Abstract
Duchenne muscular dystrophy (DMD) is a progressive neuromuscular disease caused by a mutation in the gene encoding the dystrophin protein. Catalpol is an iridoid glycoside found in Chinese herbs with anti-inflammatory, anti-oxidant, anti-apoptotic, and hypoglycemic activities that can protect against muscle wasting. In the present study we investigated the effects of catalpol on DMD. Aged Dystrophin-deficient (mdx) mice (12 months old) were treated with catalpol (100, 200 mg·kg−1·d−1, ig) for 6 weeks. At the end of the experiment, the mice were sacrificed, and gastrocnemius (GAS), tibialis anterior (TA), extensor digitorum longus (EDL), soleus (SOL) muscles were collected. We found that catalpol administration dose-dependently increased stride length and decreased stride width in Gait test. Wire grip test showed that the time of wire grip and grip strength were increased. We found that catalpol administration dose-dependently alleviated skeletal muscle damage, evidenced by reduced plasma CK and LDH activity as well as increased the weight of skeletal muscles. Catalpol administration had no effect on dystrophin expression, but exerted anti-inflammatory effects. Furthermore, catalpol administration dose-dependently decreased tibialis anterior (TA) muscle fibrosis, and inhibited the expression of TGF-β1, TAK1 and α-SMA. In primary myoblasts from mdx mice, knockdown of TAK1 abolished the inhibitory effects of catalpol on the expression levels of TGF-β1 and α-SMA. In conclusion, catalpol can restore skeletal muscle strength and alleviate skeletal muscle damage in aged mdx mice, thus may provide a novel therapy for DMD. Catalpol attenuates muscle fibrosis by inhibiting the TGF-β1/TAK1 signaling pathway.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Govoni A, Magri F, Brajkovic S, Zanetta C, Faravelli I, Corti S, et al. Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70:4585–602.
Davies KE, Nowak KJ. Molecular mechanisms of muscular dystrophies: old and new players. Nat Rev Mol Cell Biol. 2006;7:762–73.
Delaney K, Kasprzycka P, Ciemerych MA, Zimowska M. The role of TGF-β1 during skeletal muscle regeneration. Cell Biol Int. 2017;41:707–15.
Ponnusamy S, Sullivan RD, You D, Zafar N, Yang CH, Thiyagarajan T, et al. Androgen receptor agonists increase lean mass, improve cardiopulmonary functions and extend survival in preclinical models of Duchenne muscular dystrophy. Hum Mol Genet. 2017;26:2526–40.
Emery AE. The muscular dystrophies. Lancet. 2002;359:687–95.
Nguyen LN, Ferry A, Schnell FJ, Hanson GJ, Popplewell L, Dickson G, et al. Functional muscle recovery following dystrophin and myostatin exon splice modulation in aged mdx mice. Hum Mol Genet. 2019;28:3091–100.
Guiraud S, Chen H, Burns DT, Davies KE. Advances in genetic therapeutic strategies for Duchenne muscular dystrophy. Exp Physiol. 2015;100:1458–67.
Bi J, Wang XB, Chen L, Hao S, An LJ, Jiang BO, et al. Catalpol protects mesencephalic neurons against MPTP-induced neurotoxicity via attenuation of mitochondrial dysfunction and MAO-B activity. Toxicol Vitr. 2008;136:1883–9.
Chen YW, Nagaraju K, Bakay M, McIntyre O, Rawat R, Shi R, et al. Early onset of inflammation and later involvement of TGFbeta in Duchenne muscular dystrophy. Neurology. 2005;65:826–34.
Nelson CA, Hunter RB, Quigley LA, Girgenrath S, Weber WD, McCullough JA, et al. Inhibiting TGF-β activity improves respiratory function in mdx mice. Am J Pathol. 2011;178:2611–21.
Mihaly SR, Ninomiya-Tsuji J, Morioka S, Differentiation. TAK1 control of cell death. Cell Death Differ. 2014;21:1667–76.
Hindi SM, Sato S, Xiong G, Bohnert KR, Gibb AA, Gallot YS, et al. TAK1 regulates skeletal muscle mass and mitochondrial function. JCI Insight. 2018;3:e98441.
