Low-intensity training maintains functionality and fibrosis in mdx mice
DOI:
https://doi.org/10.34024/rnc.2022.v30.13541Keywords:
mdx model, cardiac muscle, fibrosis, VO2 max., Duchenne, DiaphragmAbstract
Objective. The present study investigated the effects of a low-intensity training protocol on functional, aerobic, morphological, and morphometric parameters of the diaphragm and cardiac muscle of mdx mice. Method. Male mdx mice at 8 weeks of age were submitted to a short (4 weeks) or long (8 weeks) protocol on a horizontal treadmill (9m/min,3x/week,30min/day). The mdx mice were randomly assigned to the trained (mdxT, n=8) or untrained (mdxNT, n=8) group. Measures of strength, balance, analysis of VO2 max, time to exhaustion of the animals and histomorphometry of intramuscular collagen fibers were evaluated throughout the protocol in the diaphragm and cardiac muscle. Results. There were no differences in the grip strength test and Rotarod or in cardiac muscle fibrosis deposition. In the diaphragm muscle, there was an increase in the percentage of intramuscular fibrosis in the mdxT group at T4, an increase in fibrosis in both the mdxT and mdxNT groups at T8 when compared to the control group T0. In the variables VO2max and time to exhaustion, there was no significant performance even with the time and training factor. Histopathological findings are more frequently observed at the end of the long protocol (8 weeks) in both the mdxT and mdxNT groups, mainly in the diaphragm muscle. Conclusion. Low-intensity treadmill training did not influence fibrosis deposition in cardiac muscle and diaphragm mdx over time, maintaining grip strength and aerobic capacity of mdx mice during the protocol.
Metrics
References
Chakkalakal JV, Thompson J, Parks RJ, Jasmin BJ. Molecular, cellular, and pharmacological therapies for Duchenne/Becker muscular dystrophies. FASEB J 2005;19:880-91. https://doi.org/10.1096/fj.04-1956rev
Eagle M. Report on the Muscular Dystrophy Campaign workshop: Exercise in neuromuscular diseases Newcastle, January 2002. Neuromuscul Disord 2002;12:975-83.
https://doi.org/10.1016/s0960-8966(02)00136-0
Morrison J, Lu QL, Pastoret C, Partridge T, Bou-Gharios G. T-cell-dependent fibrosis in the mdx dystrophic mouse. Lab Investig 2000;80:881-91. https://doi.org/10.1038/labinvest.3780092
Araujo APQC, Nardes F, Fortes CPDD, Pereira JA, Rebel MF, Dias CM, et al. Brazilian consensus on duchenne muscular dystrophy. Part 2: Rehabilitation and systemic care. Arq Neuropsiquiatr 2018;76:481-9. https://doi.org/10.1590/0004-282X20180062
Lessa TB, Carvalho RC, Spagnolo JD, Silva LCLC, Cortopassi SRG, Ambrósio CE. Laparoscopic guided local injection in the X-linked muscular dystrophy mouse (MDX) diaphragm. an advance in experimental therapies for duchenne muscular dystrophy1. Acta Cir Bras 2014;29:715-20. https://doi.org/10.1590/S0102-86502014001800004
Bendixen RM, Lott DJ, Senesac C, Mathur S, Vandenborne K. Participation in daily life activities and its relationship to strength and functional measures in boys with Duchenne muscular dystrophy. Disabil Rehabil 2014;36:1918-23.
