The Impact of Carnosine Loading and Rehabilitation Therapy on Exercise Capacity in Multiple Sclerosis.
Phase: NA
Conditions: Multiple Sclerosis, Exercise Therapy, Dietary Supplement
Sponsor: Hasselt University

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The 
Impact 
of 
Carnosine 
Loading 
and 
Rehabilitation Therapy on Exercise Capacity in 
Multiple Sclerosis 
NCT03418376 
Date: 10/02/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL: IMPACT OF CARNOSINE LOADING ON HOME-BASED EXERCISE THERAPY EFFECTS IN 
MULTIPLE SCLEROSIS 
INTRODUCTION 
 
Multiple Sclerosis (MS) is a neurodegenerative inflammatory disease of the central nervous 
system1 that is characterized by central nervous system demyelination and axonal loss causing a 
variety of symptoms such as spasticity, tremor, paralysis, walking difficulties and cognitive 
abnormalities2. Decreased exercise capacity, excessive (post-exercise) fatigue and reduced muscle 
contractile function3, 4 are frequently occurring comorbidities that substantially affect various daily 
life activities leading to an inactive lifestyle and lower quality of life5. This results in a disuse-related 
physiological profile and thus even greater muscle weakness and health risks than provided by the 
disease per se6. In fact, in other populations muscle weakness is an independent predictor of 
premature death7. Central mechanisms contributing to the latter symptoms include reduced motor 
firing rates, impaired motor unit recruitment and increased central motor conduction time8-12. 
However, a portion of the neuromuscular dysfunction present in MS appears to reside within the 
affected muscle8-10, 12-15.  
 
Exercise therapy and skeletal muscle dysfunction in MS 
 So far, recent immune-modulatory therapies decrease MS relapse rate and disease severity16 
but they do not slow the disease process. Because such therapies, unfortunately, do not affect 
accumulation of MS disabilities and comorbidities and because at least some MS related impairments 
are inactivity related rather than a result of non-reversible tissue injury, exercise rehabilitation therapy 
has become an important part of overall MS treatment. Indeed, a multitude of low to moderate 
intensity exercise intervention studies in MS already reported small (+10-15%) but significant 
improvements in muscle strength and exercise capacity3. Surprisingly however, effects are lower 
compared to healthy controls and some other disease populations. In an attempt to further improve 
rehabilitation outcome we therefore recently performed higher intensity training (HIT) studies in an 
animal MS model (Experimental Autoimmune Encephalomyelitis, EAE17) and in MS patients18. 
Although results are promising with substantially improved (+25-30%) muscle strength and exercise 
capacity following 8-12w of exercise17, 18 most MS subjects reported higher post exercise muscle 
fatigue and overall perceived exertion rates (BORG: 14.7±1.5 vs. 12.7±1.3) compared to low-to-
moderate intensity training15.  
To date it is difficult to address the underlying mechanisms of the overall therapeutic effect 
of exercise therapy in MS. So far several immune-related mechanisms such as altered circulating 
cytokine levels and BDNF expression19, 20 following an acute exercise bout and longer term exercise 
have been described. We recently demonstrated reduced innate markers of inflammation21 and a 
rapid exercise-induced mobilization of dendritic cells that is possibly mediated by a Flt3L- and MMP-
9-dependent processes22 following exercise in MS. This may indicate a negative feedback mechanism 
for the immune system's ability to induce tissue damage and inflammation following exercise. The 
above described neuro-immune mechanisms unfortunately remain largely speculative supporting the 
above mentioned hypothesis that indeed part of the neuromuscular dysfunction could be situated in 
the affected muscle. In this respect, we and others, have reported altered muscle contractile 
characteristics and muscle fibre composition (shift to glycolytic fibre types) as well as cross-bridge 
(Ca2+ handling) abnormalities in MS8, 14, 15. Furthermore, abnormal muscle energy metabolism in MS 
has been demonstrated involving reduced Krebs cycle and complex I and II activities12, 23, 
overproduction of reactive oxygen species (ROS24), increased basal AMP-activated protein kinase 
phosphorylation25 and delayed phosphocreatine resynthesis after exercise12, 13, 23, 25, 26. This suggests 
higher basal and exercise related energy expenditure and increased exercise-induced intramyocellular 
lactate accumulation, and thus greater perceived muscle fatigue, as recently evidenced by increased 
basal27 and exercise-induced (see Figure 1, Keytsman & Eijnde et al. Manuscript in preparation) serum 

