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 ORCID:

Hussam A. S. Murad

http://orcid.org/0000-0002-8406-4946

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Journal of Zhejiang University SCIENCE B 2016 Vol.17 No.1 P.43-53

http://doi.org/10.1631/jzus.B1500065


L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats


Author(s):  Hussam A. S. Murad

Affiliation(s):  1Department of Pharmacology, Faculty of Medicine, Rabigh, King Abdulaziz University, Jeddah 21589, Saudi Arabia; more

Corresponding email(s):   muradha2000@yahoo.com, hamurad@kau.edu.sa

Key Words:  Atorvastatin, Coenzyme Q10, L-Carnitine, Ovariectomized


Hussam A. S. Murad. L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats[J]. Journal of Zhejiang University Science B, 2016, 17(1): 43-53.

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volume="17",
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%T L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats
%A Hussam A. S. Murad
%J Journal of Zhejiang University SCIENCE B
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%DOI 10.1631/jzus.B1500065

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T1 - L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin in ovariectomized rats
A1 - Hussam A. S. Murad
J0 - Journal of Zhejiang University Science B
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PB - Zhejiang University Press & Springer
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DOI - 10.1631/jzus.B1500065


Abstract: 
Objective: Statins’ therapy in osteoporosis can aggravate muscle damage. This study was designed to assess which agent, L-Carnitine or coenzyme Q10, could enhance the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. Methods: Forty-eight female Sprague Dawley rats were used; forty rats were ovariectomized while eight were sham-operated. Eight weeks post-ovariectomy, rats were divided into ovariectomized-untreated group and four ovariectomized-treated groups (n=8) which received by gavage (mg/(kg∙d), for 8 weeks) 17β-estradiol (0.1), atorvastatin (50), atorvastatin (50)+L-Carnitine (100), or atorvastatin (50)+coenzyme Q10 (20). At the end of therapy, bone mineral density (BMD), bone mineral content (BMC), and serum levels of bone metabolic markers (BMMs) and creatine kinase (CK) were measured. Femurs were used for studying the breaking strength and histopathological changes. Results: Treatment with atorvastatin+L-Carnitine restored BMD, BMC, and bone strength to near normal levels. Estrogen therapy restored BMD and BMC to near normal levels, but failed to increase bone strength. Although atorvastatin and atorvastatin+coenzyme Q10 improved BMD, BMC, and bone strength, they failed to restore levels to normal. All treatments decreased BMMs and improved histopathological changes maximally with atorvastatin+L-Carnitine which restored levels to near normal. atorvastatin aggravated the ovariectomy-induced increase in CK level while estrogen, atorvastatin+L-Carnitine, and atorvastatin+coenzyme Q10 decreased its level mainly with atorvastatin+L-Carnitine which restored the level to near normal. Conclusions: Co-administration of L-Carnitine, but not coenzyme Q10, enhances the anti-osteoporotic effect of atorvastatin while antagonizing myopathy in ovariectomized rats. This could be valuable in treatment of osteoporotic patients. However, further confirmatory studies are needed.

左卡尼汀(而非辅酶Q10)提高阿托伐他汀在切除卵巢的老鼠的抗骨质疏松作用

目的:他汀类药物在治疗骨质疏松症时会加重肌肉损伤。本实验研究左卡尼汀和辅酶Q10对阿托伐他汀在切除卵巢的老鼠的抗骨质疏松作用的影响。
创新点:研究新的治疗骨质疏松症及其并发症的方法。
方法:选取48只雌性SD大鼠,40只大鼠切除卵巢,8只为假手术组。切除卵巢8周后,大鼠被分成去卵巢非治疗组和4个去卵巢治疗组(每组8只),通过灌胃法给药(单位为mg/(kg∙d),为期8周):雌二醇(0.1)、阿托伐他汀(50)、阿托伐他汀(50)+左卡尼汀(100)或阿托伐他汀(50)+辅酶Q10(20)。在治疗结束时,测量骨矿物质密度、骨矿物质含量及骨代谢标志物和肌酸激酶的血清水平,利用股骨研究抗断强度和组织病理学变化。
结论:相比辅酶Q10,合并给药左卡尼汀可在提高阿托伐他汀对切除卵巢的老鼠的抗骨质疏松作用的同时避免肌肉损伤。

关键词:阿托伐他汀;辅酶Q10;左卡尼汀;切除卵巢

Darkslateblue:Affiliate; Royal Blue:Author; Turquoise:Article

Reference

[1]Abdallah, H.M., Al-Abd, A.M., Asaad, G.F., et al., 2014. Isolation of anti-osteoporotic compounds from seeds of Sophora japonica. PLoS ONE, 9(6):e98559.

