The pathophysiology of motor fatigue and fatigability in multiple sclerosis

Robert Patejdl, Uwe K Zettl, Robert Patejdl, Uwe K Zettl

Abstract

Multiple Sclerosis (MS) is a heterogeneous immune mediated disease of the central nervous system (CNS). Fatigue is one of the most common and disabling symptom of MS. It interferes with daily activities on the level of cognition and motor endurance. Motor fatigue can either result from lesions in cortical networks or motor pathways ("primary fatigue") or it may be a consequence of detraining with subsequent adaptions of muscle and autonomic function. Programmed exercise interventions are used frequently to increase physical fitness in MS-patients. Studies investigating the effects of training on aerobic capacity, objective endurance and perceived fatigability have yielded heterogenous results, most likely due to the heterogeneity of interventions and patients, but probably also due to the non-uniform pathophysiology of fatigability among MS-patients. The aim of this review is to summarize the current knowledge on the pathophysiology of motor fatigability with special reference to the basic exercise physiology that underlies our understanding of both pathogenesis and treatment interventions.

Keywords: aerobic capacity; autonomic dysfunction; detraining; motor fatigue; multiple sclerosis.

Conflict of interest statement

Author RP has received research grants from Novartis. Author UZ received research support as well as speaking fees and travel funds from Almirall, Alexion, Bayer HealthCare, Bristol Myers Squibb, Biogen, Janssen, Merck Serono, Novartis, Octapharma, Roche, Sanofi Genzyme, and Teva.

Copyright © 2022 Patejdl and Zettl.

Figures

Figure 1
Figure 1
Selected physiological processes that are required to maintain stable muscle force production. Among MS-patients, most of these processes have been described in MS patients samples and, according to the given in the figure legend, were found to be altered or not. The metabolic integration between muscle, liver and other organs during exercise has not yet been characterized thoroughly by appropriate experiments in MS patients.