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lactate concentrations. Thus, impairments in both (I) muscle contraction and (II) energy supply seem 
to attenuate adequate exercise therapy outcome in MS. Consequently, any strategy that improves 
muscle contraction and/or intramyocellular energy homeostasis during exercise training may 
therefore be an interesting tool to investigate the underlying mechanisms of the overall therapeutic 
effect of exercise therapy in MS and, as such, may help to further optimize exercise rehabilitation 
protocols.  
 
 
 
Muscle carnosine loading 
Carnosine (β-alynyl-L-histidine) is found in high concentrations in mammalian skeletal 
muscle28, 29. Its physiological role is related to (I) contractile function in general and more specific to 
Ca++ handling29. In addition, (II) carnosine has also been shown to buffer muscle pH resulting from 
exercise–induced acidosis29 and it has been suggested to affect mitochondrial respiration30 and to 
protect against exercise-induced oxidative stress31. Here, carnosine reduces the production of 
thiobarbituric acid reactive substances and malondialdehyde due to lipid peroxidation28, 29. High (or 
elevated) muscle carnosine content may thus be advantageous to improve muscle contractile 
properties and/or myocellular energy supply during exercise intervention. Because skeletal muscle 
carnosine synthesis is mainly determined by β-alanine availability32, exogenous (dietary, 2-6g/d, 4-
10w) intake of β-alanine has been successfully applied to increase muscle carnosine content (+80%, 
carnosine loading) in various rodent disease models33-35 and healthy volunteers36-38. In untrained and 
aged subjects β-alanine supplementation has recently been shown to specifically improve maximal 
power output (+13-30%) in exercise types lasting 1-4min39. Interestingly, trained muscles load more 
efficiently with carnosine than untrained muscles40. Consequently, β-alanine is rapidly becoming a 
popular ergogenic substance in the (clinical) exercise/sports community.  
Carnosine’s therapeutic effect has already been shown in Alzheimer’s41 and Parkinson’s28 
disease. In these neurological disorders carnosine treatment (~1.5g/d β-alanine) improved a number 
of neurological symptoms42. Interestingly, recent pilot data (Figure 2) from the laboratories suggested 
substantially reduced (~60%) skeletal muscle carnosine content in EAE rats. In MS patients m. vastus 
lateralis carnosine content was reduced by ~20%. Though, 12 weeks of (high intense) exercise training 
did not remediate this (PRE-POST p>0.05, Figure 2). Hence, carnosine treatment in MS could be a valid 
new approach to further (I) improve exercise rehabilitation therapy in MS and (II) investigate the 
effects of MS on skeletal muscle.  The carnosine loading potential of β-alanine supplementation in 
EAE and MS patients, as well as its associated (therapeutic) effects on muscle contractile functioning 
and cellular respiration, however, have not been investigated thoroughly yet. In this regard, we have 
recently explored the effect of β-alanine and carnosine supplementation on muscle carnosine content 
during EAE. Here, β-alanine and carnosine intake delayed paralysis onset and peak as well as improved 
recovery. Furthermore (Figure 3) and compared to controls muscle carnosine concentrations 
substantially increased in these animals (Figure 4). These findings in an animal MS model warrant 
further exploration of the effects of muscle carnosine loading in MS.  
Figure 1. Serum lactate concentrations 
(means±SE’s) during submaximal (two 6-
min exercise bouts [25% of Wmax] and a 6-
min rest interval) and maximal graded 
exercise testing (cycling) in healthy 
controls (HC, n=17) and multiple sclerosis 
(MS, n=20) patients (Pilot data taken from 
Keytsman & Eijnde et al. Increased 
exercise-induced lactate accumulation in 
MS. Manuscript in preparation).  

