Generic placeholder image

Current Neurovascular Research

Editor-in-Chief

ISSN (Print): 1567-2026
ISSN (Online): 1875-5739

Research Article

Wheel Running Adversely Affects Disease Onset and Neuromuscular Interplay in Amyotrophic Lateral Sclerosis Slow Progression Mouse Model

Author(s): Elisabetta Golini, Sara Marinelli, Simona Pisu, Federica De Angelis, Valentina Vacca, Alessandro Rava, Irene Casola, Gaia Laurenzi, Emanuele Rizzuto, Alessandro Giuliani, Antonio Musarò*, Gabriella Dobrowolny and Silvia Mandillo

Volume 20, Issue 3, 2023

Published on: 28 August, 2023

Page: [362 - 376] Pages: 15

DOI: 10.2174/1567202620666230823095922

Price: $65

Abstract

Background: Physical activity in Amyotrophic Lateral Sclerosis (ALS) plays a controversial role. In some epidemiological studies, both recreational or professional sport exercise has been associated to an increased risk for ALS but the mechanisms underlying the effects of exercise have not been fully elucidated in either patients or animal models.

Methods: To better reproduce the influence of this environmental factor in the pathogenesis of ALS, we exposed SOD1G93A low-copy male mice to multiple exercise sessions at asymptomatic and pre-symptomatic disease stages in an automated home-cage running-wheel system for about 3 months.

Results: Repeated voluntary running negatively influenced disease progression by anticipating disease onset, impairing neuromuscular transmission, worsening neuromuscular decline, and exacerbating muscle atrophy. Muscle fibers and neuromuscular junctions (NMJ) as well as key molecular players of the nerve-muscle circuit were similarly affected.

Conclusion: It thus appears that excessive physical activity can be detrimental in predisposed individuals and these findings could model the increased risk of developing ALS in predisposed and specific professional athletes.

Keywords: SOD1G93A low-copy, exercise, mouse behavior, neuromuscular junction functionality, home cage monitoring, wheel running, ALS, physical activity.

