Carnosine Loading and Periodized Training in MS and HC

The Impact of Carnosine Loading and Rehabilitation Therapy on Exercise Capacity in Multiple Sclerosis.

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.

Pilot data from the (co-)applicants' laboratories suggest that EAE rats (animal MS model) and MS-patients suffer from significantly reduced muscle carnosine levels compared to healthy counterparts. The potential of β-alanine supplementation to elevate muscle carnosine content has been shown in healthy volunteers. Furthermore, the investigators have recently investigated β-alanine and carnosine supplementation in EAE animals. In MS, this has not been investigated yet. Therefore, the researchers' next step is to investigate the impact of β-alanine intake on exercise performance in MS patients. The investigators hypothesize that oral β-alanine supplementation improves exercise therapy outcomes in MS patients. 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, the investigators aim to research the ergogenic potential of β-alanine intake in MS rehabilitation and hypothesize that β-alanine supplementation optimizes exercise therapy outcome (exercise capacity, muscle contractile characteristics) in this population.

Twenty multiple sclerosis (MS) patients 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 or have an EDSS score >3. First, exercise capacity (maximal graded exercise test) will be evaluated. Heart function will be assessed by an experienced medical doctor, followed by measurement of body composition (DEXA). Maximal strength of the back- and abdominal muscles will be assessed to evaluate core stability. 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 (MSpla, n=10; HCplac, n=10) β-alanine supplementation. Groups not receiving β-alanine supplements, will receive placebo tablets. Following 6 months of exercise training (POST) measurements will be performed similar to baseline.

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.

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.

Exercise capacity will be assessed using a maximal (12-lead ECG) graded cardiopulmonary exercise test (♂: 30W+15W/min, ♀: 20W+10W/min, GE eBike Basic®) with pulmonary gas exchange analysis (Jaeger Oxycon®). VO2max (maximal oxygen uptake) will be monitored. This test will be performed at least 48 hours separated from the muscle strength test, to prevent interference of muscle fatigue. Respiratory exchange ratio (RER) values will be evaluated to verify if the test was performed maximally (RER >1.1).

During the exercise test, 2min capillary blood samples will be obtained to analyse blood lactate concentrations (Analox®) and determine the anaerobic threshold before, during and after exercise. Lactate max levels are the maximal concentrations measured during the test, whilst peak Lactate are the lactate concentrations following 2 minutes of rest after cessation of the maximal exercise test.

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 balance (Seca®) will be used to measure total body mass.

Back- and abdominal muscle strength will be assessed using an isokinetic dynamometer (System 3, Biodex, ENRAF-NONIUS, New York, USA). After adequate warming-up and movement familiarization, subjects will perform 3 maximal isometric contractions of back- and abdominal muscles for 4-5sec. The peak value of the 3 maximal contractions will be reported (peak back, and peak abdominal muscles).

Exercise capacity will be assessed using a maximal (12-lead ECG) graded cardiopulmonary exercise test (♂: 30W+15W/min, ♀: 20W+10W/min, GE eBike Basic®) with pulmonary gas exchange analysis (Jaeger Oxycon®). VO2max (maximal oxygen uptake) will be monitored. This test will be performed at least 48 hours separated from the muscle strength test, to prevent interference of muscle fatigue. Respiratory exchange ratio (RER) values will be evaluated to verify if the test was performed maximally (RER >1.1).

Inclusion criteria: Diagnosis Multiple Sclerosis. Healthy control. Aged >18y. Written informed consent. Exclusion criteria: Contraindications to perform moderate to high intensity exercise. Participation in another study. Experienced acute MS related exacerbation <6 months prior to start of the study EDSS score > 3.5