摘要
目的 探讨左旋肉碱是否能改善肿瘤恶液质的骨骼肌萎缩及可能的分子机制。方法 用100ng/ml 肿瘤坏死因子-α诱导小鼠C2C12成肌细胞萎缩建立肿瘤恶液质的骨骼肌减少的细胞模型，不同剂量左旋肉碱干预C2C12细胞肌纤维成熟过程；结晶紫染色观察各组肌纤维分化成熟状态，并通过Western Blot技术分析C2C12细胞内糖脂代谢相关蛋白的表达水平，探讨左旋肉碱能否改善骨骼肌细胞萎缩及可能的机制。结果 100μg/ml和1000μg/ml左旋肉碱干预能够促进C2C12细胞分化，抑制TNF-α诱导的肌纤维变细（P<0.001）。TNF-α组与对照组比较，肌细胞脂质代谢、糖代谢相关蛋白中 CPT-Ⅰ和PGC-1α表达下降，FOXO1、CD36以及PDK4的表达升高。左旋肉碱干预促进CPT-Ⅰ和PGC-1α的表达增加，抑制了FOXO1、CD36的表达，但对PDK4的表达无影响。结论 左旋肉碱可能通过调节肌细胞脂代谢来改善细胞肿瘤恶液质。
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.
关键词
左旋肉碱 /
TNF-&alpha /
C2C12 /
肿瘤恶液质 /
脂代谢
Key words
L-carnitine /
TNF-α /
C2C12 /
Cancer cachexia /
Lipid metabolism
1，2朱明星，1吴长蓬，3尹梁宇，1卢宗亮，1黎娜，1刘洁，1郭静，1许红霞.
左旋肉碱通过调节脂代谢改善恶液质骨骼肌细胞萎缩[J]. 肿瘤代谢与营养电子杂志. 2019, 6(3): 320-325 https://doi.org/10.16689/j.cnki.cn11-9349/r.2019.03.010
1，2ZHU Ming-xing， 1WU Chang-peng， 3YIN Liang-yu，1LU Zong-liang， 1LI Na，1LIU Jie， 1GUO Jing， 1XU Hong-xia.
L-carnitine improves skeletal muscle cell atrophy of cancer cachexia by regulating lipid metabolism[J]. Electronic Journal of Metabolism and Nutrition of Cancer. 2019, 6(3): 320-325 https://doi.org/10.16689/j.cnki.cn11-9349/r.2019.03.010
{{custom_sec.title}}
{{custom_sec.title}}
{{custom_sec.content}}
参考文献
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.
PDF(2783 KB)