[1]
Taylor JP, Brown RH Jr, Cleveland DW. Decoding ALS: from genes to mechanism. Nature 2016; 539(7628): 197-206.
[http://dx.doi.org/10.1038/nature20413] [PMID: 27830784]
[2]
Boylan K. Familial amyotrophic lateral sclerosis. Neurol Clin 2015; 33(4): 807-30.
[http://dx.doi.org/10.1016/j.ncl.2015.07.001] [PMID: 26515623]
[3]
Zou ZY, Zhou ZR, Che CH, Liu CY, He RL, Huang HP. Genetic epidemiology of amyotrophic lateral sclerosis: a systematic review and meta-analysis. J Neurol Neurosurg Psychiatry 2017; 88(7): 540-9.
[http://dx.doi.org/10.1136/jnnp-2016-315018] [PMID: 28057713]
[4]
Shatunov A, Al-Chalabi A. The genetic architecture of ALS. Neurobiol Dis 2021; 147: 105156.
[http://dx.doi.org/10.1016/j.nbd.2020.105156] [PMID: 33130222]
[5]
Gurney ME, Pu H, Chiu AY, et al. Motor neuron degeneration in mice that express a human Cu, Zn superoxide dismutase mutation. Science 1994; 264(5166): 1772-5.
[http://dx.doi.org/10.1126/science.8209258] [PMID: 8209258]
[6]
Mancuso R, Oliván S, Rando A, Casas C, Osta R, Navarro X. Sigma-1R agonist improves motor function and motoneuron survival in ALS mice. Neurotherapeutics 2012; 9(4): 814-26.
[http://dx.doi.org/10.1007/s13311-012-0140-y] [PMID: 22935988]
[7]
Turner B, Talbot K. Transgenics, toxicity and therapeutics in rodent models of mutant SOD1-mediated familial ALS. Prog Neurobiol 2008; 85(1): 94-134.
[http://dx.doi.org/10.1016/j.pneurobio.2008.01.001] [PMID: 18282652]
[8]
Nardo G, Trolese MC, Tortarolo M, et al. New insights on the mechanisms of disease course variability in als from mutant SOD1 mouse models. Brain Pathol 2016; 26(2): 237-47.
[http://dx.doi.org/10.1111/bpa.12351] [PMID: 26780365]
[9]
Schram S, Loeb JA, Song F. Disease propagation in amyotrophic lateral sclerosis (ALS): an interplay between genetics and environment. J Neuroinflammation 2020; 17(1): 175.
[http://dx.doi.org/10.1186/s12974-020-01849-7] [PMID: 32505190]
[10]
Al-Chalabi A, Hardiman O. The epidemiology of ALS: a conspiracy of genes, environment and time. Nat Rev Neurol 2013; 9(11): 617-28.
[http://dx.doi.org/10.1038/nrneurol.2013.203] [PMID: 24126629]
[11]
Swinnen B, Robberecht W. The phenotypic variability of amyotrophic lateral sclerosis. Nat Rev Neurol 2014; 10(11): 661-70.
[http://dx.doi.org/10.1038/nrneurol.2014.184] [PMID: 25311585]
[12]
Beghi E, Chiò A, Couratier P, et al. The epidemiology and treatment of ALS: Focus on the heterogeneity of the disease and critical appraisal of therapeutic trials. Amyotroph Lateral Scler 2011; 12(1): 1-10.
[http://dx.doi.org/10.3109/17482968.2010.502940] [PMID: 20698807]
[13]
Bellomo G, Piscopo P, Corbo M, et al. A systematic review on the risk of neurodegenerative diseases and neurocognitive disorders in professional and varsity athletes. Neurol Sci 2022; 43(12): 6667-91.
[http://dx.doi.org/10.1007/s10072-022-06319-x] [PMID: 35976476]
[14]
Daneshvar DH, Mez J, Alosco ML, et al. Incidence of and mortality from amyotrophic lateral sclerosis in national football league athletes. JAMA Netw Open 2021; 4(12): e2138801.
[http://dx.doi.org/10.1001/jamanetworkopen.2021.38801] [PMID: 34910152]
[15]
Blecher R, Elliott MA, Yilmaz E, et al. Contact sports as a risk factor for amyotrophic lateral sclerosis: A systematic review. Global Spine J 2019; 9(1): 104-18.