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Figure 2. Muscle carnosine concentrations 
(mmol/kg ww, means±SE’s) in sedentary 
(SED, n=15) and exercised (EX, n=16) EAE rats 
(animal MS model), in healthy controls (HC, 
n=18) and in MS patients (n=16) before (PRE) 
and after (POST) 12w of exercise intervention.  
Muscle biopsies for this pilot study were 
provided by prof. dr. Bert Op ‘t Eijnde  (Hasselt 
University)  and analysed by prof. dr. Wim 
Derave (Ghent University). As these pilot data 
are believed to be pre-competitive, the data 
have not been published yet.  
 
Figure 3. Clinical disease scores of EAE rats 
(animal MS model), without (control, n=13), 
with carnosine (carnosine, n=13) or β-alanine 
(β-alanine, n=13) supplementation. CID, 
Cummulative Disease Index. * p<0.05 for 
carnosine compared to control. ap<0.05 for 
carnosine compared to β-alanine. 
 

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Research objectives 
Increasing evidence favours exercise therapy as an efficient tool to counteract inactivity 
related secondary symptoms in MS. Furthermore, exercise therapy may affect MS-associated muscle 
contractile and energy supply dysfunctions. So far, low to moderate intensity exercise rehabilitation 
has shown to induce small but consistent improvements in several functional parameters. High 
intensity exercise training in MS seems to further improve this. However, although results are 
promising, impairments in both muscle contraction and energy supply probably attenuate therapy 
outcome. In keeping with the above described physiological role of skeletal muscle carnosine and 
because muscle carnosine content may be lower in MS, the primary aim of the present project is to 
investigate whether carnosine loading improves exercise therapy outcome (exercise capacity, body 
composition) and performance in MS. If the latter hypothesis can be confirmed, muscle carnosine 
loading could be a novel intervention to improve exercise capacity and muscle function in this 
population.  
 
 
 
Ergogenic potential of muscle carnosine loading and exercise therapy in MS 
So far, it is clear that β-alanine intake enhances exercise capacity of untrained, trained and aged 
individuals by improving contractile properties, maintaining higher intracellular energy levels and 
optimizing training adaptations. Because early fatigue of contracting musculature during rehabilitation 
is the predominant cause of exercise cessation, postponing exercise-induced fatigue by β-alanine 
supplementation will be clinically very relevant (improving exercise therapy efficiency). Consequently, 
we aim to research the ergogenic potential of β-alanine intake in MS rehabilitation and hypothesize 
that β-alanine supplementation in combination with exercise therapy optimizes therapy outcome 
(exercise capacity, body composition) and performance in this population.  
 
 
 
METHODS 
Subjects 
Twenty multiple sclerosis (MS) patients, diagnosed according to the McDonald criteria, and twenty 
healthy controls (HC), aged >18y will be included following written informed consent. Subjects will be 
excluded if they experience contraindications to participate in moderate to high intensity exercise, 
already participate in another study, experienced an acute MS exacerbation <6 months prior to the 
start of the study or have an EDSS score >3. This study will be performed in accordance with the 
Declaration of Helsinki and will be registered at ClinicalTrials.gov. 
Figure 4. Muscle carnosine concentrations 
(mmol/kg WW) in EAE rats (animal MS 
model), without (EAE CON, n=13) and with 
carnosine (EAE CA, n=13) or β-alanine (EAE 
BA, 
n=13) 
supplementation. 
*p<0.05 
compared to control group. 
 

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Study design 
Following inclusion, baseline measurements (PRE) will be performed in MS patients (n=20) and HC 
(n=20). First, exercise capacity (maximal graded exercise test) will be evaluated. Prior to the maximal 
exercise test, heart function will be assessed by an experienced medical doctor, followed by 
measurement of whole body composition (DEXA). Furthermore, maximal strength of the back- and 
abdominal muscles will be assessed to evaluate core stability (important during prolonged cycle 
training). Hereafter, MS patients and HC will be randomly allocated to one of four intervention groups 
following 6 months of moderate-to-high-intensity cardiovascular exercise therapy with (MSβ, n=10; 
HCβ, n=10) or without (MSplacebo, n=10; HCplacebo, n=10) β-alanine supplementation. Groups not 
receiving β-alanine supplements, will receive placebo tablets that will be identical in taste and 
appearance. Following 6 months of exercise training (POST) measurements will be performed similar 
to baseline.  
 
