https://doi.org/10.4081/ejtm.2020.8904
Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention
Submitted: 19 February 2020
Accepted: 12 March 2020
Published: 22 June 2020
Accepted: 12 March 2020
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
Duchenne Muscular Dystrophy is a devastating disease caused by the absence of a functional rod-shaped cytoplasmic protein called dystrophin. Several avenues are being developed aimed to restore dystrophin expression in boys affected by this X-linked disease. However, its complete cure is likely to need combinational approaches which may include regimes aimed at restoring muscle mass. Augmenting muscle growth through the manipulation of the Myostatin/Activin signalling axis has received much attention. However, we have recently shown that while manipulation of this axis in wild type mice using the sActRIIB ligand trap indeed results in muscle growth, it also had a detrimental impact on the testis. Here we examined the impact of administering a powerful Myostatin/Activin antagonist in two mouse models of Duchenne Muscular Dystrophy. We report that whilst the impact on muscle growth was not always positive, both models showed attenuated testis development. Sperm number, motility and ultrastructure were significantly affected by the sActRIIB treatment. Our report suggests that interventions based on Myostatin/Activin should investigate off-target effects on tissues as well as muscle.
Hoffman EP, Brown RH, Jr., Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919-28.
DOI: https://doi.org/10.1016/0092-8674(87)90579-4
Falzarano MS, Scotton C, Passarelli C, Ferlini A. Duchenne Muscular Dystrophy: From Diagnosis to Therapy. Molecules. 2015;20(10):18168-84.
DOI: https://doi.org/10.3390/molecules201018168
Petrof BJ, Shrager JB, Stedman HH, Kelly AM, Sweeney HL. Dystrophin protects the sarcolemma from stresses developed during muscle contraction. Proc Natl Acad Sci U S A. 1993;90(8):3710-4.
DOI: https://doi.org/10.1073/pnas.90.8.3710
Patel K, Amthor H. The function of Myostatin and strategies of Myostatin blockade-new hope for therapies aimed at promoting growth of skeletal muscle. Neuromuscul Disord. 2005;15(2):117-26.
DOI: https://doi.org/10.1016/j.nmd.2004.10.018
McPherron AC, Lawler AM, Lee SJ. Regulation of skeletal muscle mass in mice by a new TGF-beta superfamily member. Nature. 1997;387(6628):83-90.
DOI: https://doi.org/10.1038/387083a0
Olsen OE, Wader KF, Hella H, et al. Activin A inhibits BMP-signaling by binding ACVR2A and ACVR2B. Cell Commun Signal. 2015;13:27.
DOI: https://doi.org/10.1186/s12964-015-0104-z
Relizani K, Mouisel E, Giannesini B, Hourde C, et al. Blockade of ActRIIB signaling triggers muscle fatigability and metabolic myopathy. Mol Ther. 2014;22(8):1423-33.
DOI: https://doi.org/10.1038/mt.2014.90
Latres E, Mastaitis J, Fury W, Miloscio L, Trejos J, Pangilinan J, et al. Activin A more prominently regulates muscle mass in primates than does GDF8. Nat Commun. 2017;8:15153.
DOI: https://doi.org/10.1038/ncomms15153
Vaughan D, Ritvos, O., Mitchell, R., Inhibition of Activin/Myostatin signalling induces skeletal muscle hypertrophy but impairs mouse testicular development. European Journal of Translational Myology. 2020.
DOI: https://doi.org/10.4081/ejtm.2019.8737
Alexander BE, Mueller B, Vermeij MJA, van der Geest HHG, de Goeij JM. Biofouling of inlet pipes affects water quality in running seawater aquaria and compromises sponge cell proliferation. PeerJ. 2015;3:e1430.
DOI: https://doi.org/10.7717/peerj.1430
Qiao C, Li J, Jiang J, Zhu X, et al. Myostatin propeptide gene delivery by adeno-associated virus serotype 8 vectors enhances muscle growth and ameliorates dystrophic phenotypes in mdx mice. Hum Gene Ther. 2008;19(3):241-54.
DOI: https://doi.org/10.1089/hum.2007.159
Sicinski P, Geng Y, Ryder-Cook AS, et al.The molecular basis of muscular dystrophy in the mdx mouse: a point mutation. Science. 1989;244(4912):1578-80.
DOI: https://doi.org/10.1126/science.2662404
Costoya JA, Hobbs RM, Barna M, et al. Essential role of Plzf in maintenance of spermatogonial stem cells. Nat Genet. 2004;36(6):653-9.
DOI: https://doi.org/10.1038/ng1367
Zhou Q, Nie R, Li Y, et al. Expression of stimulated by retinoic acid gene 8 (Stra8) in spermatogenic cells induced by retinoic acid: an in vivo study in vitamin A-sufficient postnatal murine testes. Biol Reprod. 2008;79(1):35-42.
DOI: https://doi.org/10.1095/biolreprod.107.066795
Morais da Silva S, Hacker A, Harley V, Sox9 expression during gonadal development implies a conserved role for the gene in testis differentiation in mammals and birds. Nat Genet. 1996;14(1):62-8.
DOI: https://doi.org/10.1038/ng0996-62
Chen Q, Peng H, Lei L, et al. Aquaporin3 is a sperm water channel essential for postcopulatory sperm osmoadaptation and migration. Cell Res. 2011;21(6):922-33.
DOI: https://doi.org/10.1038/cr.2010.169
Coley WD, Bogdanik L, Vila MC, Yu Q, Van Der Meulen JH, Rayavarapu S, et al. Effect of genetic background on the dystrophic phenotype in mdx mice. Hum Mol Genet. 2016;25(1):130-45.