[http://dx.doi.org/10.1177/2192568218813916] [PMID: 30775214]
[16]
Gotkine M, Friedlander Y, Hochner H. Triathletes are over-represented in a population of patients with ALS. Amyotroph Lateral Scler Frontotemporal Degener 2014; 15(7-8): 534-6.
[http://dx.doi.org/10.3109/21678421.2014.932383] [PMID: 25007701]
[17]
Chiò A, Benzi G, Dossena M, Mutani R, Mora G. Severely increased risk of amyotrophic lateral sclerosis among Italian professional football players. Brain 2005; 128(3): 472-6.
[http://dx.doi.org/10.1093/brain/awh373] [PMID: 15634730]
[18]
Chiò A, Calvo A, Dossena M, Ghiglione P, Mutani R, Mora G. ALS in Italian professional soccer players: The risk is still present and could be soccer-specific. Amyotroph Lateral Scler 2009; 10(4): 205-9.
[http://dx.doi.org/10.1080/17482960902721634] [PMID: 19267274]
[19]
Harwood CA, Westgate K, Gunstone S, et al. Long-term physical activity: an exogenous risk factor for sporadic amyotrophic lateral sclerosis? Amyotroph Lateral Scler Frontotemporal Degener 2016; 17(5-6): 377-84.
[http://dx.doi.org/10.3109/21678421.2016.1154575] [PMID: 26998882]
[20]
Huisman MHB, Seelen M, de Jong SW, et al. Lifetime physical activity and the risk of amyotrophic lateral sclerosis. J Neurol Neurosurg Psychiatry 2013; 84(9): 976-81.
[http://dx.doi.org/10.1136/jnnp-2012-304724] [PMID: 23418211]
[21]
Beghi E, Logroscino G, Chiò A, et al. Amyotrophic lateral sclerosis, physical exercise, trauma and sports: Results of a population-based pilot case-control study. Amyotroph Lateral Scler 2010; 11(3): 289-92.
[http://dx.doi.org/10.3109/17482960903384283] [PMID: 20433412]
[22]
Zhu Y, Xu Y, Xuan R, et al. Mixed comparison of different exercise interventions for function, respiratory, fatigue, and quality of life in adults with amyotrophic lateral sclerosis: Systematic review and network meta-analysis. Front Aging Neurosci 2022; 14: 919059.
[http://dx.doi.org/10.3389/fnagi.2022.919059] [PMID: 35898325]
[23]
Ortega-Hombrados L, Molina-Torres G, Galán-Mercant A, Sánchez-Guerrero E, González-Sánchez M, Ruiz-Muñoz M. Systematic review of therapeutic physical exercise in patients with amyotrophic lateral sclerosis over time. Int J Environ Res Public Health 2021; 18(3): 1074.
[http://dx.doi.org/10.3390/ijerph18031074] [PMID: 33530383]
[24]
Rahmati M, Malakoutinia F. Aerobic, resistance and combined exercise training for patients with amyotrophic lateral sclerosis: a systematic review and meta-analysis. Physiotherapy 2021; 113: 12-28.
[http://dx.doi.org/10.1016/j.physio.2021.04.005] [PMID: 34555670]
[25]
Tsitkanou S, Della Gatta P, Foletta V, Russell A. The role of exercise as a non-pharmacological therapeutic approach for amyotrophic lateral sclerosis: beneficial or detrimental? Front Neurol 2019; 10: 783.
[http://dx.doi.org/10.3389/fneur.2019.00783] [PMID: 31379732]
[26]
Dal Bello-Haas V, Florence JM. Therapeutic exercise for people with amyotrophic lateral sclerosis or motor neuron disease. Cochrane Libr 2013; 2013(5): CD005229.
[http://dx.doi.org/10.1002/14651858.CD005229.pub3] [PMID: 23728653]
[27]
Jensen L, Djurtoft JB, Bech RD, et al. Influence of resistance training on neuromuscular function and physical capacity in ALS patients. J Neurodegener Dis 2017; 2017: 1-8.