https://doi.org/10.3109/09638288.2014.883444
Grounds MD, Radley HG, Lynch GS, Nagaraju K, De Luca A. Towards developing standard operating procedures for pre-clinical testing in the mdx mouse model of Duchenne muscular dystrophy. Neurobiol Dis 2008;31:1-19. https://doi.org/10.1016/j.nbd.2008.03.008
Vainzof M, Ayub-Guerrieri D, Onofre PCG, Martins PCM, Lopes VF, Zilberztajn D, et al. Animal models for genetic neuromuscular diseases. J Mol Neurosci 2008;34:241-8. https://doi.org/10.1007/s12031-007-9023-9
Selsby JT, Acosta P, Sleeper MM, Barton ER, Sweeney HL. Long-term wheel running compromises diaphragm function but improves cardiac and plantarflexor function in the mdx mouse. J Appl Physiol 2013;115:660-6. https://doi.org/10.1152/japplphysiol.00252.2013
Nigro G, Comi LI, Politano L, Bain RJI. The incidence and evolution of cardiomyopathy in Duchenne muscular dystrophy. Int J Cardiol 1990;26:271-7. https://doi.org/10.1016/0167-5273(90)90082-g
Benigni R, Bossa C, Tcheremenskaia O, Giuliani A. Alternatives to the carcinogenicity bioassay: In silico methods, and the in vitro and in vivo mutagenicity assays. Expert Opin Drug Metab Toxicol 2010;6:809-19. https://doi.org/10.1517/17425255.2010.486400
Laflamme MA, Murry CE. Heart regeneration. Nature 2011;473:326-35. https://doi.org/10.1038/nature10147
Shete AN, Bute SS, Deshmukh PR. A study of VO2 max and body fat percentage in female athletes. J Clin Diagnostic Res 2014;8:BC01-3. https://doi.org/10.7860/JCDR/2014/10896.5329
Ranković G, Mutavdžić V, Toskić D, Preljević A, Kocić M, Nedin-Ranković G, et al. Aerobic capacity as an indicator in different kinds of sports. Bosn J Basic Med Sci 2010;10:44-8. https://doi.org/10.17305/bjbms.2010.2734
Kodama S. CLINICIAN’S CORNER Cardiorespiratory Fitness as a Quantitative Predictor of All-Cause Mortality and Cardiovascular Events. J Am Med Assoc 2009;301:2024-35. https://doi.org/10.1001/jama.2009.681
Hyzewicz J, Ruegg UT, Takeda S. Comparison of Experimental Protocols of Physical Exercise for mdx Mice and Duchenne Muscular Dystrophy Patients. J Neuromuscul Dis 2015;2:325-42. https://doi.org/10.3233/JND-150106
Kaczor JJ, Hall JE, Payne E, Tarnopolsky MA. Low intensity training decreases markers of oxidative stress in skeletal muscle of mdx mice. Free Radic Biol Med 2007;43:145-54.
https://doi.org/10.1016/j.freeradbiomed.2007.04.003
Hyzewicz J, Tanihata J, Kuraoka M, Ito N, Miyagoe-Suzuki Y, Takeda S. Low intensity training of mdx mice reduces carbonylation and increases expression levels of proteins involved in energy metabolism and muscle contraction. Free Radic Biol Med 2015;82:122-36. http://dx.doi.org/10.1016/j.freeradbiomed.2015.01.023
du Sert NP, Hurst V, Ahluwalia A, Alam S, Avey MT, Baker M, et al. The arrive guidelines 2.0: Updated guidelines for reporting animal research. PLoS Biol 2020;18:1-12.
https://doi.org/10.1371/journal.pbio.3000410
Luca A. Use of treadmill and wheel exercise for impact on mdx mice phenotype. Neuromuscul Netw Protoc 2011;(Id):1-11. https://treat-nmd.org/wp-content/uploads/2016/08/MDX-DMD_M.2.1.001.pdf
van Putten M, Winter C, van Roon-Mom W, van Ommen GJ, ’t Hoen PAC, Aartsma-Rus A. A 3 months mild functional test regime does not affect disease parameters in young mdx mice. Neuromuscul Disord 2010;20:273-80. http://dx.doi.org/10.1016/j.nmd.2010.02.004
Aartsma-Rus A, van Putten M. Assessing functional performance in the Mdx mouse model. J Vis Exp 2014;85:1-11. https://doi.org/10.3791/51303
Rocco AB, Levalley JC, Eldridge JA, Marsh SA, Rodgers BD. A novel protocol for assessing exercise performance and dystropathophysiology in the mdx mouse. Muscle and Nerve 2014;50:541-8. https://doi.org/10.1002/mus.24184
Høydal MA, Wisløff U, Kemi OJ, Ellingsen Ø. Running speed and maximal oxygen uptake in rats and mice: Practical implications for exercise training. Eur J Prev Cardiol 2007;14:753-60.
https://doi.org/10.1097/HJR.0b013e3281eacef1
Melo DS, Costa-Pereira LV, Santos CS, Mendes BF, Costa KB, Santos CFF, et al. Severe calorie restriction reduces cardiometabolic risk factors and protects rat hearts from ischemia/reperfusion injury. Front Physiol 2016;7:1-8. https://doi.org/10.3389/fphys.2016.00106
Smith LR, Barton ER. Collagen content does not alter the passive mechanical properties of fibrotic skeletal muscle in mdx mice. Am J Physiol Cell Physiol 2014;306:C889-98.
https://doi.org/10.1152/ajpcell.00383.2013
Capogrosso RF, Mantuano P, Cozzoli A, Sanarica F, Massari AM, Conte E, et al. Contractile efficiency of dystrophic mdx mouse muscle: In vivo and ex vivo assessment of adaptation to exercise of functional end points. J Appl Physiol 2017;122:828-43.