[2]Abdoli, N., Heidari, R., Azarmi, Y., et al., 2013. Mechanisms of the statins cytotoxicity in freshly isolated rat hepatocytes. J. Biochem. Mol. Toxicol., 27(6):287-294.

[3]Amelink, G.J., Koot, R.W., Erich, W.B., et al., 1990. Sex-linked variation in creatine kinase release, and its dependence on oestradiol, can be demonstrated in an in-vitro rat skeletal muscle preparation. Acta Physiol. Scand., 138(2):115-124.

[4]Bae, Y.J., Kim, M.H., 2010. Calcium and magnesium supplementation improves serum OPG/RANKL in calcium-deficient ovariectomized rats. Calcif. Tissue Int., 87(4):365-372.

[5]Bitto, A., Burnett, B.P., Polito, F., et al., 2009. Genistein aglycone reverses glucocorticoid-induced osteoporosis and increases bone breaking strength in rats: a comparative study with alendronate. Br. J. Pharmacol., 156(8):1287-1295.

[6]Bookstaver, D.A., Burkhalter, N.A., Hatzigeorgiou, C., 2012. Effect of coenzyme Q10 supplementation on statin-induced myalgias. Am. J. Cardiol., 110(4):526-529.

[7]Bouzid, K., Bahlous, A., Kalaï, E., et al., 2010. C-telopeptides of type I collagen in postmenopausal women: an experience in a Tunisian clinical laboratory. Tunis. Med., 88(7):467-469.

[8]Brown, J.P., Albert, C., Nassar, B.A., et al., 2009. Bone turnover markers in the management of postmenopausal osteoporosis. Clin. Biochem., 42(10-11):929-942.

[9]Chang, B., Yang, J., Li, H., et al., 2011. Effects of atorvastatin on bone metabolism and bone mineral density in Wistar rats. Pharmazie, 66(7):535-537.

[10]Chirapapaisan, N., Uiprasertkul, M., Chuncharunee, A., 2012. The effect of coenzyme Q10 and curcumin on chronic methanol intoxication induced retinopathy in rats. J. Med. Assoc. Thai., 95(Suppl. 4):S76-S81.

[11]Colucci, S., Mori, G., Vaira, S., et al., 2005. L-Carnitine and isovaleryl L-carnitine fumarate positively affect human osteoblast proliferation and differentiation in vitro. Calcif. Tissue Int., 76(6):458-465.

[12]Costa, R.A., Fernandes, M.P., de Souza-Pinto, N.C., et al., 2013. Protective effects of L-carnitine and piracetam against mitochondrial permeability transition and PC3 cell necrosis induced by simvastatin. Eur. J. Pharmacol., 701(1-3):82-86. [doi:10.1016/j.ejphar.2013.01.001

[13]Cummings, S.R., Karpf, D.B., Harris, F., et al., 2002. Improvement in spine bone density and reduction in risk of vertebral fractures during treatment with antiresorptive drugs. Am. J. Med., 112(4):281-289.

[14]Endo, A., 1992. The discovery and development of HMG-CoA reductase inhibitors. J. Lipid Res., 33(11):1569-1582.

[15]Estai, M.A., Suhaimi, F., Soelaiman, I.N., et al., 2011. Bone histomorphometric study of young rats following oestrogen deficiency. Afr. J. Biotechnol., 10(56):12064-12070.

[16]Farhat, G.N., Cauley, J.A., 2008. The link between osteoporosis and cardiovascular disease. Clin. Cases Miner. Bone Metab., 5(1):19-34.

[17]Gradosova, I., Zivna, H., Palicka, V., et al., 2012. Protective effect of atorvastatin on bone tissue in orchidectomised male albino Wistar rats. Eur. J. Pharmacol., 679(1-3):144-150.

