[en] BACKGROUND: The control of muscle size is an essential feature of health. Indeed, skeletal muscle atrophy leads to reduced strength, poor quality of life, and metabolic disturbances. Consequently, strategies aiming to attenuate muscle wasting and to promote muscle growth during various (pathological) physiological states like sarcopenia, immobilization, malnutrition, or cachexia are needed to address this extensive health issue. In this study, we tested the effects of urolithin B, an ellagitannin-derived metabolite, on skeletal muscle growth. METHODS: C2C12 myotubes were treated with 15 muM of urolithin B for 24 h. For in vivo experiments, mice were implanted with mini-osmotic pumps delivering continuously 10 mug/day of urolithin B during 28 days. Muscle atrophy was studied in mice with a sciatic nerve denervation receiving urolithin B by the same way. RESULTS: Our experiments reveal that urolithin B enhances the growth and differentiation of C2C12 myotubes by increasing protein synthesis and repressing the ubiquitin-proteasome pathway. Genetic and pharmacological arguments support an implication of the androgen receptor. Signalling analyses suggest a crosstalk between the androgen receptor and the mTORC1 pathway, possibly via AMPK. In vivo experiments confirm that urolithin B induces muscle hypertrophy in mice and reduces muscle atrophy after the sciatic nerve section. CONCLUSIONS: This study highlights the potential usefulness of urolithin B for the treatment of muscle mass loss associated with various (pathological) physiological states.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Rodriguez, Julie
Pierre, Nicolas ; Université de Liège - ULiège > Département des sciences cliniques > Hépato-gastroentérologie
Naslain, Damien
Bontemps, Francoise
Ferreira, Daneel
Priem, Fabian
Deldicque, Louise
Francaux, Marc
Language :
English
Title :
Urolithin B, a newly identified regulator of skeletal muscle mass.
Publication date :
2017
Journal title :
Journal of Cachexia, Sarcopenia and Muscle
ISSN :
2190-5991
eISSN :
2190-6009
Publisher :
Wiley, Berlin, Germany
Volume :
8
Issue :
4
Pages :
583-597
Peer reviewed :
Peer Reviewed verified by ORBi
Commentary :
(c) 2017 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders.
Glass DJ. Skeletal muscle hypertrophy and atrophy signaling pathways. Int J Biochem Cell Biol 2005;37:1974–1984.
Cerda B, Periago P, Espin JC, Tomas-Barberan FA. Identification of urolithin a as a metabolite produced by human colon microflora from ellagic acid and related compounds. J Agric Food Chem 2005;53:5571–5576.
Espin JC, Gonzalez-Barrio R, Cerda B, Lopez-Bote C, Rey AI, Tomas-Barberan FA. Iberian pig as a model to clarify obscure points in the bioavailability and metabolism of ellagitannins in humans. J Agric Food Chem 2007;55:10476–10485.
Gonzalez-Barrio R, Truchado P, Ito H, Espin JC, Tomas-Barberan FA. UV and MS identification of urolithins and nasutins, the bioavailable metabolites of ellagitannins and ellagic acid in different mammals. J Agric Food Chem 2011;59:1152–1162.
Seeram NP, Henning SM, Zhang Y, Suchard M, Li Z, Heber D. Pomegranate juice ellagitannin metabolites are present in human plasma and some persist in urine for up to 48 hours. J Nutr 2006;136:2481–2485.
Cerda B, Espin JC, Parra S, Martinez P, Tomas-Barberan FA. The potent in vitro antioxidant ellagitannins from pomegranate juice are metabolised into bioavailable but poor antioxidant hydroxy-6H-dibenzopyran-6-one derivatives by the colonic microflora of healthy humans. Eur J Nutr 2004;43:205–220.
Sreekumar S, Sithul H, Muraleedharan P, Azeez JM, Sreeharshan S. Pomegranate fruit as a rich source of biologically active compounds. Biomed Res Int 2014;2014:686921.
Gimenez-Bastida JA, Gonzalez-Sarrias A, Larrosa M, Tomas-Barberan F, Espin JC, Garcia-Conesa MT. Ellagitannin metabolites, urolithin A glucuronide and its aglycone urolithin A, ameliorate TNF-α-induced inflammation and associated molecular markers in human aortic endothelial cells. Mol Nutr Food Res 2012;56:784–796.
Larrosa M, Gonzalez-Sarrias A, Yanez-Gascon MJ, Selma MV, Azorin-Ortuno M, Toti S, et al. Anti-inflammatory properties of a pomegranate extract and its metabolite urolithin-A in a colitis rat model and the effect of colon inflammation on phenolic metabolism. J Nutr Biochem 2010;21:717–725.
Qiu Z, Zhou B, Jin L, Yu H, Liu L, Liu Y, et al. In vitro antioxidant and antiproliferative effects of ellagic acid and its colonic metabolite, urolithins, on human bladder cancer T24 cells. Food Chem Toxicol 2013;59:428–437.