References

    1. Patejdl R, Penner IK, Noack TK, Zettl UK. Multiple sclerosis and fatigue: a review on the contribution of inflammation and immune-mediated neurodegeneration. Autoimmun Rev. (2016) 15:210–20. 10.1016/j.autrev.2015.11.005
    1. Rommer PS, Eichstädt K, Ellenberger D, Flachenecker P, Friede T, Haas J, et al. . Symptomatology and symptomatic treatment in multiple sclerosis: results from a nationwide MS registry. Mult Scler. (2019) 25:1641–52. 10.1177/1352458518799580
    1. Marrie RA, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T. The burden of mental comorbidity in multiple sclerosis: frequent, underdiagnosed, and undertreated. Multiple Sclerosis. (2009) 15:385–92. 10.1177/1352458508099477
    1. Crayton H, Heyman RA, Rossman HS. A multimodal approach to managing the symptoms of multiple sclerosis. Neurology. (2004) 63:S12–8. 10.1212/WNL.63.11_suppl_5.S12
    1. Horowski S, Zettl UK, Benecke R, Walter U. Sonographic basal ganglia alterations are related to non-motor symptoms in multiple sclerosis. J Neurol. (2011) 258:195–202. 10.1007/s00415-010-5707-0
    1. Ellenberger D, Flachenecker P, Haas J, Hellwig K, Paul F, Stahmann A, et al. . Is benign MS really benign? what a meaningful classification beyond the EDSS must take into consideration. Mult Scler Relat Disord. (2020) 46:102485. 10.1016/j.msard.2020.102485
    1. Ellenberger D, Flachenecker P, Fneish F, Frahm N, Hellwig K, Paul F, et al. . Aggressive multiple sclerosis: a matter of measurement and timing. Brain. (2020) 143:e97. 10.1093/brain/awaa306
    1. Fischer M, Kunkel A, Bublak P, Faiss JH, Hoffmann F, Sailer M, et al. . How reliable is the classification of cognitive impairment across different criteria in early and late stages of multiple sclerosis? J Neurol Sci. (2014) 343:91–9. 10.1016/j.jns.2014.05.042
    1. Greim B, Engel C, Apel A, Zettl UK. Fatigue in neuroimmunological diseases. J Neurol. (2007) 254:II102–6. 10.1007/s00415-007-2025-2
    1. Hadjimichael O, Vollmer T, Oleen-Burkey M. Fatigue characteristics in multiple sclerosis: the North American research committee on multiple sclerosis (NARCOMS) survey. Health Qual Life Outcomes. (2008) 6:100. 10.1186/1477-7525-6-100
    1. Stuke K, Flachenecker P, Zettl UK, Elias WG, Freidel M, Haas J, et al. . Symptomatology of MS: results from the German MS registry. J Neurol. (2009) 256:1932–5. 10.1007/s00415-009-5257-5
    1. Hubbard AL, Golla H, Lausberg H. What's in a name? that which we call multiple sclerosis fatigue. Mult Scler. (2020) 2020:1352458520941481. 10.1177/1352458520941481
    1. Anderson G, Berk M, Maes M. Biological phenotypes underpin the physio-somatic symptoms of somatization, depression, and chronic fatigue syndrome. Acta Psychiatr Scand. (2014) 129:83–97. 10.1111/acps.12182
    1. Fischer JS, LaRocca NG, Miller DM, Ritvo PG, Andrews H, Paty D. Recent developments in the assessment of quality of life in multiple sclerosis (MS). Multiple Sclerosis. (1999) 5:251–9. 10.1177/135245859900500410
    1. Penner IK, Raselli C, Stocklin M, Opwis K, Kappos L, Calabrese P. The fatigue scale for motor and cognitive functions (FSMC): validation of a new instrument to assess multiple sclerosis-related fatigue. Mult Scler. (2009) 15:1509–17. 10.1177/1352458509348519
    1. Pust GEA, Pöttgen J, Randerath J, Lau S, Heesen C, Gold SM, et al. . In search of distinct MS-related fatigue subtypes: results from a multi-cohort analysis in 1. 403 MS patients. J Neurol. (2019) 266:1663–73. 10.1007/s00415-019-09311-2
    1. Iriarte J, Subira ML, Castro P. Modalities of fatigue in multiple sclerosis: correlation with clinical and biological factors. Mult Scler. (2000) 6:124–30. 10.1191/135245800678827572
    1. Konsman JP, Parnet P, Dantzer R. Cytokine-induced sickness behaviour: mechanisms and implications. Trends Neurosci. (2002) 25:154–9. 10.1016/S0166-2236(00)02088-9
    1. Leavitt VM, Meo E de, Riccitelli G, Rocca MA, Comi G, Filippi M, et al. . Elevated body temperature is linked to fatigue in an Italian sample of relapsing-remitting multiple sclerosis patients. J Neurol. (2015) 262:2440–2. 10.1007/s00415-015-7863-8
    1. Frohman TC, Davis SL, Beh S, Greenberg BM, Remington G, Frohman EM. Uhthoff's phenomena in MS–clinical features and pathophysiology. Nat Rev Neurol. (2013) 9:535–40. 10.1038/nrneurol.2013.98
    1. Liepert J, Mingers D, Heesen C, Baumer T, Weiller C. Motor cortex excitability and fatigue in multiple sclerosis: a transcranial magnetic stimulation study. Mult Scler. (2005) 11:316–21. 10.1191/1352458505ms1163oa
