanisms. A total of 30 male Sprague‑Dawley (SD) rats were randomly divided into three equal groups: An accelerated aging group that received 125 mg/kg/day D‑galactose; a melatonin‑treated group of D‑galactose‑aged rats that received 10 mg/kg/day melatonin; and a control group receiving normal saline. ATP, ADP and AMP levels in the left ventricular myocardium of rats were determined by high performance liquid chromatography and the total adenylic acid number (TAN) was subsequently calculated. Bax, Bcl‑2, and cytochrome c (cyt‑c) protein expression levels in myocardial mitochondria and cytoplasm were quantified by western blot analysis. In the melatonin‑treated group, ATP levels were significantly higher when compared with the untreated control group and the accelerated‑ageing group (0.068 vs. 0.052 and 0.058; P=0.002 and P=0.045, respectively), and TAN was significantly increased in the melatonin‑treated group when compared with controls (P=0.011). In addition, cyt‑c levels in the cytoplasm, but not in the mitochondria, were significantly higher in the accelerated‑aging group compared with the control and melatonin‑treated groups (P=0.001 and P=0.002, respectively). Bcl‑2 and Bax ratios were significantly higher in the control and melatonin‑treated groups when compared with the accelerated‑aging group (P=0.004 and P=0.032, respectively). These results suggest that melatonin exhibits a protective effect on mitochondrial function in a rat model of accelerated aging.

View Figures

View References

1	Harman D: The free radical theory of aging. Antioxid Redox Signal. 5:557–561. 2003. View Article : Google Scholar : PubMed/NCBI
2	Rodríguez MI, Carretero M, Escames G, López LC, Maldonado MD, Tan DX, Reiter RJ and Acuña-Castroviejo D: Chronic melatonin treatment prevents age-dependent cardiac mitochondrial dysfunction in senescence-accelerated mice. Free Radic Res. 41:15–24. 2007. View Article : Google Scholar : PubMed/NCBI
3	Takeda T: Senescence-accelerated mouse (SAM): A biogerontological resource in aging research. Neurobiol Aging. 20:105–110. 1999. View Article : Google Scholar : PubMed/NCBI
4	Rizvi SI and Jha R: Strategies for the discovery of anti-aging compounds. Expert Opin Drug Discov. 6:89–102. 2011. View Article : Google Scholar : PubMed/NCBI
5	Acuña-Castroviejo D, Martín M, Macías M, Escames G, León J, Khaldy H and Reiter RJ: Melatonin, mitochondria, and cellular bioenergetics. J Pineal Res. 30:65–74. 2001. View Article : Google Scholar : PubMed/NCBI
6	Rodriguez MI, Escames G, López LC, García JA, Ortiz F, López A and Acuña-Castroviejo D: Melatonin administration prevents cardiac and diaphragmatic mitochondrial oxidative damage in senescence-accelerated mice. J Endocrinol. 194:637–643. 2007. View Article : Google Scholar : PubMed/NCBI
7	Escames G, Lopez A, García JA, García L, Acuña-Castroviejo D, García JJ and López LC: The role of mitochondria in brain aging and the effects of melatonin. Curr Neuropharmacol. 8:182–193. 2010. View Article : Google Scholar : PubMed/NCBI
8	Petrosillo G, Moro N, Paradies V, Ruggiero FM and Paradies G: Increased susceptibility to Ca(2+)-induced permeability transition and to cytochrome c release in rat heart mitochondria with aging: Effect of melatonin. J Pineal Res. 48:340–346. 2010. View Article : Google Scholar : PubMed/NCBI
9	Judge S and Leeuwenburgh C: Cardiac mitochondrial bioenergetics, oxidative stress, and aging. Am J Physiol Cell Physiol. 292:C1983–C1992. 2007. View Article : Google Scholar : PubMed/NCBI