https://doi.org/10.1152/japplphysiol.00776.2015
Bassaglia Y, Gautron J. Fast and slow rat muscles degenerate and regenerate differently after whole crush injury. J Muscle Res Cell Motil 1995;16:420-9. https://doi.org/10.1007/BF00114507
Delaney K, Kasprzycka P, Ciemerych MA, Zimowska M. The role of TGF-β1 during skeletal muscle regeneration. Cell Biol Int 2017;41:706-15. https://doi.org/10.1002/cbin.10725
Yucel N, Chang AC, Day JW, Rosenthal N, Blau HM. Humanizing the mdx mouse model of DMD: the long and the short of it. NPJ Regen Med 2018;3:4. https://doi.org/10.1038/s41536-018-0045-4
Corrado G, Lissoni A, Beretta S, Terenghi L, Tadeo G, Foglia-Manzillo G, et al. Prognostic value of electrocardiograms, ventricular late potentials, ventricular arrhythmias, and left ventricular systolic dysfunction in patients with Duchenne muscular dystrophy. Am J Cardiol 2002;89:838-41. https://doi.org/10.1016/s0002-9149(02)02195-1
Kamogawa Y, Biro S, Maeda M, Setoguchi M, Hirakawa T, Yoshida H, et al. Dystrophin-deficient myocardium is vulnerable to pressure overload in vivo. Cardiovasc Res 2001;50:509-15.
https://doi.org/10.1016/s0008-6363(01)00205-x
Finsterer J, Stöllberger C. The heart in human dystrophinopathies. Cardiology 2003;99:1-19. https://doi.org/10.1159/000068446
Costas JM, Nye DJ, Henley JB, Plochocki JH. Voluntary exercise induces structural remodeling in the hearts of dystrophin-deficient mice. Muscle Nerve 2010;42:881-5.
https://doi.org/10.1002/mus.21783
Nakamura A. X-linked dilated cardiomyopathy: A cardiospecific phenotype of dystrophinopathy. Pharmaceuticals 2015;8:303-20. https://doi.org/10.3390/ph8020303
Ferry A, Benchaouir R, Joanne P, Peat RA, Mougenot N, Agbulut O, et al. Effect of voluntary physical activity initiated at age 7 months on skeletal hindlimb and cardiac muscle function in mdx mice of both genders. Muscle Nerve 2015;52:788-94.
https://doi.org/10.1002/mus.24604
Van Erp C, Loch D, Laws N, Trebbin A, Hoey AJ. Timeline of cardiac dystrophy in 3-18-month-old mdx mice. Muscle Nerve 2010;42:504-13. https://doi.org/10.1002/mus.21716
Schill KE, Altenberger AR, Lowe J, Periasamy M, Villamena FA, Rafael-Fortney JiA, et al. Muscle damage, metabolism, and oxidative stress in mdx mice: Impact of aerobic running. Muscle Nerve 2016;54:110-7. https://doi.org/10.1002/mus.25015
Deconinck AE, Rafael JA, Skinner JA, Brown SC, Potter AC, Metzinger L, et al. Utrophin-dystrophin-deficient mice as a model for Duchenne muscular dystrophy. Cell 1997;90:717-27.
https://doi.org/10.1016/s0092-8674(00)80532-2
Willmann R, Possekel S, Dubach-Powell J, Meier T, Ruegg MA. Mammalian animal models for Duchenne muscular dystrophy. Neuromuscul Disord 2009;19:241-9.
http://dx.doi.org/10.1016/j.nmd.2008.11.015
Ishizaki M, Suga T, Kimura E, Shiota T, Kawano R, Uchida Y, et al. Mdx respiratory impairment following fibrosis of the diaphragm. Neuromuscul Disord 2008;18:342-8.
https://doi.org/10.1016/j.nmd.2008.02.002
Dupont-Versteegden EE, McCarter RJ, Katz MS. Voluntary exercise decreases progression of muscular dystrophy in diaphragm of mdx mice. J Appl Physiol 1994;77:1736-41.
https://doi.org/10.1152/jappl.1994.77.4.1736
Barbin ICC, Pereira JA, Bersan Rovere M, Oliveira Moreira D, Marques MJ, Santo Neto H. Diaphragm degeneration and cardiac structure in mdx mouse: Potential clinical implications for Duchenne muscular dystrophy. J Anat 2016;228:784-91.
https://doi.org/10.1111/joa.12443
Frinchi M, MacAluso F, Licciardi A, Perciavalle V, Coco M, Belluardo N, et al. Recovery of damaged skeletal muscle in mdx mice through low-intensity endurance exercise. Int J Sports Med 2014;35:19-27.
https://doi.org/10.1055/s-0033-1343405
Morici G, Frinchi M, Pitruzzella A, Di Liberto V, Barone R, Pace A, et al. Mild Aerobic Exercise Training Hardly Affects the Diaphragm of mdx Mice. J Cell Physiol 2017;232:2044-52.
Downloads
Published
Issue
Section
License
Copyright (c) 2022 Ana Flávia Santos, Thaís Peixoto Gaid Machado, Luana Aparecida Alves, Ana Paula Santos, Alex Sander Dias Machado
This work is licensed under a Creative Commons Attribution 4.0 International License.
How to Cite
Accepted 2022-06-23
Published 2022-11-22