[18]Gülçin, I., 2006. Antioxidant and antiradical activities of L-carnitine. Life Sci., 78(8):803-811.

[19]Høegh-Andersen, P., Tankó, L.B., Andersen, T.L., et al., 2004. Ovariectomized rats as a model of postmenopausal osteoarthritis: validation and application. Arthritis Res. Ther., 6(2):R169-R180.

[20]Hooshmand, S., Balakrishnan, A., Clark, R.M., et al., 2008. Dietary L-carnitine supplementation improves bone mineral density by suppressing bone turnover in aged ovariectomized rats. Phytomedicine, 15(8):595-601.

[21]Huber, C., Collishaw, S., Mosley, J.R., et al., 2007. Selective estrogen receptor modulator inhibits osteocyte apoptosis during abrupt estrogen withdrawal: implications for bone quality maintenance. Calcif. Tissue Int., 81(2):139-144.

[22]Jun, D.W., Cho, W.K., Jun, J.H., et al., 2011. Prevention of free fatty acid-induced hepatic lipotoxicity by carnitine via reversal of mitochondrial dysfunction. Liver Int., 31(9):1315-1324.

[23]Karahan, S., Kincaid, S.A., Lauten, S.D., et al., 2002. In vivo whole body and appendicular bone mineral density in rats: a dual energy X-ray absorptiometry study. Comp. Med., 52(2):143-151.

[24]Kaufmann, P., Török, M., Zahno, A., et al., 2006. Toxicity of statins on rat skeletal muscle mitochondria. Cell. Mol. Life Sci., 63(19-20):2415-2425.

[25]Kharode, Y.P., Sharp, M.C., Bodine, P.V., 2008. Utility of the ovariectomized rat as a model for human osteoporosis in drug discovery. In: Westendorf, J.J. (Ed.), Osteoporosis. Methods and Protocols, Humana Press, Vol. 455, p.111-124.

[26]Ko, Y.J., Wu, J.B., Ho, H.Y., et al., 2012. Antiosteoporotic activity of Davallia formosana. J. Ethnopharmacol., 139(2):558-565.

[27]Krakauer, T., 2008. Nuclear factor-κB: fine-tuning a central integrator of diverse biologic stimuli. Int. Rev. Immunol., 27(5):286-292.

[28]Kumaran, S., Subathra, M., Balu, M., et al., 2005. Supplementation of L-carnitine improves mitochondrial enzymes in heart and skeletal muscle of aged rats. Exp. Aging Res., 31(1):55-67.

[29]Kwak, H.B., Thalacker-Mercer, A., Anderson, E.J., et al., 2012. Simvastatin impairs ADP-stimulated respiration and increases mitochondrial oxidative stress in primary human skeletal myotubes. Free Radic. Biol. Med., 52(1):198-207.

[30]La Guardia, P.G., Alberici, L.C., Ravagnani, F.G., et al., 2013. Protection of rat skeletal muscle fibers by either L-carnitine or coenzyme Q10 against statins toxicity mediated by mitochondrial reactive oxygen generation. Front. Physiol., 15:103.

[31]Liu, S.Z., Yan, H., Hou, W.K., et al., 2009. Relationships between endothelial nitric oxide synthase gene polymorphisms and osteoporosis in postmenopausal women. J. Zhejiang Univ.-Sci. B, 10(8):609-618.

[32]Luegmayr, E., Glantschnig, H., Wesolowski, G.A., et al., 2004. Osteoclast formation, survival and morphology are highly dependent on exogenous cholesterol/lipoproteins. Cell Death Differ., 11:S108-S118.

[33]Majima, T., Komatsu, Y., Fukao, A., et al., 2007. Short term effects of atorvastatin on bone turnover in male patients with hypercholesterolemia. Endocr. J., 54(1):145-151.

[34]Mallinson, J.E., Constantin-Teodosiu, D., Glaves, P.D., et al., 2012. Pharmacological activation of the pyruvate dehydrogenase complex reduces statin-mediated upregulation of FOXO gene targets and protects against statin myopathy in rodents. J. Physiol., 590(24):6389-63402.