    1. Chen MH, Wylie GR, Sandroff BM, Dacosta-Aguayo R, DeLuca J, Genova HM. Neural mechanisms underlying state mental fatigue in multiple sclerosis: a pilot study. J Neurol. (2020) 267:2372–82. 10.1007/s00415-020-09853-w
    1. Dahl O-P, Stordal E, Lydersen S, Midgard R. Anxiety and depression in multiple sclerosis. a comparative population-based study in Nord-Trondelag County, Norway. Multiple Sclerosis. (2009) 15:1495–501. 10.1177/1352458509351542
    1. Tarasiuk J, Kapica-Topczewska K, Czarnowska A, Chorazy M, Kochanowicz J, Kułakowska A. Co-occurrence of fatigue and depression in people with multiple sclerosis: a mini-review. Front Neurol. (2021) 12:817256. 10.3389/fneur.2021.817256
    1. Gobbi C, Rocca MA, Riccitelli G, Pagani E, Messina R, Preziosa P, et al. . Influence of the topography of brain damage on depression and fatigue in patients with multiple sclerosis. Mult Scler. (2014) 20:192–201. 10.1177/1352458513493684
    1. Gobbi C, Rocca M, Pagani E, Riccitelli G, Pravata E, Radaelli M, et al. . Forceps minor damage and co-occurrence of depression and fatigue in multiple sclerosis. Mult Scler J. (2014) 20:1633–40. 10.1177/1352458514530022
    1. Penner I-K, Bechtel N, Raselli C, Stöcklin M, Opwis K, Kappos L, et al. . Fatigue in multiple sclerosis: relation to depression, physical impairment, personality and action control. Mult Scler. (2007) 13:1161–7. 10.1177/1352458507079267
    1. Stamoula E, Siafis S, Dardalas I, Ainatzoglou A, Matsas A, Athanasiadis T, et al. . Antidepressants on multiple sclerosis: a review of in vitro and in vivo models. Front Immunol. (2021) 12:677879. 10.3389/fimmu.2021.677879
    1. Brenner P, Piehl F. Fatigue and depression in multiple sclerosis: pharmacological and non-pharmacological interventions. Acta Neurol Scand. (2016) 134:47–54. 10.1111/ane.12648
    1. Has Silemek AC, Fischer L, Pöttgen J, Penner I-K, Engel AK, Heesen C, et al. . Functional and structural connectivity substrates of cognitive performance in relapsing remitting multiple sclerosis with mild disability. Neuroimage Clin. (2020) 25:102177. 10.1016/j.nicl.2020.102177
    1. Ruiu E, Dubbioso R, Madsen KH, Svolgaard O, Raffin E, Andersen KW, et al. . Probing context-dependent modulations of ipsilateral premotor-motor connectivity in relapsing-remitting multiple sclerosis. Front Neurol. (2020) 11:193. 10.3389/fneur.2020.00193
    1. Bigland-Ritchie B, Woods JJ. Changes in muscle contractile properties and neural control during human muscular fatigue. Muscle Nerve. (1984) 7:691–9. 10.1002/mus.880070902
    1. Heitmann H, Haller B, Tiemann L, Mühlau M, Berthele A, Tölle TR, et al. . Longitudinal prevalence and determinants of pain in multiple sclerosis: results from the German national multiple sclerosis cohort study. Pain. (2020) 161:787–96. 10.1097/j.pain.0000000000001767
    1. Leavitt VM, DeLuca J. Central fatigue: issues related to cognition, mood and behavior, and psychiatric diagnoses. PM R. (2010) 2:332–7. 10.1016/j.pmrj.2010.03.027
    1. Scheidegger O, Kamm CP, Humpert SJ, Rosler KM. Corticospinal output during muscular fatigue differs in multiple sclerosis patients compared to healthy controls. Mult Scler. (2012) 18:1500–6. 10.1177/1352458512438722
    1. Djajadikarta ZJ, Dongés SC, Brooks J, Kennedy DS, Gandevia SC, Taylor JL. Impaired central drive to plantarflexors and minimal ankle proprioceptive deficit in people with multiple sclerosis. Mult Scler Relat Disord. (2020) 46:102584. 10.1016/j.msard.2020.102584
    1. Sheean GL, Murray NM, Rothwell JC, Miller DH, Thompson AJ. An electrophysiological study of the mechanism of fatigue in multiple sclerosis. Brain. (1997)120:299–315. 10.1093/brain/120.2.299
    1. Martinez MW, Kim JH, Shah AB, Phelan D, Emery MS, Wasfy MM, et al. . Exercise-induced cardiovascular adaptations and approach to exercise and cardiovascular disease: JACC state-of-the-art review. J Am Coll Cardiol. (2021) 78:1453–70. 10.1016/j.jacc.2021.08.003
    1. Duchateau J, Enoka RM. Human motor unit recordings: origins and insight into the integrated motor system. Brain Res. (2011) 1409:42–61. 10.1016/j.brainres.2011.06.011
    1. Mujika I, Padilla S. Detraining: loss of training-induced physiological and performance adaptations. part I: short term insufficient training stimulus. Sports Med. (2000) 30:79–87. 10.2165/00007256-200030020-00002
    1. Mujika I, Padilla S. Detraining: loss of training-induced physiological and performance adaptations. part II: long term insufficient training stimulus. Sports Med. (2000) 30:145–54. 10.2165/00007256-200030030-00001
    1. Kluger BM, Krupp LB, Enoka RM. Fatigue and fatigability in neurologic illnesses: proposal for a unified taxonomy. Neurology. (2013) 80:409–16. 10.1212/WNL.0b013e31827f07be
