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Abstract Objective To explore the underlying mechanisms of L-carnitine on improving cancer cachexia. Methods 100ng/ml TNF-α was used in murine myoblast cell-line C2C12 to induce cell atrophy. Cell model of cancer cachexia associated skeletal muscle loss was established. Differentiation status of skeletal muscle fiber treated by different doses of L-carnitine was observed under microscope after stained by crystal violet. Lipid metabolism related protein expressions in C2C12 were analyzed using Western Blot to explore the underlying mechanisms of L-carnitine on improving cancer cachexia. Results 100μg/ml and 1000μg/ml L-carnitine treatments induced differentiation of C2C12 and increased the diameter of skeletal muscle fiber (P<0.001). TNF-α group compared with the control group， the expression of CPT-I and PGC-1α decreased， while FOXO1， CD36 and PDK4 elevated. L-carnitine induced PGC1-α and CPT-I expressions but inhibited FOXO1 and CD36 expressions. L-carnitine had no effects on PDK4 expression. Conclusion L-carnitine improves cancer associated cachexia and increases skeletal muscle protein via regulating lipid metabolism capacity.
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1.Fearon K， Strasser F， Anker SD， et al. Definition and classification of cancer cachexia: an international consensus. Lancet Oncol. 2011;12(5):489-495.
2.Haehling SV， Anker SD. Cachexia as major underestimated unmet medical need: facts and numbers. Int J Cardiol. 2012;161(3):121-123.
3.Penet MF， Bhujwalla ZM. Cancer cachexia， recent advances， and future directions. Cancer J. 2015;21(2):117-122.
4.Gregory JF 3rd， Cuskelly GJ， Shane B， et al. Primed，constant infusion with ［H-2(3)］serine allows in vivo kinetic measurement of serine turnover， homocysteine remethylation， and transsulfuration processes in human one-carbon metabolism. Am J Clin Nutr. 2000;72(6):1535-1541.
5.Jiang F， Zhang Z， Zhang Y， et al. L-carnitine ameliorates cancer cachexia in mice partly via the carnitine palmitoyltransferase-associated ppar-gamma signaling pathway. Oncol Res Treat. 2015;38(10):511-516.
6.Szefel J， Kruszewski WJ， Ciesielski M， et al. L-carnitine and cancer cachexia. I. L-carnitine distribution and metabolic disorders in cancer cachexia. Oncol Rep. 2012;28(1):319-323.
7.Li Q， Guo-Ross S， Lewis DV， et al. Dietary prenatal choline supplementation alters postnatal hippocampal structure and function. J Neurophysiol. 2004;91(4):1545-1555.
8.He F， Jin JQ， Qin QQ， et al. Resistin regulates fatty acid beta oxidation by suppressing expression of peroxisome proliferator activator receptor gamma-coactivator 1alpha (PGC-1α). Cell Physiol Biochem. 2018;46(5):2165-2172.
9.Eijkelenboom A， Burgering BM. FOXOs: signalling integrators for homeostasis maintenance. Nat Rev Mol Cell Biol. 2013;14(2):83-97.
10.Sanchez AM， Candau RB， Bernardi H. FoxO transcription factors: their roles in the maintenance of skeletal muscle homeostasis. Cell Mol Life Sci. 2014;71(9):1657-1671.
11.Bastie CC， Nahle Z， McLoughlin T， et al. FoxO1 stimulates fatty acid uptake and oxidation in muscle cells through CD36-dependent and -independent mechanisms. J Biol Chem. 2005;280(14):14222-14229.
12.Piao L， Sidhu VK， Fang YH， et al. FOXO1-mediated upregulation of pyruvate dehydrogenase kinase-4(PDK4) decreases glucose oxidation and impairs right ventricular function in pulmonary hypertension: therapeutic benefits of dichloroacetate. J Mol Med (Berl). 2013;91(3):333-346.
13.Alamdari N， Aversa Z， Castillero E， et al. Resveratrol prevents dexamethasone-induced expression of the muscle atrophy-related ubiquitin ligases atrogin-1 and MuRF1 in cultured myotubes through a SIRT1-dependent mechanism. Biochem Biophys Res Commun. 2012;417(1):528-533.
14.Maglara AA， Vasilaki A， Jackson MJ， et al. Damage to developing mouse skeletal muscle myotubes in culture: protective effect of heat shock proteins. J Physiol. 2003;548(Pt 3):837-846.
15.Wang DT， Yin Y， Yang YJ， et al. Resveratrol prevents TNF-α-induced muscle atrophy via regulation of Akt/mTOR/FoxO1 signaling in C2C12 myotubes. Int Immunopharmacol. 2014;19(2):206-213.
16.骆衍新. 欧洲癌症恶液质临床治疗指南解读. 肿瘤代谢与营养电子杂志. 2014;1(1):33-35.
17.Morley JE， Argiles JM， Evans WJ， et al. Nutritional recommendations for the management of sarcopenia. J Am Med Dir Assoc. 2010;11(6):391-396.
18.Evangeliou A， Vlassopoulos D. Carnitine metabolism and deficit—when supplementation is necessary? Curr Pharm Biotechnol. 2003;4(3):211-219.
19.Laviano A， Meguid MM， Guijarro A， et al. Antimyopathic effects of carnitine and nicotine. Curr Opin Clin Nutr Metab Care. 2006;9(4):442-448.
20.Gramignano G， Lusso MR， Madeddu C， et al. Efficacy of l-carnitine administration on fatigue， nutritional status， oxidative stress， and related quality of life in 12 advanced cancer patients undergoing anticancer therapy. Nutrition. 2006;22(2):136-145.
21.Son YH， Jang EJ， Kim YW， et al. Sulforaphane prevents dexamethasone-induced muscle atrophy via regulation of the Akt/Foxo1 axis in C2C12 myotubes. Biomed Pharmacother. 2017;95:1486-1492.
22.Rohrig F， Schulze A. The multifaceted roles of fatty acid synthesis in cancer. Nat Rev Cancer. 2016;16(11):732-749.
23.Lundsgaard AM， Fritzen AM， Kiens B. Molecular regulation of fatty acid oxidation in skeletal muscle during aerobic exercise. Trends Endocrinol Metab. 2018;29(1):18-30.
24.Liu S， Wu HJ， Zhang ZQ， et al. L-carnitine ameliorates cancer cachexia in mice by regulating the expression and activity of carnitine palmityl transferase. Cancer Biol Ther. 2011;12(2):125-130.
25.Casals N， Zammit V， Herrero L， et al. Carnitine palmitoyltransferase 1C: from cognition to cancer. Prog Lipid Res. 2016;61:134-148.
26.Shao H， Mohamed EM， Xu GG， et al. Carnitine palmitoyltransferase 1A functions to repress FoxO transcription factors to allow cell cycle progression in ovarian cancer. Oncotarget. 2016;7(4):3832-3846. |
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