[35]Mazroa, S.A., Asker, S.A., 2010. Myotoxic effects of atorvastatin drug (Lipitor) on the skeletal muscles of adult male albino rats and the effect of L-carnitine co-administration light microscopical, immunohistochemical and biochemical study. Egypt J. Histol., 33(3):520-531.

[36]Miyazaki, T., Matsunaga, T., Miyazaki, S., et al., 2004. Changes in receptor activator of nuclear factor-κB, and its ligand, osteoprotegerin, bone-type alkaline phosphatase, and tartrate-resistant acid phosphatase in ovariectomized rats. J. Cell. Biochem., 93(3):503-512.

[37]Moon, H.J., Ko, W.K., Jung, M.S., et al., 2013. Coenzyme Q10 regulates osteoclast and osteoblast differentiation. J. Food Sci., 78(5):H785-H891.

[38]Moustafa, A.M., Boshra, V., 2011. The possible role of L-carnitine on the skeletal muscle of ovariectomized rats. J. Mol. Histol., 42(3):217-225. [doi:10.1007/s10735-011-9326-6

[39]Muthusami, S., Ramachandran, I., Muthusamy, B., et al., 2005. Ovariectomy induces oxidative stress and impairs bone antioxidant system in adult rats. Clin. Chim. Acta, 360(1-2):81-86.

[40]Nakahara, K., Yada, T., Kuriyama, M., et al., 1994. Cytosolic Ca2+ increase and cell damage in L6 rat myoblasts by HMG-CoA reductase inhibitors. Biochem. Biophys. Res. Commun., 202(3):1579-1585.

[41]Nakamura, Y., Naito, M., Hayashi, K., et al., 2008. Effect of combined treatment with alendronate and calcitriol on femoral neck strength in osteopenic rats. J. Orthop. Surg. Res., 17(1):51-61. [doi:10.1186/1749-799X-3-51

[42]Ning, W.H., Zhao, K., 2013. Propionyl-L-carnitine induces eNOS activation and nitric oxide synthesis in endothelial cells via PI3 and Akt kinases. Vascul. Pharmacol., 59(3-4):76-82.

[43]Ott, S.M., 2001. Fractures after long-term alendronate therapy. J. Clin. Endocrinol. Metab., 86(4):1835-1836.

[44]Parfitt, A.M., 2002. High bone turnover is intrinsically harmful: two paths to a similar conclusion: the Parfitt view. J. Bone Miner. Res., 17(8):1558-1560.

[45]Patano, N., Mancini, L., Settanni, M.P., et al., 2008. L-Carnitine fumarate and isovaleryl-L-carnitine fumarate accelerate the recovery of bone volume/total volume ratio after experimentally induced osteoporosis in pregnant mice. Calcif. Tissue Int., 82(3):221-228.

[46]Reddy Nagareddy, P., Lakshmana, M., 2005. Assessment of experimental osteoporosis using CT scanning, quantitative X-ray analysis and impact test in calcium deficient ovariectomized rats. J. Pharmacol. Toxicol., 52(3):350-355.

[47]Russo, E., Donato di Paola, E., Gareri, P., et al., 2013. Pharmacodynamic potentiation of antiepileptic drugs’ effects by some HMG-CoA reductase inhibitors against audiogenic seizures in DBA/2 mice. Pharmacol. Res., 70(1):1-12.

[48]Schaars, C.F., Stalenhoef, A.F., 2008. Effects of ubiquinone (coenzyme Q10) on myopathy in statin users. Curr. Opin. Lipidol., 19(6):553-557.

[49]Seeman, E., Devogelaer, J.P., Lorenc, R., et al., 2008. Strontium ranelate reduces the risk of vertebral fractures in patients with osteopenia. J. Bone Miner. Res., 23(3):433438.

[50]Seif, A.A., 2014. Nigella Sativa reverses osteoporosis in ovariectomized rats. BMC Complement. Altern. Med., 14(1):22.

[51]Siekmann, L., Bonora, R., Burtis, C.A., et al., 2002. IFCC primary reference procedures for the measurement of catalytic activity concentrations of enzymes at 37 °C. Part 7. Certification of four reference materials for the determination of enzymatic activity of γ-glutamyltransferase, lactate dehydrogenase, alanine aminotransferase and creatine kinase according to IFCC Reference Procedures at 37 °C. Clin. Chem. Lab. Med., 40(7):739-745.