    1. Enoka RM, Almuklass AM, Alenazy M, Alvarez E, Duchateau J. Distinguishing between fatigue and fatigability in multiple sclerosis. Neurorehabil Neural Repair. (2021) 35:960–73. 10.1177/15459683211046257
    1. Krupp LB, LaRocca NG, Muir-Nash J, Steinberg AD. The fatigue severity scale. application to patients with multiple sclerosis and systemic lupus erythematosus. Arch Neurol. (1989) 46:1121–3. 10.1001/archneur.1989.00520460115022
    1. Fisk JD, Ritvo PG, Ross L, Haase DA, Marrie TJ, Schlech WF. Measuring the functional impact of fatigue: initial validation of the fatigue impact scale. Clin Infect Dis. (1994) 18:S79–83. 10.1093/clinids/18.Supplement_1.S79
    1. Cattaneo D, Gervasoni E, Anastasi D, Di Giovanni R, Brichetto G, Carpinella I, et al. . Prevalence and patterns of subclinical motor and cognitive impairments in non-disabled individuals with early multiple sclerosis: a multicenter cross-sectional study. Ann Phys Rehabil Med. (2021) 65:101491. 10.1016/j.rehab.2021.101491
    1. Beckerman H, Eijssen IC, van Meeteren J, Verhulsdonck MC, Groot V de. Fatigue profiles in patients with multiple sclerosis are based on severity of fatigue and not on dimensions of fatigue. Sci Rep. (2020) 10:4167. 10.1038/s41598-020-61076-1
    1. Rooney S, McFadyen A, Wood L, Moffat F, Paul PL. Minimally important difference of the fatigue severity scale and modified fatigue impact scale in people with multiple sclerosis. Mult Scler Relat Disord. (2019) 35:158–63. 10.1016/j.msard.2019.07.028
    1. Rooney S, Wood L, Moffat F, Paul L. Prevalence of fatigue and its association with clinical features in progressive and non-progressive forms of multiple sclerosis. Mult Scler Relat Disord. (2019) 28:276–82. 10.1016/j.msard.2019.01.011
    1. Steens A, Vries A de, Hemmen J, Heersema T, Heerings M, Maurits N, et al. . Fatigue perceived by multiple sclerosis patients is associated with muscle fatigue. Neurorehabil Neural Repair. (2012) 26:48–57. 10.1177/1545968311416991
    1. Loy BD, Taylor RL, Fling BW, Horak FB. Relationship between perceived fatigue and performance fatigability in people with multiple sclerosis: a systematic review and meta-analysis. J Psychosom Res. (2017) 100:1–7. 10.1016/j.jpsychores.2017.06.017
    1. Gould JR, Reineberg AE, Cleland BT, Knoblauch KE, Clinton GK, Banich MT, et al. . Adjustments in torque steadiness during fatiguing contractions are inversely correlated with IQ in persons with multiple sclerosis. Front Physiol. (2018) 9:1404. 10.3389/fphys.2018.01404
    1. Taul-Madsen L, Dalgas U, Kjølhede T, Hvid LG, Petersen T, Riemenschneider M, et al. . Head-to-head comparison of an isometric and a concentric fatigability protocol and the association with fatigue and walking in persons with multiple sclerosis. Neurorehabil Neural Repair. (2020) 34:523–32. 10.1177/1545968320920250
    1. Ramari C, Moraes AG, Tauil CB, von Glehn F, Motl R, de David AC. Knee flexor strength and balance control impairment may explain declines during prolonged walking in women with mild multiple sclerosis. Mult Scler Relat Disord. (2018) 20:181–5. 10.1016/j.msard.2018.01.024
    1. Aldughmi M, Bruce J, Siengsukon CF. Relationship between fatigability and perceived fatigue measured using the neurological fatigue index in people with multiple sclerosis. Int J MS Care. (2017) 19:232–9. 10.7224/1537-2073.2016-059
    1. Moumdjian L, Gervasoni E, van Halewyck F, Eijnde BO, Wens I, van Geel F, et al. . Walking endurance and perceived symptom severity after a single maximal exercise test in persons with mild disability because of multiple sclerosis. Int J Rehabil Res. (2018) 41:316–22. 10.1097/MRR.0000000000000305
    1. Thickbroom GW, Sacco P, Kermode AG, Archer SA, Byrnes ML, Guilfoyle A, et al. . Central motor drive and perception of effort during fatigue in multiple sclerosis. J Neurol. (2006) 253:1048–53. 10.1007/s00415-006-0159-2
    1. Andreasen AK, Jakobsen J, Petersen T, Andersen H. Fatigued patients with multiple sclerosis have impaired central muscle activation. Multiple Sclerosis. (2009) 15:818–27. 10.1177/1352458509105383
    1. Chen S, Sierra S, Shin Y, Goldman MD. Gait speed trajectory during the six-minute walk test in multiple sclerosis: a measure of walking endurance. Front Neurol. (2021) 12:698599. 10.3389/fneur.2021.698599
    1. Cederberg KLJ, Sikes EM, Bartolucci AA, Motl RW. Walking endurance in multiple sclerosis: Meta-analysis of six-minute walk test performance. Gait Posture. (2019) 73:147–53. 10.1016/j.gaitpost.2019.07.125