Trombold JR, Barnes JN, Critchley L, Coyle EF. Ellagitannin consumption improves strength recovery 2–3 d after eccentric exercise. Med Sci Sports Exerc 2010;42:493–498.
Rodriguez J, Gilson H, Jamart C, Naslain D, Pierre N, Deldicque L, et al. Pomegranate and green tea extracts protect against ER stress induced by a high-fat diet in skeletal muscle of mice. Eur J Nutr 2014;doi:10.1007/s00394-014-0717-9.
Li M, Kai Y, Qiang H, Dongying J. Biodegradation of gallotannins and ellagitannins. J Basic Microbiol 2006;46:68–84.
Li H, Choudhary SK, Milner DJ, Munir MI, Kuisk IR, Capetanaki Y. Inhibition of desmin expression blocks myoblast fusion and interferes with the myogenic regulators MyoD and myogenin. J Cell Biol 1994;124:827–841.
Gingras AC, Kennedy SG, O'Leary MA, Sonenberg N, Hay N. 4E-BP1, a repressor of mRNA translation, is phosphorylated and inactivated by the Akt(PKB) signaling pathway. Genes Dev 1998;12:502–513.
Sabers CJ, Martin MM, Brunn GJ, Williams JM, Dumont FJ, Wiederrecht G, et al. Isolation of a protein target of the FKBP12-rapamycin complex in mammalian cells. J Biol Chem 1995;270:815–822.
Goodman CA, Mabrey DM, Frey JW, Miu MH, Schmidt EK, Pierre P, et al. Novel insights into the regulation of skeletal muscle protein synthesis as revealed by a new nonradioactive in vivo technique. FASEB J 2011;25:1028–1039.
Sakuma K, Aoi W, Yamaguchi A. The intriguing regulators of muscle mass in sarcopenia and muscular dystrophy. Front Aging Neurosci 2014;6:230.
Kim J, Kundu M, Viollet B, Guan KL. AMPK and mTOR regulate autophagy through direct phosphorylation of Ulk1. Nat Cell Biol 2011;13:132–141.
Sandri M, Sandri C, Gilbert A, Skurk C, Calabria E, Picard A, et al. Foxo transcription factors induce the atrophy-related ubiquitin ligase atrogin-1 and cause skeletal muscle atrophy. Cell 2004;117:399–412.
Brunet A, Bonni A, Zigmond MJ, Lin MZ, Juo P, Hu LS, et al. Akt promotes cell survival by phosphorylating and inhibiting a Forkhead transcription factor. Cell 1999;96:857–868.
Bodine SC, Latres E, Baumhueter S, Lai VK, Nunez L, Clarke BA, et al. Identification of ubiquitin ligases required for skeletal muscle atrophy. Science 2001;294:1704–1708.
Zhao J, Brault JJ, Schild A, Cao P, Sandri M, Schiaffino S, et al. FoxO3 coordinately activates protein degradation by the autophagic/lysosomal and proteasomal pathways in atrophying muscle cells. Cell Metab 2007;6:472–483.
Mammucari C, Milan G, Romanello V, Masiero E, Rudolf R, Del Piccolo P, et al. FoxO3 controls autophagy in skeletal muscle in vivo. Cell Metab 2007;6:458–471.
White JP, Gao S, Puppa MJ, Sato S, Welle SL, Carson JA. Testosterone regulation of Akt/mTORC1/FoxO3a signaling in skeletal muscle. Mol Cell Endocrinol 2013;365:174–186.
Adams LS, Zhang Y, Seeram NP, Heber D, Chen S. Pomegranate ellagitannin-derived compounds exhibit antiproliferative and antiaromatase activity in breast cancer cells in vitro. Cancer Prev Res (Phila) 2010;3:108–113.
Furr BJ, Tucker H. The preclinical development of bicalutamide: pharmacodynamics and mechanism of action. Urology 1996;47:13–25, discussion 9-32.
Espin JC, Larrosa M, Garcia-Conesa MT, Tomas-Barberan F. Biological significance of urolithins, the gut microbial ellagic acid-derived metabolites: the evidence so far. Evid Based Complement Alternat Med 2013;2013:270418.
Rodriguez J, Vernus B, Chelh I, Cassar-Malek I, Gabillard JC, Hadj Sassi A, et al. Myostatin and the skeletal muscle atrophy and hypertrophy signaling pathways. Cell Mol Life Sci 2014;71:4361–4371.
Ogawa M, Kariya Y, Kitakaze T, Yamaji R, Harada N, Sakamoto T, et al. The preventive effect of beta-carotene on denervation-induced soleus muscle atrophy in mice. Br J Nutr 2013;109:1349–1358.
Dyle MC, Ebert SM, Cook DP, Kunkel SD, Fox DK, Bongers KS, et al. Systems-based discovery of tomatidine as a natural small molecule inhibitor of skeletal muscle atrophy. J Biol Chem 2014;289:14913–14924.
Kunkel SD, Suneja M, Ebert SM, Bongers KS, Fox DK, Malmberg SE, et al. mRNA expression signatures of human skeletal muscle atrophy identify a natural compound that increases muscle mass. Cell Metab 2011;13:627–638.