Zhao JL, Zhang T, Shao X, Zhu JJ, Guo MZ. Curcumin ameliorates peritoneal fibrosis via inhibition of transforming growth factor-activated kinase 1 (TAK1) pathway in a rat model of peritoneal dialysis. BMC Complement Alter Med. 2019;19:280.
Huang WJ, Niu HS, Lin MH, Cheng JT, Hsu FL. Antihyperglycemic effect of catalpol in streptozotocin-induced diabetic rats. J Nat Prod. 2010;73:1170–2.
Liu JY, Zheng CZ, Hao XP, Zhang DJ, Mao AW, Yuan P. Catalpol ameliorates diabetic atherosclerosis in diabetic rabbits. Am J Transl Res. 2016;8:4278–88.
Xu DQ, Wang L, Jiang ZZ, Zhao GL, Hassan HM, Sun LX, et al. A new hypoglycemic mechanism of catalpol revealed by enhancing MyoD/MyoG-mediated myogenesis. Life Sci. 2018;209:313–23.
Mcdonald AA, Hebert SL, Kunz MD, Ralles SJ, Mcloon LK. Disease course in mdx:utrophin+/− mice: comparison of three mouse models of Duchenne muscular dystrophy. Physiol Rep. 2015;3:e12391.
Haddix SG, Lee YI, Kornegay JN, Thompson WJ. Cycles of myofiber degeneration and regeneration lead to remodeling of the neuromuscular junction in two mammalian models of Duchenne muscular dystrophy. PLoS One. 2018;13:e0205926.
Carnwath JW, Shotton DM. Muscular dystrophy in the mdx mouse: histopathology of the soleus and extensor digitorum longus muscles. J Neurol Sci. 1987;80:39–54.
Pastoret C, Sebille A. mdx mice show progressive weakness and muscle deterioration with age. J Neurol Sci. 1995;129:97–105.
Roig M, Roma J, Fargas A, Munell F. Longitudinal pathologic study of the gastrocnemius muscle group in mdx mice. Acta Neuropathol. 2004;107:27–34.
Koopman R, van Loon LJ. Aging, exercise, and muscle protein metabolism. J Appl Physiol. 2009;106:2040–8.
Xu DQ, Jiang ZZ, Sun ZR, Wang L, Zhao GL, Hassan HM, et al. Mitochondrial dysfunction and inhibition of myoblast differentiation in mice with high-fat-diet-induced pre-diabetes. J Cell Physiol. 2019;234:7510–23.
Harris JB. Myotoxic phospholipases A2 and the regeneration of skeletal muscles. Toxicon 2003;42:933–45.
Loro E, Sengupta K, Bogdanovich S, Whig K, Schultz DC, Huryn DM, et al. High-throughput identification of post-transcriptional utrophin up-regulators for Duchenne muscle dystrophy (DMD) therapy. Sci Rep. 2020;10:2132.
Duan D. Micro-utrophin therapy for duchenne muscular dystrophy. Mol Ther. 2019;27:1872–4.
Gilbert R, Nalbantoglu J, Petrof BJ, Ebihara S, Guibinga GH, Tinsley JM, et al. Adenovirus-mediated utrophin gene transfer mitigates the dystrophic phenotype of mdx mouse muscles. Hum Gene Ther. 1999;10:1299–310.
Desguerre I, Arnold L, Vignaud A, Cuvellier S, Yacoub-Youssef H, Gherardi RK, et al. A new model of experimental fibrosis in hindlimb skeletal muscle of adult mdx mouse mimicking muscular dystrophy. Muscle Nerve. 2012;45:803–14.
Liu JY, Zhang DJ. Amelioration by catalpol of atherosclerotic lesions in hypercholesterolemic rabbits. Planta Med. 2015;81:175–84.
Liu Z, Zhu P, Zhang L, Xiong B, Tao J, Guan W, et al. Autophagy inhibition attenuates the induction of anti-inflammatory effect of catalpol in liver fibrosis. Biomed Pharmacother. 2018;103:1262–71.
Choi HJ, Jang HJ, Chung TW, Jeong SI, Cha J, Choi JY, et al. Catalpol suppresses advanced glycation end-products-induced inflammatory responses through inhibition of reactive oxygen species in human monocytic THP-1 cells. Fitoterapia. 2013;86:19–28.