    1. Ng AV, Miller RG, Gelinas D, Kent-Braun JA. Functional relationships of central and peripheral muscle alterations in multiple sclerosis. Muscle Nerve. (2004) 29:843–52. 10.1002/mus.20038
    1. Haan A de, Ruiter CJ de, van der Woude LHV, Jongen PJH. Contractile properties and fatigue of quadriceps muscles in multiple sclerosis. Muscle Nerve. (2000) 23:1534–41. 10.1002/1097-4598(200010)23:10<1534::aid-mus9>;2-d
    1. Ruiter CJ de, Jongen PJ, van der Woude LH, Haan A de. Contractile speed and fatigue of adductor pollicis muscle in multiple sclerosis. Muscle Nerve. (2001) 24:1173–80. 10.1002/mus.1129
    1. Coates KD, Aboodarda SJ, Krüger RL, Martin T, Metz LM, Jarvis SE, et al. . Multiple sclerosis-related fatigue: the role of impaired corticospinal responses and heightened exercise fatigability. J Neurophysiol. (2020) 124:1131–43. 10.1152/jn.00165.2020
    1. Sharma KR, Kent-Braun J, Mynhier MA, Weiner MW, Miller RG. Evidence of an abnormal intramuscular component of fatigue in multiple sclerosis. Muscle Nerve. (1995) 18:1403–11. 10.1002/mus.880181210
    1. Devasahayam AJ, Kelly LP, Wallack EM, Ploughman M. Oxygen cost during mobility tasks and its relationship to fatigue in progressive multiple sclerosis. Arch Phys Med Rehabil. (2019) 100:2079–88. 10.1016/j.apmr.2019.03.017
    1. Venckunas T, Mieziene B, Emeljanovas A. Aerobic capacity is related to multiple other aspects of physical fitness: a study in a large sample of lithuanian schoolchildren. Front Physiol. (2018) 9:1797. 10.3389/fphys.2018.01797
    1. Astrand PO, Ryhming I. A nomogram for calculation of aerobic capacity (physical fitness) from pulse rate during sub-maximal work. J Appl Physiol. (1954) 7:218–21. 10.1152/jappl.1954.7.2.218
    1. Midgley AW, McNaughton LR, Polman R, Marchant D. Criteria for determination of maximal oxygen uptake: a brief critique and recommendations for future research. Sports Med. (2007) 37:1019–28. 10.2165/00007256-200737120-00002
    1. Issekutz B, Rodahl K. Respiratory quotient during exercise. J Appl Physiol. (1961) 16:606–10. 10.1152/jappl.1961.16.4.606
    1. Heine M, Hoogervorst ELJ, Hacking HGA, Verschuren O, Kwakkel G. Validity of maximal exercise testing in people with multiple sclerosis and low to moderate levels of disability. Phys Ther. (2014) 94:1168–75. 10.2522/ptj.20130418
    1. Heine M, van den Akker LE, Verschuren O, Visser-Meily A, Kwakkel G. Reliability and responsiveness of cardiopulmonary exercise testing in fatigued persons with multiple sclerosis and low to mild disability. PLoS ONE. (2015) 10:e0122260. 10.1371/journal.pone.0122260
    1. Langeskov-Christensen M, Heine M, Kwakkel G, Dalgas U. Aerobic capacity in persons with multiple sclerosis: a systematic review and meta-analysis. Sports Med. (2015) 45:905–23. 10.1007/s40279-015-0307-x
    1. Heine M, van de Port I, Rietberg MB, van Wegen EEH, Kwakkel G. Exercise therapy for fatigue in multiple sclerosis. Cochrane Database Syst Rev. (2015) 2015:CD009956. 10.1002/14651858.CD009956.pub2
    1. Koseoglu BF, Gokkaya NKO, Ergun U, Inan L, Yesiltepe E. Cardiopulmonary and metabolic functions, aerobic capacity, fatigue and quality of life in patients with multiple sclerosis. Acta Neurol Scand. (2006) 114:261–7. 10.1111/j.1600-0404.2006.00598.x
    1. Sandroff BM, Sosnoff JJ, Motl RW. Physical fitness, walking performance, and gait in multiple sclerosis. J Neurol Sci. (2013) 328:70–6. 10.1016/j.jns.2013.02.021
    1. Sandroff BM, Motl RW. Fitness and cognitive processing speed in persons with multiple sclerosis: a cross-sectional investigation. J Clin Exp Neuropsychol. (2012) 34:1041–52. 10.1080/13803395.2012.715144
    1. Motl RW, Fernhall B. Accurate prediction of cardiorespiratory fitness using cycle ergometry in minimally disabled persons with relapsing-remitting multiple sclerosis. Arch Phys Med Rehabil. (2012) 93:490–5. 10.1016/j.apmr.2011.08.025
    1. Langeskov-Christensen M, Langeskov-Christensen D, Overgaard K, Møller AB, Dalgas U. Validity and reliability of VO2-max measurements in persons with multiple sclerosis. J Neurol Sci. (2014) 342:79–87. 10.1016/j.jns.2014.04.028
    1. Ponichtera-Mulcare JA, Mathews T, Glaser RM, Gupta SC. Maximal Aerobic Exercise Of Individuals With Multiple Sclerosis Using Three Modes Of Ergometry (1995).
    1. Morrison EH, Cooper DM, White LJ, Larson J, Leu S-Y, Zaldivar F, et al. . Ratings of perceived exertion during aerobic exercise in multiple sclerosis. Arch Phys Med Rehabil. (2008) 89:1570–4. 10.1016/j.apmr.2007.12.036
    1. Klaren RE, Sandroff BM, Fernhall B, Motl RW. Comprehensive profile of cardiopulmonary exercise testing in ambulatory persons with multiple sclerosis. Sports Med. (2016) 46:1365–79. 10.1007/s40279-016-0472-6
