Behavioral, Biochemical and Pathological Characterization of a new MDX Mouse Model of Duchenne Muscular Dystrophy

Fengjiao Wang; Jing Wen; Baojian Guo; Liangmiao Wu; Zheng Liu; Zhang Zaijun

Behavioral, Biochemical and Pathological Characterization of a new MDX Mouse Model of Duchenne Muscular Dystrophy

Fengjiao Wang, Jing Wen, Baojian Guo, Liangmiao Wu, Zheng Liu, Zhang Zaijun

Abstract

Background Duchenne muscular dystrophy (DMD) is an X-linked inherited neuromuscular disorder due to mutations in the dystrophin gene. Animal models that accurately reflect pathological conditions and disease characteristics are key factors in the discovery and development of new anti-DMD drugs.
Aim Here, we evaluated motor behavior, pathological and biochemical characters of a new DMD mouse model built up by the Nanjing Biomedical Research Institute of Nanjing University (NBRI).
Methods The pole test and open-field test were used to assess the movement disorders in DMD mouse model. The gastrocnemius (GAS), biceps, triceps, soleus, and tibialis anterior muscles of mice were subjected to weight analysis to evaluate the skeletal muscle pseudohypertrophy. Meanwhile, immunofluorescence and Western blotting were used to detect the expression of dystrophin in the GAS. Serum levels of creatine kinase (CK) and lactate dehydrogenase (LDH) that accurately reflect muscle damage were detected. Masson staining was used to evaluate the fibrosis of GAS and diaphragm (DIA).
Results The novel DMD mouse showed significant behavioral disorders and exhibited high serum levels of CK and LDH. Western blotting and immunofluorescence staining showed decreased significantly with dystrophin level in the GAS. Besides, the mdx mouse of DMD developed fibrosis in both GAS and DIA.
Conclusion Taken together, our results indicated that the behavioral, biochemical and pathological characterization of the mdx mouse model is similar to human DMD. This mdx mouse model may provide insights into the pathophysiology of DMD and the effects of anti-DMD drugs.

Keywords

Traditional Chinese Medicine

Full Text:

References

Govoni A, Magri F, Brajkovic S, et al. Ongoing therapeutic trials and outcome measures for Duchenne muscular dystrophy. Cell Mol Life Sci. 2013;70(23):4585-4602. doi:10.1007/s00018-013-1396-z.

Jennekens FG, ten Kate LP, de Visser M, Wintzen AR. Diagnostic criteria for Duchenne and Becker muscular dystrophy and myotonic dystrophy. Neuromuscul Disord. 1991;1(6):389-391. doi:10.1016/0960-8966(91)90001-9.

Finsterer J. Cardiopulmonary support in duchenne muscular dystrophy. Lung. 2006 Jul-Aug;184(4):205-215. doi: 10.1007/s00408-005-2584-x.

Mann CJ, Perdiguero E, Kharraz Y, et al. Aberrant repair and fibrosis development in skeletal muscle. Skelet Muscle. 2011;1(1):21. doi:10.1186/2044-5040-1-21.

Desguerre I, Mayer M, Leturcq F, Barbet JP, Gherardi RK, Christov C. Endomysial fibrosis in Duchenne muscular dystrophy: a marker of poor outcome associated with macrophage alternative activation. J Neuropathol Exp Neurol. 2009;68(7):762-773. doi:10.1097/NEN.0b013e3181aa31c2.

Melacini, P.; Vianello, A.; Villanova, C., et al. Cardiac and respiratory involvement in advanced stage Duchenne muscular dystrophy. Neuromuscular Disorders. 1996; 6: 367-376. doi:10.1016/0960-8966(96)00357-4.

McGreevy JW, Hakim CH, McIntosh MA, Duan D. Animal models of Duchenne muscular dystrophy: from basic mechanisms to gene therapy. Dis Model Mech. 2015;8(3):195-213. doi:10.1242/dmm.018424.

Bulfield G, Siller WG, Wight PA, Moore KJ. X chromosome-linked muscular dystrophy (mdx) in the mouse. Proc Natl Acad Sci U S A. 1984;81(4):1189-1192. doi:10.1073/pnas.81.4.1189.

Gillis, J. M. Understanding dystrophinopathies: an inventory of the structural and functional consequences of the absence of dystrophin in muscles of the mdx mouse. Journal of Muscle Research & Cell Motility. 1999; 20: 605-625.doi:10.1023/a:1005545325254.

Tanabe Y, Esaki K, Nomura T. Skeletal muscle pathology in X chromosome-linked muscular dystrophy (mdx) mouse. Acta Neuropathol. 1986;69(1-2):91-95. doi:10.1007/BF00687043.

Wu L, Su Z, Zha L, et al. Tetramethylpyrazine Nitrone Reduces Oxidative Stress to Alleviate Cerebral Vasospasm in Experimental Subarachnoid Hemorrhage Models. Neuromolecular Med. 2019;21(3):262-274. doi:10.1007/s12017-019-08543-9.

Xu B, Zheng C, Chen X, et al. Dysregulation of Myosin Complex and Striated Muscle Contraction Pathway in the Brains of ALS-SOD1 Model Mice. ACS Chem Neurosci. 2019;10(5):2408-2417. doi:10.1021/acschemneuro.8b00704.

Gasper MC, Gilchrist JM. Creatine kinase: a review of its use in the diagnosis of muscle disease. Med Health R I. 2005;88(11):398-404.