10	Lesnefsky EJ, Moghaddas S, Tandler B, Kerner J and Hoppel CL: Mitochondrial dysfunction in cardiac disease: Ischemia-reperfusion, aging, and heart failure. J Mol Cell Cardiol. 33:1065–1089. 2001. View Article : Google Scholar : PubMed/NCBI
11	Lee SJ, Jin Y, Yoon HY, Choi BO, Kim HC, Oh YK, Kim HS and Kim WK: Ciclopirox protects mitochondria from hydrogen peroxide toxicity. Br J Pharmacol. 145:469–476. 2005.PubMed/NCBI
12	Poeggeler B, Durand G, Polidori A, Pappolla MA, Vega-Naredo I, Coto-Montes A, Böker J, Hardeland R and Pucci B: Mitochondrial medicine: Neuroprotection and life extension by the new amphiphilic nitrone LPBNAH acting as a highly potent antioxidant agent. J Neurochem. 95:962–973. 2005. View Article : Google Scholar : PubMed/NCBI
13	Schapira AH: Mitochondrial involvement in Parkinson's disease, Huntington's disease, hereditary spastic paraplegia and Friedreich's ataxia. Biochim Biophys Acta. 1410:159–170. 1999. View Article : Google Scholar : PubMed/NCBI
14	Barlow-Walden LR, Reiter RJ, Abe M, Pablos M, Menendez-Pelaez A, Chen LD and Poeggeler B: Melatonin stimulates brain glutathione peroxidase activity. Neurochem Int. 26:497–502. 1995. View Article : Google Scholar : PubMed/NCBI
15	Tan DX, Chen LD, Poeggeler B, Manchester LC and Reiter RJ: Melatonin: A potent endogenous hydroxyl radical scavenger. Endocrine J. 1:57–60. 1993.
16	Hardeland R: Melatonin and the theories of aging: A critical appraisal of melatonin's role in antiaging mechanisms. J Pineal Res. 55:325–356. 2013.PubMed/NCBI
17	Acuna-Castroviejo D, Escames G, Rodriguez MI and Lopez LC: Melatonin role in the mitochondrial function. Front Biosci. 12:947–963. 2007. View Article : Google Scholar : PubMed/NCBI
18	Reiter RJ: Oxidative processes and antioxidative defense mechanisms in the aging brain. FASEB J. 9:526–533. 1995.PubMed/NCBI
19	Reiter RJ, Tan DX, Mayo JC, Sainz RM, Leon J and Czarnocki Z: Melatonin as an antioxidant: Biochemical mechanisms and pathophysiological implications in humans. Acta Biochim Pol. 50:1129–1146. 2003.PubMed/NCBI
20	Okatani Y, Wakatsuki A, Shinohara K, Taniguchi K and Fukaya T: Melatonin protects against oxidative mitochondrial damage induced in rat placenta by ischemia and reperfusion. J Pineal Res. 31:173–178. 2001. View Article : Google Scholar : PubMed/NCBI
21	Okatani Y, Wakatsuki A, Reiter RJ and Miyahara Y: Melatonin reduces oxidative damage of neural lipids and proteins in senescence-accelerated mouse. Neurobiol Aging. 23:639–644. 2002. View Article : Google Scholar : PubMed/NCBI
22	Lardone PJ, Alvarez-García O, Carrillo-Vico A, Vega-Naredo I, Caballero B, Guerrero JM and Coto-Montes A: Inverse correlation between endogenous melatonin levels and oxidative damage in some tissues of SAM P8 mice. J Pineal Res. 40:153–157. 2006. View Article : Google Scholar : PubMed/NCBI
23	Bubenik GA and Konturek SJ: Melatonin and aging: Prospects for human treatment. J Physiol Pharmacol. 62:13–19. 2011.PubMed/NCBI
24	Reiter RJ, Richardson BA, Johnson LY, Ferguson BN and Dinh DT: Pineal melatonin rhythm: Reduction in aging Syrian hamsters. Science. 210:1372–1373. 1980. View Article : Google Scholar : PubMed/NCBI
25	Reiter RJ, Craft CM, Johnson JE Jr, King TS, Richardson BA, Vaughan GM and Vaughan MK: Age-associated reduction in nocturnal pineal melatonin levels in female rats. Endocrinology. 109:1295–1297. 1981. View Article : Google Scholar : PubMed/NCBI
26	Karasek M: Melatonin, human aging, and age-related diseases. Exp Gerontol. 39:1723–1729. 2004. View Article : Google Scholar : PubMed/NCBI