    1. Driehuis ER, van den Akker LE, Groot V de, Beckerman H. Aerobic capacity explains physical functioning and participation in patients with multiple sclerosis-related fatigue. J Rehabil Med. (2018) 50:185–92. 10.2340/16501977-2306
    1. Valet M, Lejeune T, Glibert Y, Hakizimana JC, van Pesch V, El Sankari S, et al. . Fatigue and physical fitness of mildly disabled persons with multiple sclerosis: a cross-sectional study. Int J Rehabil Res. (2017) 40:268–74. 10.1097/MRR.0000000000000238
    1. Rooney S, Wood L, Moffat F, Paul L. Is fatigue associated with aerobic capacity and muscle strength in people with multiple sclerosis: a systematic review and meta-analysis. Arch Phys Med Rehabil. (2019) 100:2193–204. 10.1016/j.apmr.2019.06.014
    1. Wolf F, Rademacher A, Joisten N, Proschinger S, Schlagheck ML, Bloch W, et al. . The aerobic capacity - fatigue relationship in persons with multiple sclerosis is not reproducible in a pooled analysis of two randomized controlled trials. Mult Scler Relat Disord. (2021) 58:103476. 10.1016/j.msard.2021.103476
    1. Feltham MG, Collett J, Izadi H, Wade DT, Morris MG, Meaney AJ, et al. . Cardiovascular adaptation in people with multiple sclerosis following a twelve week exercise programme suggest deconditioning rather than autonomic dysfunction caused by the disease. results from a randomized controlled trial. Eur J Phys Rehabil Med. (2013) 49:765–74.
    1. Trefts E, Williams AS, Wasserman DH. Exercise and the regulation of hepatic metabolism. Prog Mol Biol Transl Sci. (2015) 135:203–25. 10.1016/bs.pmbts.2015.07.010
    1. Clark MG, Patten GS, Filsell OH, Rattigan S. Co-ordinated regulation of muscle glycolysis and hepatic glucose output in exercise by catecholamines acting via alpha-receptors. FEBS Lett. (1983) 158:1–6. 10.1016/0014-5793(83)80664-4
    1. Ahlborg G, Felig P, Hagenfeldt L, Hendler R, Wahren J. Substrate turnover during prolonged exercise in man. splanchnic and leg metabolism of glucose, free fatty acids, and amino acids. J Clin Invest. (1974) 53:1080–90. 10.1172/JCI107645
    1. Hu C, Hoene M, Plomgaard P, Hansen JS, Zhao X, Li J, et al. . Muscle-liver substrate fluxes in exercising humans and potential effects on hepatic metabolism. J Clin Endocrinol Metab. (2020) 105:1196-209. 10.1210/clinem/dgz266
    1. Nielsen HB, Febbraio MA, Ott P, Krustrup P, Secher NH. Hepatic lactate uptake versus leg lactate output during exercise in humans. J Appl Physiol. (1985). (2007) 103:1227–33. 10.1152/japplphysiol.00027.2007
    1. Lenman AJ, Tulley FM, Vrbova G, Dimitrijevic MR, Towle JA. Muscle fatigue in some neurological disorders. Muscle Nerve. (1989) 12:938–42. 10.1002/mus.880121111
    1. Kirmaci ZIK, Firat T, Özkur HA, Neyal AM, Neyal A, Ergun N. Muscle architecture and its relationship with lower extremity muscle strength in multiple sclerosis. Acta Neurol Belg. (2021). 10.1007/s13760-021-01768-1
    1. Kent-Braun JA, Ng AV, Castro M, Weiner MW, Gelinas D, Dudley GA, et al. . Strength, skeletal muscle composition, and enzyme activity in multiple sclerosis. J Appl Physiol (1985). (1997) 83:1998–2004. 10.1152/jappl.1997.83.6.1998
    1. Kent-Braun JA, Sharma KR, Miller RG, Weiner MW. Postexercise phosphocreatine resynthesis is slowed in multiple sclerosis. Muscle Nerve. (1994) 17:835–41. 10.1002/mus.880170802
    1. Castro MJ, Kent-Braun JA, Ng AV, Miller RG, Dudley GA. Muscle fiber type-specific myofibrillar actomyosin Ca2+ ATPase activity in multiple sclerosis. Muscle Nerve. (1998) 21:547–9. 10.1002/(sici)1097-4598(199804)21:4<547::aid-mus18>;2-u
    1. Kent-Braun JA, Sharma KR, Weiner MW, Miller RG. Effects of exercise on muscle activation and metabolism in multiple sclerosis. Muscle Nerve. (1994) 17:1162–9. 10.1002/mus.880171006
    1. DePauw EM, Rouhani M, Flanagan AM, Ng AV. Forearm muscle mitochondrial capacity and resting oxygen uptake: relationship to symptomatic fatigue in persons with multiple sclerosis. Mult Scler J Exp Transl Clin. (2021) 7:20552173211028875. 10.1177/20552173211028875
    1. Harp MA, McCully KK, Moldavskiy M, Backus D. Skeletal muscle mitochondrial capacity in people with multiple sclerosis. Mult Scler J Exp Transl Clin. (2016) 2:2055217316678020. 10.1177/2055217316678020
    1. Huang M, Jay O, Davis SL. Autonomic dysfunction in multiple sclerosis: implications for exercise. Auton Neurosci. (2015) 188:82–5. 10.1016/j.autneu.2014.10.017
    1. Westerdahl E, Gunnarsson M, Wittrin A, Nilsagård Y. Pulmonary function and respiratory muscle strength in patients with multiple sclerosis. Mult Scler Int. (2021) 2021:5532776. 10.1155/2021/5532776
