1Department of Clinical Nutrition, Daping Hospital, Army Medical University, Chongqing 400042, China; 2No.75220 Force, Chinese People’s Liberation Army, Huizhou 516133, Guangdong, China; 3Institute of Hepatopancreatobiliary Surgery, Southwest Hospital, Army Medical University, Chongqing 400042, China
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.
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.