[http://dx.doi.org/10.1155/2017/1436519] [PMID: 28596929]
[28]
Harwood CA, McDermott CJ, Shaw PJ. Physical activity as an exogenous risk factor in motor neuron disease (MND): A review of the evidence. Amyotroph Lateral Scler 2009; 10(4): 191-204.
[http://dx.doi.org/10.1080/17482960802549739] [PMID: 19263258]
[29]
Just-Borràs L, Hurtado E, Cilleros-Mañé V, et al. Running and swimming prevent the deregulation of the BDNF/TrkB neurotrophic signalling at the neuromuscular junction in mice with amyotrophic lateral sclerosis. Cell Mol Life Sci 2020; 77(15): 3027-40.
[http://dx.doi.org/10.1007/s00018-019-03337-5] [PMID: 31646358]
[30]
Flis DJ, Dzik K, Kaczor JJ, et al. Swim training modulates skeletal muscle energy metabolism, oxidative stress, and mitochondrial cholesterol content in amyotrophic lateral sclerosis mice. Oxid Med Cell Longev 2018; 2018: 1-12.
[http://dx.doi.org/10.1155/2018/5940748] [PMID: 29849903]
[31]
Desseille C, Deforges S, Biondi O, et al. Specific physical exercise improves energetic metabolism in the skeletal muscle of amyotrophic-lateral- sclerosis mice. Front Mol Neurosci 2017; 10: 332.
[http://dx.doi.org/10.3389/fnmol.2017.00332] [PMID: 29104532]
[32]
Deforges S, Branchu J, Biondi O, et al. Motoneuron survival is promoted by specific exercise in a mouse model of amyotrophic lateral sclerosis. J Physiol 2009; 587(14): 3561-72.
[http://dx.doi.org/10.1113/jphysiol.2009.169748] [PMID: 19491245]
[33]
Carreras I, Yuruker S, Aytan N, et al. Moderate exercise delays the motor performance decline in a transgenic model of ALS. Brain Res 2010; 1313: 192-201.
[http://dx.doi.org/10.1016/j.brainres.2009.11.051] [PMID: 19968977]
[34]
Kirkinezos IG, Hernandez D, Bradley WG, Moraes CT. Regular exercise is beneficial to a mouse model of amyotrophic lateral sclerosis. Ann Neurol 2003; 53(6): 804-7.
[http://dx.doi.org/10.1002/ana.10597] [PMID: 12783429]
[35]
Veldink JH, Bär PR, Joosten EAJ, Otten M, Wokke JHJ, van den Berg LH. Sexual differences in onset of disease and response to exercise in a transgenic model of ALS. Neuromuscul Disord 2003; 13(9): 737-43.
[http://dx.doi.org/10.1016/S0960-8966(03)00104-4] [PMID: 14561497]
[36]
Kaspar BK, Frost LM, Christian L, Umapathi P, Gage FH. Synergy of insulin-like growth factor-1 and exercise in amyotrophic lateral sclerosis. Ann Neurol 2005; 57(5): 649-55.
[http://dx.doi.org/10.1002/ana.20451] [PMID: 15852403]
[37]
Lewis KEA, Bennett W, Blizzard CL, West AK, Chung RS, Chuah MI. The influence of metallothionein treatment and treadmill running exercise on disease onset and survival in SOD1 G93A amyotrophic lateral sclerosis mice. Eur J Neurosci 2020; 52(4): 3223-41.
[http://dx.doi.org/10.1111/ejn.14682] [PMID: 31954073]
[38]
Liebetanz D, Hagemann K, Von Lewinski F, Kahler E, Paulus W. Extensive exercise is not harmful in amyotrophic lateral sclerosis. Eur J Neurosci 2004; 20(11): 3115-20.
[http://dx.doi.org/10.1111/j.1460-9568.2004.03769.x] [PMID: 15579165]
[39]
Mahoney DJ, Rodriguez C, Devries M, Yasuda N, Tarnopolsky MA. Effects of high-intensity endurance exercise training in the G93A mouse model of amyotrophic lateral sclerosis. Muscle Nerve 2004; 29(5): 656-62.
[http://dx.doi.org/10.1002/mus.20004] [PMID: 15116368]