[52]Sirvent, P., Mercier, J., Vassort, G., et al., 2005a. Simvastatin triggers mitochondria-induced Ca2+ signaling alteration in skeletal muscle. Biochem. Biophys. Res. Commun., 329(3):1067-1075.

[53]Sirvent, P., Bordenave, S., Vermaelen, M., et al., 2005b. Simvastatin induces impairment in skeletal muscle while heart is protected. Biochem. Biophys. Res. Commun., 338(3):1426-1434.

[54]Sirvent, P., Mercier, J., Lacampagne, A., 2008. New insights into mechanisms of statin-associated myotoxicity. Curr. Opin. Pharmacol., 8(3):333-338.

[55]Sotiriadou, S., Kyparos, A., Mougios, V., et al., 2003. Estrogen effect on some enzymes in female rats after downhill running. Physiol. Res., 52(6):743-748.

[56]Staal, A., Frith, J.C., French, M.H., et al., 2003. The ability of statins to inhibit bone resorption is directly related to their inhibitory effect on HMG-CoA reductase activity. J. Bone Miner. Res., 18(1):88-96.

[57]Taha, D.A., de Moor, C.H., Barrett, D.A., et al., 2014. Translational insight into statin-induced muscle toxicity: from cell culture to clinical studies. Transl. Res., 164(2):85-109.

[58]Tian, L., Dang, X.Q., Wang, C.S., et al., 2013. Effects of sodium ferulate on preventing steroid-induced femoral head osteonecrosis in rabbits. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 14(5):426-437.

[59]Tsartsalis, A.N., Dokos, C., Kaiafa, G.D., et al., 2012. Statins, bone formation and osteoporosis: hope or hype? Hormones (Athens), 11(2):126-139.

[60]Uyar, Y., Baytur, Y., Inceboz, U., et al., 2009. Comparative effects of risedronate, atorvastatin, estrogen and SERMs on bone mass and strength in ovariectomized rats. Maturitas, 63(3):261-267.

[61]Venero, C.V., Thompson, P.D., 2009. Managing statin myopathy. Endocrinol. Metab. Clin. North Am., 38(1):121-136.

[62]Viereck, V., Gründker, C., Blaschke, S., et al., 2005. Atorvastatin stimulates the production of osteoprotegerin by human osteoblasts. J. Cell. Biochem., 96(6):1244-1253.

[63]Virmani, A., Gaetani, F., Binienda, Z., 2005. Effects of metabolic modifiers such as carnitines, coenzyme Q10, and PUFAs against different forms of neurotoxic insults: metabolic inhibitors, MPTP, and methamphetamine. Ann. N. Y. Acad. Sci., 1053(1):183-191.

[64]Wang, J., Guo, T., 2013. Metabolic remodeling in chronic heart failure. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 14(8):688-695.

[65]Writing Group for the ISCD Position Development Conference, 2004. Position statement: executive summary. The Writing Group for the International Society for Clinical Densitometry (ISCD) Position Development Conference. J. Clin. Densitom., 7(1):7-12.

[66]Yao, W., Farmer, R., Cooper, R., et al., 2006. Simvastatin did not prevent nor restore ovariectomy-induced bone loss in adult rats. J. Musculoskelet. Neuronal. Interact., 6(3):277-283.

[67]Young, J.M., Molyneux, S.L., Reinheimer, A.M., et al., 2011. Relationship between plasma coenzyme Q10, asymmetric dimethylarginine and arterial stiffness in patients with phenotypic or genotypic familial hypercholesterolemia on long-term statin therapy. Atherosclerosis, 218(1): 188-193.

[68]Zhang, Y., Zheng, Y.X., Zhu, J.M., et al., 2015. Effects of antiepileptic drugs on bone mineral density and bone metabolism in children: a meta-analysis. J. Zhejiang Univ.-Sci. B (Biomed. & Biotechnol.), 16(7):611-621.

[69]Zlatohlavek, L., Vrablik, M., Grauova, B., et al., 2012. The effect of coenzyme Q10 in statin myopathy. Neuro Endocrinol. Lett., 33(Suppl. 2):98-101.

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