Zhang Y, Huang JJ, Wang ZQ, Wang N, Wu ZY. Value of muscle enzyme measurement in evaluating different neuromuscular diseases. Clinica Chimica Acta; International Journal of Clinical Chemistry. 2012 Feb;413(3-4):520-524. doi: 10.1016/j.cca.2011.11.016.

Ebashi S, Toyokura Y, Momoi H, Sugita H. High creatine phosphokinase activity of sera of progressive muscular dystrophy. The Journal of Biochemistry. 1959; 46:103-104. https://doi.org/10.1093/jb/46.1.103.

Fang WJ, Wang CJ, He Y, Zhou YL, Peng XD, Liu SK. Resveratrol alleviates diabetic cardiomyopathy in rats by improving mitochondrial function through PGC-1? deacetylation. Acta Pharmacol Sin. 2018;39(1):59-73. doi:10.1038/aps.2017.50.

Sosa JM, Huber DE, Welk B, Fraser HL. Development and application of MIPAR™: a novel software package for two- and three-dimensional microstructural characterization. Integr Mater Manuf Innov. 2014; 3: 123-140.

Martigne L, Salleron J, Mayer M, et al. Natural evolution of weight status in Duchenne muscular dystrophy: a retrospective audit. Br J Nutr. 2011;105(10):1486-1491. doi:10.1017/S0007114510005180.

Kornegay JN, Childers MK, Bogan DJ, et al. The paradox of muscle hypertrophy in muscular dystrophy. Phys Med Rehabil Clin N Am. 2012;23(1):149-xii. doi:10.1016/j.pmr.2011.11.014.

Duddy W, Duguez S, Johnston H, et al. Muscular dystrophy in the mdx mouse is a severe myopathy compounded by hypotrophy, hypertrophy and hyperplasia. Skelet Muscle. 2015;5:16. Published 2015 May 1. doi:10.1186/s13395-015-0041-y.

Zubrzycka-Gaarn EE, Hutter OF, Karpati G, et al. Dystrophin is tightly associated with the sarcolemma of mammalian skeletal muscle fibers. Exp Cell Res. 1991;192(1):278-288. doi:10.1016/0014-4827(91)90187-y.

Zatz M, Rapaport D, Vainzof M, et al. Serum creatine-kinase (CK) and pyruvate-kinase (PK) activities in Duchenne (DMD) as compared with Becker (BMD) muscular dystrophy. J Neurol Sci. 1991;102(2):190-196. doi:10.1016/0022-510x(91)90068-i.

Verma S, Anziska Y, Cracco J. Review of Duchenne muscular dystrophy (DMD) for the pediatricians in the community. Clin Pediatr (Phila). 2010;49(11):1011-1017. doi:10.1177/0009922810378738.

Taniguti AP, Pertille A, Matsumura CY, Santo Neto H, Marques MJ. Prevention of muscle fibrosis and myonecrosis in mdx mice by suramin, a TGF-?1 blocker. Muscle & Nerve. 2011; 43: 82-87. doi.org/10.1002/mus.21869.

Cabrera D, Gutiérrez J, Cabello-Verrugio C, et al. Andrographolide attenuates skeletal muscle dystrophy in mdx mice and increases efficiency of cell therapy by reducing fibrosis. Skelet Muscle. 2014;4:6. doi:10.1186/2044-5040-4-6.

Gosselin LE, Williams JE, Deering M, Brazeau D, Koury S, Martinez DA. Localization and early time course of TGF-beta 1 mRNA expression in dystrophic muscle. Muscle Nerve. 2004;30(5):645-653. doi:10.1002/mus.20150.

Hoffman EP, Brown RH Jr, Kunkel LM. Dystrophin: the protein product of the Duchenne muscular dystrophy locus. Cell. 1987;51(6):919-928. doi:10.1016/0092-8674(87)90579-4.

Kohler M, Clarenbach CF, Böni L, Brack T, Russi EW, Bloch KE. Quality of life, physical disability, and respiratory impairment in Duchenne muscular dystrophy. Am J Respir Crit Care Med. 2005;172(8):1032-1036. doi:10.1164/rccm.200503-322OC.

Collins CA, Morgan JE. Duchenne's muscular dystrophy: animal models used to investigate pathogenesis and develop therapeutic strategies. Int J Exp Pathol. 2003;84(4):165-172. doi:10.1046/j.1365-2613.2003.00354.x.

Ahmad G, Amiji M. Use of CRISPR/Cas9 gene-editing tools for developing models in drug discovery. Drug Discov Today. 2018;23(3):519-533. doi:10.1016/j.drudis.2018.01.014.

Shrock E, Güell M. CRISPR in Animals and Animal Models. Progress in Molecular Biology and Translational Science. 2017 ;152:95-114. DOI: 10.1016/bs.pmbts.2017.07.010.

Glesby MJ, Rosenmann E, Nylen EG, Wrogemann K. Serum CK, calcium, magnesium, and oxidative phosphorylation in mdx mouse muscular dystrophy. Muscle Nerve. 1988;11(8):852-856. doi:10.1002/mus.880110809.

Spurney CF, Sali A, Guerron AD, et al. Losartan decreases cardiac muscle fibrosis and improves cardiac function in dystrophin-deficient mdx mice. J Cardiovasc Pharmacol Ther. 2011;16(1):87-95. doi:10.1177/1074248410381757.

Refbacks

There are currently no refbacks.

This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.

Journal of Pharmaceutical and Biomedical Sciences