[40]
Garbugino L, Golini E, Giuliani A, Mandillo S. Prolonged voluntary running negatively affects survival and disease prognosis of male sod1g93a low-copy transgenic mice. Front Behav Neurosci 2018; 12: 275.
[http://dx.doi.org/10.3389/fnbeh.2018.00275] [PMID: 30483078]
[41]
De Bono JP, Adlam D, Paterson DJ, Channon KM. Novel quantitative phenotypes of exercise training in mouse models. Am J Physiol Regul Integr Comp Physiol 2006; 290(4): R926-34.
[http://dx.doi.org/10.1152/ajpregu.00694.2005] [PMID: 16339385]
[42]
Garland T Jr, Schutz H, Chappell MA, et al. The biological control of voluntary exercise, spontaneous physical activity and daily energy expenditure in relation to obesity: human and rodent perspectives. J Exp Biol 2011; 214(2): 206-29.
[http://dx.doi.org/10.1242/jeb.048397] [PMID: 21177942]
[43]
Meijer JH, Robbers Y. Wheel running in the wild. Proc Biol Sci 2014; 281(1786): 20140210.
[http://dx.doi.org/10.1098/rspb.2014.0210] [PMID: 24850923]
[44]
Mandillo S, Heise I, Garbugino L, et al. Early motor deficits in mouse disease models are reliably uncovered using an automated home cage wheel-running system: a cross-laboratory validation. Dis Model Mech 2014; 7(3): dmm.013946.
[http://dx.doi.org/10.1242/dmm.013946] [PMID: 24423792]
[45]
Alexander GM, Erwin KL, Byers N, et al. Effect of transgene copy number on survival in the G93A SOD1 transgenic mouse model of ALS. Brain Res Mol Brain Res 2004; 130(1-2): 7-15.
[http://dx.doi.org/10.1016/j.molbrainres.2004.07.002] [PMID: 15519671]
[46]
Acevedo-Arozena A, Kalmar B, Essa S, et al. A comprehensive assessment of the SOD1G93A low-copy transgenic mouse, which models human amyotrophic lateral sclerosis. Dis Model Mech 2011; 4(5): 686-700.
[http://dx.doi.org/10.1242/dmm.007237] [PMID: 21540242]
[47]
Mandillo S, Tucci V, Hölter SM, et al. Reliability, robustness, and reproducibility in mouse behavioral phenotyping: a cross-laboratory study. Physiol Genomics 2008; 34(3): 243-55.
[http://dx.doi.org/10.1152/physiolgenomics.90207.2008] [PMID: 18505770]
[48]
Mandillo S, Golini E, Marazziti D, Di Pietro C, Matteoni R, Tocchini-Valentini GP. Mice lacking the Parkinson’s related GPR37/PAEL receptor show non-motor behavioral phenotypes: age and gender effect. Genes Brain Behav 2013; 12(4): 465-77.
[http://dx.doi.org/10.1111/gbb.12041] [PMID: 23574697]
[49]
Leitner M, Menzies S. CL Working with ALS mice Guidelines for preclinical testing and colony management: Prize4Life. Bar Harbor, ME: MA and The Jackson Laboratory 2009; pp. 1-21.
[50]
Rizzuto E, Pisu S, Musarò A, Del Prete Z. Measuring neuromuscular junction functionality in the SOD1G93A animal model of amyotrophic lateral sclerosis. Ann Biomed Eng 2015; 43(9): 2196-206.
[http://dx.doi.org/10.1007/s10439-015-1259-x] [PMID: 25631208]
[51]
Rizzuto E, Pisu S, Nicoletti C, Del Prete Z, Musarò A. Measuring neuromuscular junction functionality. J Vis Exp 2017; (126): 185-9.
[52]
Del Prete Z, Musarò A, Rizzuto E. Measuring mechanical properties, including isotonic fatigue, of fast and slow MLC/mIgf-1 transgenic skeletal muscle. Ann Biomed Eng 2008; 36(7): 1281-90.
[http://dx.doi.org/10.1007/s10439-008-9496-x] [PMID: 18415017]
[53]
