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Figure S2. Graphical overview of the protein structure of murine MOG. (PDF 357 kb)

Figure S6. Flow cytometric evaluation of the proportion of Treg, Breg and NK cells in splenocytes. (PDF 289 kb)

Figure S1. Graphical overview of the culture protocol for murine bone marrow-derived dendritic cells. (PDF 271 kb)

Figure S5. Representation of individual clinical scores. (PDF 349 kb)

Figure S3. Nucleotide sequence of the Sig-full length MOG-LAMP-3 and Sig-extracellular MOG-LAMP-3 constructs. (PDF 385 kb)

Table S1. Amino acid sequences of the myelin peptides used for screening for inter- and intramolecular epitope spreading. (PDF 317 kb)

Figure S4. Graphical overview of the experimental set-up of the in vivo experiment. (PDF 279 kb)

Table S2. Clinical data of MOG35–55 EAE mice. (PDF 393 kb)

Introduction Low-to-moderate intensity exercise improves muscle contractile properties and endurance capacity in multiple sclerosis (MS). The impact of high intensity exercise remains unknown. Methods Thirty-four MS patients were randomized into a sedentary control group (SED, n = 11) and 2 exercise groups that performed 12 weeks of a high intensity interval (HITR, n = 12) or high intensity continuous cardiovascular training (HCTR, n = 11), both in combination with resistance training. M.vastus lateralis fiber cross sectional area (CSA) and proportion, knee-flexor/extensor strength, body composition, maximal endurance capacity and self-reported physical activity levels were assessed before and after 12 weeks. Results Compared to SED, 12 weeks of high intensity exercise increased mean fiber CSA (HITR: +21±7%, HCTR: +23±5%). Furthermore, fiber type I CSA increased in HCTR (+29±6%), whereas type II (+23±7%) and IIa (+23±6%,) CSA increased in HITR. Muscle strength improved in HITR and HCTR (between +13±7% and +45±20%) and body fat percentage tended to decrease (HITR: -3.9±2.0% and HCTR: -2.5±1.2%). Furthermore, endurance capacity (Wmax +21±4%, time to exhaustion +24±5%, VO2max +17±5%) and lean tissue mass (+1.4±0.5%) only increased in HITR. Finally self-reported physical activity levels increased 73±19% and 86±27% in HCTR and HITR, respectively. Conclusion High intensity cardiovascular exercise combined with resistance training was safe, well tolerated and improved muscle contractile characteristics and endurance capacity in MS. This work was supported by MS Fund, Limburg, Flanders, Belgium. Ulrik Dalgas has received research support, travel grants and/or teaching honorary from Biogen Idec, Merck Serono and Sanofi Aventis and further serves as PI for the ongoing Biogen sponsored ACTIMS study. This does not alter our adherence to Plos One policies on sharing data and materials. Furthermore, the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Acknowledgments We thank all MS patients for participating in this study. Our gratitude goes to prof. dr. Niel Hens (Interuniversity Institute for Biostatistics and Statistical Bioinformatics, Hasselt University, Belgium and Centre for Health Economics Research & Modelling Infectious Diseases, Vaccine and Infectious Disease Institute, University of Antwerp, Belgium) for statistical advise and discussion, to prof. dr. Bart Van Wijmeersch (Rehabilitation and MS Center, Overpelt, Belgium) for the recruitment and medical examination of all patients and to Devid Muys, without whose help and support this study would not have been possible.

Patients with MS (pwMS) experience muscle weakness and lowered muscle oxidative capacity. To explore the etiology for the development of such muscle phenotype we studied skeletal muscle AMP-activated protein kinase (phospho-AMPKα, governing mitochondrial biogenesis) and mammalian target of rapamycin (phospho-mTOR, governing myofibrillar biogenesis) phosphorylation in pwMS. After assessment of body composition, muscle strength, exercise tolerance and muscle fiber type, muscle phospho-AMPKα and phosphomTOR was assessed in 14 pwMS and 10 healthy controls (part 1). Next, an endurance exercise bout was executed by 9 pwMS and 7 healthy subjects, with assessment of changes in muscle phospho-AMPKα and phospho-mTOR (part 2). Elevated basal muscle phosphoAMPKα and phospho-mTOR was present in MS (p