    1. Hansen D, Wens I, Keytsman C, Verboven K, Dendale P, Eijnde BO. Ventilatory function during exercise in multiple sclerosis and impact of training intervention: cross-sectional and randomized controlled trial. Eur J Phys Rehabil Med. (2015) 51:557–68.
    1. Keytsman C, Hansen D, Wens I, Eijnde BO. Exercise-induced lactate responses in multiple sclerosis: a retrospective analysis. NeuroRehabilitation. (2019) 45:99–106. 10.3233/NRE-192740
    1. Davis SL, Wilson TE, White AT, Frohman EM. Thermoregulation in multiple sclerosis. J Appl Physiol (1985). (2010) 109:1531–7. 10.1152/japplphysiol.00460.2010
    1. Allen DR, Huang M, Parupia IM, Dubelko AR, Frohman EM, Davis SL. Impaired sweating responses to a passive whole body heat stress in individuals with multiple sclerosis. J Neurophysiol. (2017) 118:7–14. 10.1152/jn.00897.2016
    1. Allen DR, Huang MU, Morris NB, Chaseling GK, Frohman EM, Jay O, et al. . Impaired thermoregulatory function during dynamic exercise in multiple sclerosis. Med Sci Sports Exerc. (2019) 51:395–404. 10.1249/MSS.0000000000001821
    1. Chaseling GK, Filingeri D, Allen D, Barnett M, Vucic S, Davis SL, et al. . Blunted sweating does not alter the rise in core temperature in people with multiple sclerosis exercising in the heat. Am J Physiol Regul Integr Comp Physiol. (2021) 320:R258–67. 10.1152/ajpregu.00090.2020
    1. Racosta JM, Sposato LA, Morrow SA, Cipriano L, Kimpinski K, Kimpiski K, et al. . Cardiovascular autonomic dysfunction in multiple sclerosis: a meta-analysis. Mult Scler Relat Disord. (2015) 4:104–11. 10.1016/j.msard.2015.02.002
    1. Mincu RI, Magda SL, Mihaila S, Florescu M, Mihalcea DJ, Velcea A, et al. . Impaired cardiac function in patients with multiple sclerosis by comparison with normal subjects. Sci Rep. (2018) 8:3300. 10.1038/s41598-018-21599-0
    1. Rapp D, Keßler M, Pinkhardt E, Otto M, Tumani H, Senel M. Stress cardiomyopathy associated with the first manifestation of multiple sclerosis: a case report. BMC Neurol. (2020) 20:227. 10.1186/s12883-020-01757-6
    1. Videira G, Castro P, Vieira B, Filipe JP, Santos R, Azevedo E, et al. . Autonomic dysfunction in multiple sclerosis is better detected by heart rate variability and is not correlated with central autonomic network damage. J Neurol Sci. (2016) 367:133–7. 10.1016/j.jns.2016.05.049
    1. Flachenecker P, Wolf A, Krauser M, Hartung HP, Reiners K. Cardiovascular autonomic dysfunction in multiple sclerosis: correlation with orthostatic intolerance. J Neurol. (1999) 246:578–86. 10.1007/s004150050407
    1. Flachenecker P, Reiners K, Krauser M, Wolf A, Toyka KV. Autonomic dysfunction in multiple sclerosis is related to disease activity and progression of disability. Multiple Sclerosis. (2001) 7:327–34. 10.1177/135245850100700509
    1. Habek M, Crnošija L, Lovrić M, Junaković A, Krbot Skorić M, Adamec I. Sympathetic cardiovascular and sudomotor functions are frequently affected in early multiple sclerosis. Clin Auton Res. (2016) 26:385–93. 10.1007/s10286-016-0370-x
    1. Winder K, Linker RA, Seifert F, Wang R, Lee D-H, Engelhorn T, et al. . Cerebral lesion correlates of sympathetic cardiovascular activation in multiple sclerosis. Hum Brain Mapp. (2019) 40:5083–93. 10.1002/hbm.24759
    1. Hansen D, Wens I, Dendale P, Eijnde BO. Exercise-onset heart rate increase is slowed in multiple sclerosis patients: does a disturbed cardiac autonomic control affect exercise tolerance? NeuroRehabilitation. (2013) 33:139–46. 10.3233/NRE-130938
    1. Hansen D, Wens I, Keytsman C, Eijnde BO, Dendale P. Is long-term exercise intervention effective to improve cardiac autonomic control during exercise in subjects with multiple sclerosis? a randomized controlled trial. Eur J Phys Rehabil Med. (2015) 51:223–31.
    1. Marongiu E, Olla S, Magnani S, Palazzolo G, Sanna I, Tocco F, et al. . Metaboreflex activity in multiple sclerosis patients. Eur J Appl Physiol. (2015) 115:2481–90. 10.1007/s00421-015-3271-0
    1. Magnani S, Olla S, Pau M, Palazzolo G, Tocco F, Doneddu A, et al. . Effects of six months training on physical capacity and metaboreflex activity in patients with multiple sclerosis. Front Physiol. (2016) 7:531. 10.3389/fphys.2016.00531
    1. Gervasoni E, Bove M, Sinatra M, Grosso C, Rovaris M, Cattaneo D, et al. . Cardiac autonomic function during postural changes and exercise in people with multiple sclerosis: a cross-sectional study. Mult Scler Relat Disord. (2018) 24:85–90. 10.1016/j.msard.2018.06.003