Personius KE, Sawyer RP. Variability and failure of neurotransmission in the diaphragm of mdx mice. Neuromuscul Disord 2006; 16(3): 168-77.
[http://dx.doi.org/10.1016/j.nmd.2006.01.002] [PMID: 16483776]
[54]
Dobrowolny G, Martini M, Scicchitano BM, et al. Muscle expression of SOD1. Antioxid Redox Signal 2018; 28(12): 1105-19.
[http://dx.doi.org/10.1089/ars.2017.7054] [PMID: 28931313]
[55]
Dobrowolny G, Lepore E, Martini M, et al. Metabolic changes associated with muscle expression of SOD1G93A. Front Physiol 2018; 9: 831.
[http://dx.doi.org/10.3389/fphys.2018.00831] [PMID: 30042688]
[56]
Witzemann V, Brenner HR, Sakmann B. Neural factors regulate AChR subunit mRNAs at rat neuromuscular synapses. J Cell Biol 1991; 114(1): 125-41.
[http://dx.doi.org/10.1083/jcb.114.1.125] [PMID: 1646821]
[57]
Cohen TJ, Waddell DS, Barrientos T, et al. The histone deacetylase HDAC4 connects neural activity to muscle transcriptional reprogramming. J Biol Chem 2007; 282(46): 33752-9.
[http://dx.doi.org/10.1074/jbc.M706268200] [PMID: 17873280]
[58]
Tang H, Macpherson P, Marvin M, et al. A histone deacetylase 4/myogenin positive feedback loop coordinates denervation-dependent gene induction and suppression. Mol Biol Cell 2009; 20(4): 1120-31.
[http://dx.doi.org/10.1091/mbc.e08-07-0759] [PMID: 19109424]
[59]
Williams AH, Valdez G, Moresi V, et al. MicroRNA-206 delays ALS progression and promotes regeneration of neuromuscular synapses in mice. Science 2009; 326(5959): 1549-54.
[http://dx.doi.org/10.1126/science.1181046] [PMID: 20007902]
[60]
Bruneteau G, Simonet T, Bauché S, et al. Muscle histone deacetylase 4 upregulation in amyotrophic lateral sclerosis: potential role in reinnervation ability and disease progression. Brain 2013; 136(8): 2359-68.
[http://dx.doi.org/10.1093/brain/awt164] [PMID: 23824486]
[61]
Donnelly J, Blair SN, Jakicic JM, Manore MM, Rankin JW, Smith BK. American college of sports medicine position stand. appropriate physical activity intervention strategies for weight loss and prevention of weight regain for adults. Med Sci Sports Exerc 2009; 41(2): 459-71.
[http://dx.doi.org/10.1249/MSS.0b013e3181949333] [PMID: 19127177]
[62]
Ngo ST, Steyn FJ, McCombe PA. Body mass index and dietary intervention: Implications for prognosis of amyotrophic lateral sclerosis. J Neurol Sci 2014; 340(1-2): 5-12.
[http://dx.doi.org/10.1016/j.jns.2014.02.035] [PMID: 24629478]
[63]
Ferri A, Coccurello R. What is “Hyper” in the ALS Hypermetabolism? Mediators Inflamm 2017; 2017: 1-11.
[http://dx.doi.org/10.1155/2017/7821672] [PMID: 29081604]
[64]
Dupuis L, Oudart H, René F, de Aguilar J-LG, Loeffler JP. Evidence for defective energy homeostasis in amyotrophic lateral sclerosis: Benefit of a high-energy diet in a transgenic mouse model. Proc Natl Acad Sci USA 2004; 101(30): 11159-64.
[http://dx.doi.org/10.1073/pnas.0402026101] [PMID: 15263088]
[65]
Dupuis L, Pradat PF, Ludolph AC, Loeffler JP. Energy metabolism in amyotrophic lateral sclerosis. Lancet Neurol 2011; 10(1): 75-82.
[http://dx.doi.org/10.1016/S1474-4422(10)70224-6] [PMID: 21035400]
[66]
Dobrowolny G, Aucello M, Rizzuto E, et al. Skeletal muscle is a primary target of SOD1G93A-mediated toxicity. Cell Metab 2008; 8(5): 425-36.
[http://dx.doi.org/10.1016/j.cmet.2008.09.002] [PMID: 19046573]
[67]