Exercise program 
Moderate-to-high-intensity cardiovascular exercise therapy 
All participants will perform a home-based supervised exercise training program. Participants will 
receive weekly training instructions using a smartphone based heart rate monitor app (Polar®). 
Training involves cycling, performed independently on their personal race bicycle. The exercise training 
program (6 months) involves 3 week cycles (week I-III). During week I, subjects will perform high 
volume moderate intensity cardiovascular cycle training (3x/week). Twice a week, subjects perform 3h 
training sessions (70-80% HRmax*) and once a week a 1.5h session will be executed (80-90% HRmax). 
During week II, subjects will perform low volume maximum intensity interval cycle training (3/w). High 
intensity interval cycle training (HIIT) will consist of 3x maximal sprints (90-100% HRmax) of 1.5min, 
interspersed with 3min rest intervals. A 5min standardized warming up and 5min cooling down will be 
performed. Week III involves a recovery week where subjects will perform one training session of 1.5h 
at an exercise intensity of 70-80% HRmax and one session of HIIT. Throughout the intervention program 
at least 3 collective tours will be organized, where all subjects will perform a training session together, 
to improve group dynamics and motivation.  
*obtained from the maximal graded exercise test 
β-alanine supplementation 
The supplementation protocol of β-alanine (Etixx® Omega Pharma Belgium NV) involves oral intake of 
4 x 800mg (3.2g/day29, 43) daily with at least 2h apart of slow-release β-alanine during the first 12 
weeks. After this loading period, subjects will receive a maintenance dose of 2 x 800mg (1.6g/day) β-
alanine for the remaining study duration. Placebo groups will follow the same supplementation 
protocol with placebo tablets that will have identical taste and appearance. All subjects will be 
advised to take the tablets together with meals. This supplement is frequently used to improve sport 
performances in athletes. The beta-alanine supplement consists of beta-alanine, 
hydroxymethylcellulose, cellulose, siliciumdioxide, magnesium stearate and zinc. In some cases, 
taking beta-alanine can provoke a tingling feel (paresthesia) on the skin which is reversible within the 
hour. However, this is not dangerous and completely reversible. To prevent this paresthesia, β-
alanine tablets will consist of slow-release β-alanine which, together with the spread intake 
throughout the day, will not provoke this discomfort.  
 

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Measurements 
 
Exercise capacity & serum lactate. Exercise capacity will be assessed using a maximal (12-lead ECG) 
graded cardiopulmonary exercise test (♂: 30W+15W/min, ♀: 20W+10W/min) with pulmonary gas 
exchange analysis (Jaeger Oxycon®). Subjects will perform the exercise test on their personal bicycle 
(Cyclus2® Leipzig, Germany).  VO2, VE, RER will be monitored and 2min capillary blood samples will be 
obtained to analyse blood lactate concentrations (Analox®) and determine the anaerobic threshold 
before, during and after exercise. RER values will be evaluated to verify if the test was performed 
maximally (RER >1.1).  
 
 
 
Body composition Whole body fat and lean tissue mass will be obtained using Dual Energy X-ray 
Absorptiometry scan (DEXA) (Hologic Series Delphi-A Fan Beam X-ray Bone Densitometer, Vilvoorde, 
Belgium). A calibrated analogue weight scale (Seca®) will be used to measure total body mass.  
 
 
Statistical analysis 
Baseline differences between groups and post-intervention differences will be analysed using an 
unpaired student’s t-test and a 4x2 ANOVA for repeated measures, respectively (SAS Institute®). The 
threshold for statistical significance will be set at p<0.05.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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