General conclusion: In conclusion, this PhD thesis demonstrated that the prevalence of IGT in MS is higher compared to healthy subjects. Furthermore, this secondary healthy complication, as well as some clinical relevant aspects such as muscle strength, muscle mass and endurance capacity, can be improved by means of combined endurance and resistance exercise, whereas the level of improvements are dependent on the applied exercise intensity. MS also seems to negatively affect skeletal muscle fiber characteristics, muscle strength and muscle mass of, predominantly, the lower limbs of mildly affected MS patients. This can be improved by high intensity combined exercise, that was demonstrated to be safe and well tolerated in moderately affected MS patients. These results are clinically relevant because, similar to other populations, adequate exercise therapy is not only able to improve important aspects of health related fitness but is also able to counteract secondary health complications. In combination with other therapeutic strategies this probably further enhances quality of life and physical functioning of MS patients. Multiple Sclerose (MS) is een progressieve auto-immune aandoening van het centrale zenuwstelsel en wordt meestal gediagnostiseerd tussen de leeftijd van 20 en 40 jaar. Wereldwijd worden er meer dan 2,5 miljoen mensen geconfronteerd met deze ziekte. Ondanks intensief wetenschappelijk onderzoek is de onderliggende oorzaak van MS nog steeds niet volledig gekend. De variabele distributie van de schade in de myeline schede van de zenuwen kan leiden tot zeer uiteenlopende symptomen, waaronder spierzwakte en vermoeidheid. Als gevolg van deze laatstgenoemde symptomen zijn mensen met MS vaak minder fysiek actief wat resulteert in een verlies aan functionele spierkracht en inspanningscapaciteit. In andere populaties werd reeds herhaaldelijk aangetoond dat een verminderde hoeveelheid fysieke activiteit in belangrijke mate bijdraagt tot de ontwikkeling van chronische aandoeningen en het ontstaan van risico factoren die deel uitmaken van het metabole syndroom, een term die de gecombineerde aanwezigheid van verschillende cardiovasculaire risico’s, zoals verhoogde bloeddruk, glucose intolerantie en hoge cholesterol, groepeert. Zodoende komen verstoorde glucose tolerantie en insuline resistentie frequenter voor, waardoor het risico voor de ontwikkeling van type II suikerziekte en cardiovasculaire aandoeningen sterk toeneemt. Op basis van een systematische literatuur analyse kon in studie 1 worden geconcludeerd dat MS patiënten inderdaad een verhoogd risico hebben op de ontwikkeling van secundaire gezondheidsproblemen, zoals cardiovasculaire aandoeningen en het metabole syndroom in het algemeen. De methodologie van de geïncludeerde literatuur was echter meestal van een beperkte kwaliteit, waardoor het onduidelijk is waar het verhoogde risico aan toegeschreven kan worden. In een poging enkele van deze vragen te beantwoorden werd dit doctoraatsonderzoek in belangrijke mate gericht op het voorkomen en remediëren van glucose intolerantie in MS. Dit werd onderzocht in een reeks van studies, uitgevoerd bij zowel het MS proefdiermodel als bij mensen met MS.

Heller et al.(2013) state that in multiple sclerosis patients, inversion of the foot at terminal swing is insufficiently corrected. However, it is the inversion of the foot at the end of the stance phase that is insufficiently corrected because of poor eversion of the foot in the early swing phase, which results in early ground contact of the outside border of the still partially inverted foot in the terminal swing phase. In minimally impaired multiple sclerosis patients walking on a treadmill, this leads to the producing of characteristic high-pitched shuffling sounds, generated in fact by a temporary friction of the outside border of the shod foot-in-terminal-swing, along the surface of the treadmill belt. Scientific Contract Research by K. J. van Zwieten, at the University of Hasselt, Belgium : "Foot inversion and eversion movements in stance and swing - some comparative-anatomical and functional morphological aspects (R-3500)", 1-01-2012 - 31-12-2013.