Basualto-Alarcon C, Jorquera G, Altamirano F, Jaimovich E, Estrada M. Testosterone signals through mTOR and androgen receptor to induce muscle hypertrophy. Med Sci Sports Exerc 2013;45:1712–1720.
Ibebunjo C, Eash JK, Li C, Ma Q, Glass DJ. Voluntary running, skeletal muscle gene expression, and signaling inversely regulated by orchidectomy and testosterone replacement. Am J Physiol Endocrinol Metab 2011;300:E327–E340.
Serra C, Sandor NL, Jang H, Lee D, Toraldo G, Guarneri T, et al. The effects of testosterone deprivation and supplementation on proteasomal and autophagy activity in the skeletal muscle of the male mouse: differential effects on high-androgen responder and low-androgen responder muscle groups. Endocrinology 2013;154:4594–4606.
Shen M, Zhang Z, Ratnam M, Dou QP. The interplay of AMP-activated protein kinase and androgen receptor in prostate cancer cells. J Cell Physiol 2014;229:688–695.
Zhao W, Pan J, Wang X, Wu Y, Bauman WA, Cardozo CP. Expression of the muscle atrophy factor muscle atrophy F-box is suppressed by testosterone. Endocrinology 2008;149:5449–5460.
Zhao W, Pan J, Zhao Z, Wu Y, Bauman WA, Cardozo CP. Testosterone protects against dexamethasone-induced muscle atrophy, protein degradation and MAFbx upregulation. J Steroid Biochem Mol Biol 2008;110:125–129.
Pires-Oliveira M, Maragno AL, Parreiras-e-Silva LT, Chiavegatti T, Gomes MD, Godinho RO. Testosterone represses ubiquitin ligases atrogin-1 and Murf-1 expression in an androgen-sensitive rat skeletal muscle in vivo. J Appl Physiol (1985). 2010;108:266–273.
Chen SA, Besman MJ, Sparkes RS, Zollman S, Klisak I, Mohandas T, et al. Human aromatase: cDNA cloning, Southern blot analysis, and assignment of the gene to chromosome 15. DNA 1988;7:27–38.
Satoh K, Sakamoto Y, Ogata A, Nagai F, Mikuriya H, Numazawa M, et al. Inhibition of aromatase activity by green tea extract catechins and their endocrinological effects of oral administration in rats. Food Chem Toxicol 2002;40:925–933.
Coward RM, Rajanahally S, Kovac JR, Smith RP, Pastuszak AW, Lipshultz LI. Anabolic steroid induced hypogonadism in young men. J Urol 2013;190:2200–2205.
Herbst KL, Anawalt BD, Amory JK, Matsumoto AM, Bremner WJ. The male contraceptive regimen of testosterone and levonorgestrel significantly increases lean mass in healthy young men in 4 weeks, but attenuates a decrease in fat mass induced by testosterone alone. J Clin Endocrinol Metab 2003;88:1167–1173.
O'Leary MF, Hood DA. Effect of prior chronic contractile activity on mitochondrial function and apoptotic protein expression in denervated muscle. J Appl Physiol (1985) 2008;105:114–120.
Quy PN, Kuma A, Pierre P, Mizushima N. Proteasome-dependent activation of mammalian target of rapamycin complex 1 (mTORC1) is essential for autophagy suppression and muscle remodeling following denervation. J Biol Chem 2013;288:1125–1134.
O'Leary MF, Hood DA. Denervation-induced oxidative stress and autophagy signaling in muscle. Autophagy 2009;5:230–231.
Beehler BC, Sleph PG, Benmassaoud L, Grover GJ. Reduction of skeletal muscle atrophy by a proteasome inhibitor in a rat model of denervation. Exp Biol Med (Maywood) 2006;231:335–341.
MacDonald EM, Andres-Mateos E, Mejias R, Simmers JL, Mi R, Park JS, et al. Denervation atrophy is independent from Akt and mTOR activation and is not rescued by myostatin inhibition. Dis Model Mech 2014;7:471–481.
Shao C, Liu M, Wu X, Ding F. Time-dependent expression of myostatin RNA transcript and protein in gastrocnemius muscle of mice after sciatic nerve resection. Microsurgery 2007;27:487–493.
Pierre N, Barbe C, Gilson H, Deldicque L, Raymackers JM, Francaux M. Activation of ER stress by hydrogen peroxide in C2C12 myotubes. Biochem Biophys Res Commun 2014;450:459–463.
Rodriguez J, Fernandez-Verdejo R, Pierre N, Priem F, Francaux M. Endurance training attenuates catabolic signals induced by TNF-α in muscle of mice. Med Sci Sports Exerc 2015.
von Haehling S, Morley JE, Coats AJS, Anker SD. Ethical guidelines for publishing in the Journal of Cachexia, Sarcopenia and Muscle: update 2015. J Cachexia Sarcopenia Muscle 2015;6:315–316.