DOI: https://doi.org/10.1093/hmg/ddv460
Fukada S, Morikawa D, Yamamoto Y, et al. Genetic background affects properties of satellite cells and mdx phenotypes. Am J Pathol. 2010;176(5):2414-24.
DOI: https://doi.org/10.2353/ajpath.2010.090887
Campbell C, McMillan HJ, Mah JK, et al. Myostatin inhibitor ACE-031 treatment of ambulatory boys with Duchenne muscular dystrophy: Results of a randomized, placebo-controlled clinical trial. Muscle Nerve. 2017;55(4):458-64.
DOI: https://doi.org/10.1002/mus.25268
Li ZB, Kollias HD, Wagner KR. Myostatin directly regulates skeletal muscle fibrosis. J Biol Chem. 2008;283(28):19371-8.
DOI: https://doi.org/10.1074/jbc.M802585200
Schneyer A, Tortoriello D, Sidis Y, et al. Follistatin-related protein (FSRP): a new member of the follistatin gene family. Mol Cell Endocrinol. 2001;180(1-2):33-8.
DOI: https://doi.org/10.1016/S0303-7207(01)00501-9
Maguer-Satta V, Bartholin L, Jeanpierre S, et al. Expression of FLRG, a novel activin A ligand, is regulated by TGF-beta and during hematopoiesis [corrected]. Exp Hematol. 2001;29(3):301-8.
DOI: https://doi.org/10.1016/S0301-472X(00)00675-5
Sidis Y, Mukherjee A, Keutmann H, et al. Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins. Endocrinology. 2006;147(7):3586-97.
DOI: https://doi.org/10.1210/en.2006-0089
Hill JJ, Davies MV, Pearson AA, et al. The myostatin propeptide and the follistatin-related gene are inhibitory binding proteins of myostatin in normal serum. J Biol Chem. 2002;277(43):40735-41.
DOI: https://doi.org/10.1074/jbc.M206379200
Tortoriello DV, Sidis Y, Holtzman DA, el al. Human follistatin-related protein: a structural homologue of follistatin with nuclear localization. Endocrinology. 2001;142(8):3426-34.
DOI: https://doi.org/10.1210/endo.142.8.8319
Xia Y, Sidis Y, Schneyer A. Overexpression of follistatin-like 3 in gonads causes defects in gonadal development and function in transgenic mice. Mol Endocrinol. 2004;18(4):979-94.
DOI: https://doi.org/10.1210/me.2003-0364
Oldknow KJ, Seebacher J, Goswami T, et al. Follistatin-like 3 (FSTL3) mediated silencing of transforming growth factor beta (TGFbeta) signaling is essential for testicular aging and regulating testis size. Endocrinology. 2013;154(3):1310-20.
DOI: https://doi.org/10.1210/en.2012-1886
Bartholin L, Maguer-Satta V, Hayette S, et al. Transcription activation of FLRG and follistatin by activin A, through Smad proteins, participates in a negative feedback loop to modulate activin A function. Oncogene. 2002;21(14):2227-35.
DOI: https://doi.org/10.1038/sj.onc.1205294
Tillet E, Bailly S. Emerging roles of BMP9 and BMP10 in hereditary hemorrhagic telangiectasia. Front Genet. 2014;5:456.
Glasser CE, Gartner MR, Wilson D, el al. Locally acting ACE-083 increases muscle volume in healthy volunteers. Muscle Nerve. 2018;57(6):921-6.
DOI: https://doi.org/10.1002/mus.26113
Lach-Trifilieff E, Minetti GC, Sheppard K, et al. An antibody blocking activin type II receptors induces strong skeletal muscle hypertrophy and protects from atrophy. Mol Cell Biol. 2014;34(4):606-18.
DOI: https://doi.org/10.1128/MCB.01307-13
Garito T, Roubenoff R, Hompesch M, et al. Bimagrumab improves body composition and insulin sensitivity in insulin-resistant individuals. Diabetes Obes Metab. 2018;20(1):94-102.
DOI: https://doi.org/10.1111/dom.13042
Rodino-Klapac LR, Haidet AM, Kota J, et al. Inhibition of myostatin with emphasis on follistatin as a therapy for muscle disease. Muscle Nerve. 2009;39(3):283-96.
DOI: https://doi.org/10.1002/mus.21244
Dias V, Meachem S, Rajpert-De Meyts E, et al. Activin receptor subunits in normal and dysfunctional adult human testis. Hum Reprod. 2008;23(2):412-20.
DOI: https://doi.org/10.1093/humrep/dem343
Suragani RN, Cadena SM, Cawley SM, et al. Transforming growth factor-beta superfamily ligand trap ACE-536 corrects anemia by promoting late-stage erythropoiesis. Nat Med. 2014;20(4):408-14.
DOI: https://doi.org/10.1038/nm.3512
Guerra A, Oikonomidou PR, Sinha S, et al. Lack of Gdf11 does not improve anemia or prevent the activity of RAP-536 in a mouse model of beta-thalassemia. Blood. 2019;134(6):568-72.
DOI: https://doi.org/10.1182/blood.2019001057
How to Cite
Vaughan, D., Kretz, O., Alqallaf, A., Mitchell, R., von der Heide, J. L., Vaiyapuri, S., Matsakas, A., Pasternack, A., Collins-Hooper, H., Ritvos, O., Ballesteros, R., Huber, T. B., Amthor, H., Mukherjee, A., & Patel, K. (2020). Diminution in sperm quantity and quality in mouse models of Duchenne Muscular Dystrophy induced by a myostatin-based muscle growth-promoting intervention. European Journal of Translational Myology, 30(2), 276–285. https://doi.org/10.4081/ejtm.2020.8904
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