    1. Motl RW, Gosney JL. Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis. Multiple Sclerosis. (2008) 14:129–35. 10.1177/1352458507080464
    1. Andreu-Caravaca L, Ramos-Campo DJ, Chung LH, Rubio-Arias JÁ. Dosage and effectiveness of aerobic training on cardiorespiratory fitness, functional capacity, balance, and fatigue in people with multiple sclerosis: a systematic review and meta-analysis. Arch Phys Med Rehabil. (2021) 102:1826–39. 10.1016/j.apmr.2021.01.078
    1. Dalgas U, Stenager E, Ingemann-Hansen T. Multiple sclerosis and physical exercise: recommendations for the application of resistance-, endurance- and combined training. Mult Scler. (2008) 14:35–53. 10.1177/1352458507079445
    1. Learmonth YC, Motl RW. Exercise training for multiple sclerosis: a narrative review of history, benefits, safety, guidelines, and promotion. Int J Environ Res Public Health. (2021). 10.3390/ijerph182413245
    1. Pilutti LA, Greenlee TA, Motl RW, Nickrent MS, Petruzzello SJ. Effects of exercise training on fatigue in multiple sclerosis: a meta-analysis. Psychosom Med. (2013) 75:575–80. 10.1097/PSY.0b013e31829b4525
    1. Asano M, Finlayson ML. Meta-analysis of three different types of fatigue management interventions for people with multiple sclerosis: exercise, education, and medication. Mult Scler Int. (2014) 2014:798285. 10.1155/2014/798285
    1. Petajan JH, Gappmaier E, White AT, Spencer MK, Mino L, Hicks RW. Impact of aerobic training on fitness and quality of life in multiple sclerosis. Ann Neurol. (1996) 39:432–41. 10.1002/ana.410390405
    1. Mostert S, Kesselring J. Effects of a short-term exercise training program on aerobic fitness, fatigue, health perception and activity level of subjects with multiple sclerosis. Mult Scler. (2002) 8:161–8. 10.1191/1352458502ms779oa
    1. Ponichtera-Mulcare JA, Mathews T, Barrett PJ, Gupta SC. Change in aerobic fitness of patients with multiple sclerosis during a 6-month training program. Sport Med Train Rehabil. (1997) 7:265–72. 10.1080/15438629709512089
    1. Rodgers MM, Mulcare JA, King DL, Mathews T, Gupta SC, Glaser RM. Gait characteristics of individuals with multiple sclerosis before and after a 6-month aerobic training program. J Rehabil Res Dev. (1999) 36:183–8.
    1. Kargarfard M, Etemadifar M, Baker P, Mehrabi M, Hayatbakhsh R. Effect of aquatic exercise training on fatigue and health-related quality of life in patients with multiple sclerosis. Arch Phys Med Rehabil. (2012) 93:1701–8. 10.1016/j.apmr.2012.05.006
    1. Gehlsen GM, Grigsby SA, Winant DM. Effects of an aquatic fitness program on the muscular strength and endurance of patients with multiple sclerosis. Phys Ther. (1984) 64:653–7. 10.1093/ptj/64.5.653
    1. Bansi J, Bloch W, Gamper U, Kesselring J. Training in MS: influence of two different endurance training protocols (aquatic versus overland) on cytokine and neurotrophin concentrations during three week randomized controlled trial. Mult Scler. (2013) 19:613–21. 10.1177/1352458512458605
    1. Zrzavy T, Pfitzner A, Flachenecker P, Rommer P, Zettl UK. Effects of normobaric hypoxic endurance training on fatigue in patients with multiple sclerosis: a randomized prospective pilot study. J Neurol. (2021) 268:4809–15. 10.1007/s00415-021-10596-5
    1. Mähler A, Balogh A, Csizmadia I, Klug L, Kleinewietfeld M, Steiniger J, et al. . Metabolic, mental and immunological effects of normoxic and hypoxic training in multiple sclerosis patients: a pilot study. Front Immunol. (2018) 9:2819. 10.3389/fimmu.2018.02819
    1. Riksfjord SM, Brændvik SM, Røksund OD, Aamot I-L. Ventilatory efficiency and aerobic capacity in people with multiple sclerosis: a randomized study. SAGE Open Med. (2017) 5:2050312117743672. 10.1177/2050312117743672
    1. Torres-Costoso A, Martínez-Vizcaíno V, Reina-Gutiérrez S, Álvarez-Bueno C, Guzmán-Pavón MJ, Pozuelo-Carrascosa DP, et al. . Effect of exercise on fatigue in multiple sclerosis: a network meta-analysis comparing different types of exercise. Arch Phys Med Rehabil. (2022) 103:970–87.e18. 10.1016/j.apmr.2021.08.008
    1. Ferreira APS, Pegorare ABGdS, Salgado PR, Casafus FS, Christofoletti G. Impact of a pelvic floor training program among women with multiple sclerosis: a controlled clinical trial. Am J Phys Med Rehabil. (2016) 95:1–8. 10.1097/PHM.0000000000000302
    1. van der Steeg GE, Takken T. Reference values for maximum oxygen uptake relative to body mass in Dutch/Flemish subjects aged 6-65 years: the LowLands fitness registry. Eur J Appl Physiol. (2021) 121:1189–96. 10.1007/s00421-021-04596-6

Source: PubMed

Szponzorok és közreműködők

Egészségi állapot

Kábítószer-beavatkozások

3
Iratkozz fel