Lepore E, Casola I, Dobrowolny G, Musarò A. Neuromuscular junction as an entity of nerve-muscle communication. Cells 2019; 8(8): 906.
[http://dx.doi.org/10.3390/cells8080906] [PMID: 31426366]
[68]
Massih B, Veh A, Schenke M, et al. A 3D cell culture system for bioengineering human neuromuscular junctions to model ALS. Front Cell Dev Biol 2023; 11: 996952.
[http://dx.doi.org/10.3389/fcell.2023.996952] [PMID: 36866276]
[69]
Margotta C, Fabbrizio P, Ceccanti M, et al. Immune-mediated myogenesis and acetylcholine receptor clustering promote a slow disease progression in ALS mouse models. Inflamm Regen 2023; 43(1): 19.
[http://dx.doi.org/10.1186/s41232-023-00270-w] [PMID: 36895050]
[70]
Fabbrizio P, Margotta C, D’Agostino J, et al. Intramuscular IL-10 administration enhances the activity of myogenic precursor cells and improves motor function in ALS mouse model. Cells 2023; 12(7): 1016.
[http://dx.doi.org/10.3390/cells12071016] [PMID: 37048088]
[71]
Casola I, Scicchitano BM, Lepore E, et al. Circulating myomiRs in muscle denervation: From surgical to ALS pathological condition. Cells 2021; 10(8): 2043.
[http://dx.doi.org/10.3390/cells10082043] [PMID: 34440812]
[72]
Xu K, Ji M, Huang X, Peng Y, Wu W, Zhang J. Differential regulatory roles of MicroRNAs in porcine intramuscular and subcutaneous adipocytes. J Agric Food Chem 2020; 68(13): 3954-62.
[http://dx.doi.org/10.1021/acs.jafc.9b08191] [PMID: 32146812]
[73]
Maixner N, Haim Y, Blüher M, et al. Visceral adipose tissue E2F1-miRNA206/210 pathway associates with type 2 diabetes in humans with extreme obesity. Cells 2022; 11(19): 3046.
[http://dx.doi.org/10.3390/cells11193046] [PMID: 36231008]
[74]
Julian TH, Glascow N, Barry ADF, et al. Physical exercise is a risk factor for amyotrophic lateral sclerosis: Convergent evidence from Mendelian randomisation, transcriptomics and risk genotypes. EBioMedicine 2021; 68: 103397.
[http://dx.doi.org/10.1016/j.ebiom.2021.103397] [PMID: 34051439]
[75]
Chapman L, Cooper-Knock J, Shaw PJ. Physical activity as an exogenous risk factor for amyotrophic lateral sclerosis: a review of the evidence. Brain 2023; 146(5): 1745-57.
[http://dx.doi.org/10.1093/brain/awac470] [PMID: 36918362]
[76]
Dadon-Nachum M, Melamed E, Offen D. The “dying-back” phenomenon of motor neurons in ALS. J Mol Neurosci 2011; 43(3): 470-7.
[http://dx.doi.org/10.1007/s12031-010-9467-1] [PMID: 21057983]
[77]
Verma S, Khurana S, Vats A, et al. Neuromuscular junction dysfunction in amyotrophic lateral sclerosis. Mol Neurobiol 2022; 59(3): 1502-27.
[http://dx.doi.org/10.1007/s12035-021-02658-6] [PMID: 34997540]
[78]
Musarò A. Understanding ALS: new therapeutic approaches. FEBS J 2013; 280(17): 4315-22.
[http://dx.doi.org/10.1111/febs.12087] [PMID: 23217177]
[79]
Majmudar S, Wu J, Paganoni S. Rehabilitation in amyotrophic lateral sclerosis: Why it matters. Muscle Nerve 2014; 50(1): 4-13.
[http://dx.doi.org/10.1002/mus.24202] [PMID: 24510737]
[80]
Meng L, Li X, Li C, et al. Effects of exercise in patients with amyotrophic lateral sclerosis. Am J Phys Med Rehabil 2020; 99(9): 801-10.
[http://dx.doi.org/10.1097/PHM.0000000000001419] [PMID: 32452880]

Rights & Permissions Print Export Cite as
© 2023 Bentham Science Publishers | Privacy Policy