Xu DQ, Li CJ, Jiang ZZ, Wang L, Huang HF, Li ZJ, et al. The hypoglycemic mechanism of catalpol involves increased AMPK-mediated mitochondrial biogenesis. Acta Pharmacol Sin. 2020;41:791–9.
Dowling JJ. Eteplirsen therapy for Duchenne muscular dystrophy: skipping to the front of the line. Nat Rev Neurol. 2016;12:675–6.
Crone M, Mah JK. Current and emerging therapies for duchenne muscular dystrophy. Curr Treat Options Neurol. 2018;20:17–31.
Stein CA. Eteplirsen approved for duchenne muscular dystrophy: the FDA faces a difficult choice. Mol Ther. 2016;24:1884–5.
Verhaart IE, Aartsma-Rus A. Therapeutic developments for Duchenne muscular dystrophy. Nat Rev Neurol. 2019;15:373–86.
Aartsma-Rus A, Krieg AM. FDA approves eteplirsen for duchenne muscular dystrophy: the next chapter in the eteplirsen saga. Nucleic Acid Ther. 2017;27:1–3.
Spurney CF, Rocha CT, Henricson E, Florence J, Mayhew J, Gorni K, et al. CINRG pilot trial of coenzyme Q10 in steroid-treated Duchenne muscular dystrophy. Muscle Nerve. 2011;44:174–8.
Dorchies OM, Reutenauer-Patte J, Dahmane E, Ismail HM, Petermann O, Patthey- Vuadens O, et al. The anticancer drug tamoxifen counteracts the pathology in a mouse model of duchenne muscular dystrophy. Am J Pathol. 2013;182:485–504.
Nagy S, Hafner P, Schmidt S, Rubino-Nacht D, Schadelin S, Bieri O, et al. Tamoxifen in Duchenne muscular dystrophy (TAMDMD): study protocol for a multicenter, randomized, placebo-controlled, double-blind phase 3 trial. Trials. 2019;20:637.
Ogura Y, Hindi SM, Sato S, Xiong G, Akira S, Kumar A. TAK1 modulates satellite stem cell homeostasis and skeletal muscle repair. Nat Commun. 2015;6:10123.
Xu D, Zhao L, Jiang J, Li S, Sun Z, Huang X. A potential therapeutic effect of catalpol in Duchenne muscular dystrophy revealed by binding with TAK1. J Cachexia Sarcopenia Muscle. 2020. https://doi.org/10.1002/jcsm.12581.
Yan C, Yang Q, Gong Z. Transgenic expression of tgfb1a induces hepatic inflammation, fibrosis and metastasis in zebrafish. Biochem Biophys Res Commun. 2019;509:175–81.
Acknowledgements
This work was supported by grants from the Scholar of the 14th Batch of “Six Talents Peak” High-level Talent Selection Program (SWYY-094); the Postgraduate Research Practice Innovation Program of Jiangsu Province (KYCX19-0763); the “Double First-Class” University Project (CPU2018GY33); and the National Natural Science Foundation of China (Nos. 81773827 and 81573514 to ZZJ; No. 81773995 to LYZ).
Author information
Authors and Affiliations
Contributions
DQX, SJL, and LZ, did the research work, discussed the results, and wrote the manuscript. XFH and CJL collected and analyzed the data. LXS, and XHL, reviewed the manuscript. ZZJ, conceived the experiments, researched the data, and edited/reviewed the manuscript. LYZ, is the guarantor of this work, has full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.
Corresponding authors
Ethics declarations
Conflict of interest
The authors declare that they have no conflict of interest.
Supplementary information
Rights and permissions
About this article
Cite this article
Xu, Dq., Zhao, L., Li, Sj. et al. Catalpol counteracts the pathology in a mouse model of Duchenne muscular dystrophy by inhibiting the TGF-β1/TAK1 signaling pathway. Acta Pharmacol Sin 42, 1080–1089 (2021). https://doi.org/10.1038/s41401-020-00515-1
Received:
Accepted:
Published:
Version of record:
Issue date:
DOI: https://doi.org/10.1038/s41401-020-00515-1