27	Wei H, Li L, Song Q, Ai H, Chu J and Li W: Behavioural study of the D-galactose induced aging model in C57BL/6J mice. Behav Brain Res. 157:245–251. 2005. View Article : Google Scholar : PubMed/NCBI
28	Song X, Bao M, Li D and Li YM: Advanced glycation in D-galactose induced mouse aging model. Mech Ageing Dev. 108:239–251. 1999. View Article : Google Scholar : PubMed/NCBI
29	Deng HB, Cheng CL, Cui DP, Li DD, Cui L and Cai NS: Structural and functional changes of immune system in aging mouse induced by D-galactose. Biomed Environ Sci. 19:432–438. 2006.PubMed/NCBI
30	Hammond JB and Kruger NJ: The bradford method for protein quantitation. Methods Mol Biol. 3:25–32. 1988.PubMed/NCBI
31	Khlyntseva SV, Bazel YR, Vishnikin AB and Andruch V: Methods for the determination of adenosine triphosphate and other adenine nucleotides. J Analytic Chem. 64:657–673. 2009. View Article : Google Scholar
32	Lee SD, Kuo WW, Ho YJ, Lin AC, Tsai CH, Wang HF, Kuo CH, Yang AL, Huang CY and Hwang JM: Cardiac Fas-dependent and mitochondria-dependent apoptosis in ovariectomized rats. Maturitas. 61:268–277. 2008. View Article : Google Scholar : PubMed/NCBI
33	Karyn M Usher, Steven W Hansen, Jennifer S Amoo, Allison P Bernstein and Mary Ellen P. McNally: Precision of internal standard and external standard methods in high performance liquid chromatography. LCGC Special Issues. 33:40–46. 2015.
34	Yang Y, Duan W, Jin Z, Yi W, Yan J, Zhang S, Wang N, Liang Z, Li Y, Chen W, et al: JAK2/STAT3 activation by melatonin attenuates the mitochondrial oxidative damage induced by myocardial ischemia/reperfusion injury. J Pineal Res. 55:275–286. 2013. View Article : Google Scholar : PubMed/NCBI
35	Carretero M, Escames G, López LC, Venegas C, Dayoub JC, García L and Acuña-Castroviejo D: Long-term melatonin administration protects brain mitochondria from aging. J Pineal Res. 47:192–200. 2009. View Article : Google Scholar : PubMed/NCBI
36	Martín M, Macías M, León J, Escames G, Khaldy H and Acuña-Castroviejo D: Melatonin increases the activity of the oxidative phosphorylation enzymes and the production of ATP in rat brain and liver mitochondria. Int J Biochem Cell Biol. 34:348–357. 2002. View Article : Google Scholar : PubMed/NCBI
37	Atkinson DE and Fall L: Adenosine triphosphate conservation in biosynthetic regulation. Escherichia coli phosphoribosylpyrophosphate synthase. J Biol Chem. 242:3241–3242. 1967.PubMed/NCBI
38	Lopez LC, Escames G, Ortiz F, Ros E and Acuña-Castroviejo D: Melatonin restores the mitochondrial production of ATP in septic mice. Neuro Endocrinol Lett. 27:623–630. 2006.PubMed/NCBI
39	Karasek M, Reiter RJ, Cardinali DP and Pawlikowski M: Future of melatonin as a therapeutic agent. Neuro Endocrinol Lett. 23:(Suppl 1). S118–S121. 2002.
40	Galano A, Tan DX and Reiter RJ: On the free radical scavenging activities of melatonin's metabolites, AFMK and AMK. J Pineal Res. 54:245–257. 2013. View Article : Google Scholar : PubMed/NCBI
41	Galano A, Tan DX and Reiter RJ: Melatonin as a natural ally against oxidative stress: A physicochemical examination. J Pineal Res. 51:1–16. 2011. View Article : Google Scholar : PubMed/NCBI
42	Green DR and Reed JC: Mitochondria and apoptosis. Science. 281:1309–1312. 1998. View Article : Google Scholar : PubMed/NCBI
43	Fang X, Chen M and Chen R: Cytochrome C and Apoptosis. J Foreign Medical Sciences (Clinical Biochemistry and Laboratory Medicine). 26:43–46. 2005.
44	Shimizu S, Narita M and Tsujimoto Y: Bcl-2 family proteins regulate the release of apoptogenic cytochrome c by the mitochondrial channel VDAC. Nature. 399:483–487. 1999. View Article : Google Scholar : PubMed/NCBI