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Muscle weakness and fatigue are primary manifestations of multiple sclerosis (MS), a chronic disease of the central nervous system. Interventions that enhance muscle function may improve overall physical well-being of MS patients. Recently, we described that levels of carnosine, an endogenous muscle dipeptide involved in contractile function and fatigue-resistance, are reduced in muscle tissue from MS patients and a monophasic rodent MS model (experimental autoimmune encephalomyelitis, EAE). In the present study, we aimed to (1) confirm this finding in a chronic EAE model, along with the characterization of structural and functional muscle alterations, and (2) investigate the effect of carnosine supplementation to increase/restore muscle carnosine levels and improve muscle function in EAE. We performed muscle immunohistochemistry and ex vivo contractility measurements to examine muscle structure and function at different stages of EAE, and following nutritional intervention (oral carnosine: 3, 15 or 30 g/L in drinking water). Immunohistochemistry revealed progressively worsening muscle fiber atrophy and a switch towards a fast-twitch muscle phenotype during EAE. Using ex vivo muscle contractility experiments, we observed reductions in muscle strength and contraction speed, but no changes in muscle fatigability of EAE mice. However, carnosine levels were unaltered during all stages of EAE, and even though oral carnosine supplementation dose-dependently increased muscle carnosine levels up to + 94% after 56 days EAE, this did not improve muscle function of EAE mice. In conclusion, EAE mice display significant, yet time-dependent, muscular alterations, and carnosine intervention does not improve muscle function in EAE.

Aims Type 2 diabetes mellitus (T2DM) is associated with reduced exercise capacity and cardiovascular diseases, both increasing morbidity and risk for premature death. As exercise intolerance often relates to cardiac dysfunction, it remains to be elucidated to what extent such an interplay occurs in T2DM patients without overt cardiovascular diseases. Design: Cross-sectional study, NCT03299790. Methods and results Fifty-three T2DM patients underwent exercise echocardiography (semi-supine bicycle) with combined ergospirometry. Cardiac output (CO), left ventricular longitudinal strain (LS), oxygen uptake (O2), and oxygen (O2) extraction were assessed simultaneously at rest, low-intensity exercise, and high-intensity exercise. Glycaemic control and lipid profile were assessed in the fasted state. Participants were assigned according to their exercise capacity being adequate or impaired (EXadequate: O2peak 0.05). At rest, CO was similar in the EXimpaired group vs. EXadequate group (5.1 ± 1 L/min vs. 4.6 ± 1.4 L/min, P > 0.05) and increased equally during exercise. EXimpaired patients displayed a 30.7% smaller increase in O2 extraction during exercise compared to the EXadequate group (P = 0.016) which resulted in a lower O2 extraction at high-intensity exercise (12.5 ± 2.8 mL/dL vs. 15.3 ± 3.9 mL/dL, P = 0.012). Left ventricular longitudinal strain was similar at rest but increased significantly less in the EXimpaired vs. EXadequate patients (1.9 ± 2.5% vs. 5.9 ± 4.1%, P = 0.004). Conclusions In asymptomatic T2DM patients, an impaired exercise capacity is associated with an impaired response in oxygen extraction and myocardial deformation (LS). Trial registry Effect of High-intensity Interval Training on Cardiac Function and Regulation of Glycemic Control in Diabetic Cardiomyopathy (https://clinicaltrials.gov/ct2/show/NCT03299790).

BACKGROUND: Persons with Multiple Sclerosis have elevated resting serum lactate concentrations compared to healthy controls (HC). OBJECTIVE: To evaluate lactate concentrations during acute exercise and/or following training in MS compared to HC. METHODS: In this retrospective study, blood lactate concentrations (mmol/l) originating from two previous studies were analyzed. Lactate concentrations originated from acute submaximal (MSsubmax; HC, n = 11; MS, n = 32) or maximal (MSmax; HC, n = 20; MS, n = 24) exercise tests and following a 24-week mild to moderate intensity (MSsubmax, n = 12) or 12-week high intensity interval (MSmax, n = 13) exercise intervention. RESULTS: Under submaximal conditions in MS and compared to HC, lactaterest (MS: 2.7 +/- 0.6 vs HC: 2.3 +/- 0.7 was significantly (p < 0.05) elevated. After 24 weeks of mild-to-moderate-intensity exercise training and compared to PRE-values, lactate(bout2) (2.5 +/- 0.7 vs 3.4 +/- 1.1) significantly (p < 0.05) decreased during submaximal testing in MSsubmax. Under maximal conditions, lactatestart (2.3 +/- 1.0 vs 1.7 +/- 0.9) was significantly (p > 0.05) elevated in MS. Twelve weeks of high intensity interval training did not improve this (p > 0.05). CONCLUSIONS: Under the conditions of this retrospective analysis we conclude that lactate concentrations during acute submaximal and maximal exercise in persons with MS are similar compared to healthy controls. Moderate intensity exercise therapy appeared to improve lactate accumulation but high intensity exercise therapy did not.

Background and purpose The development of myocardial fibrosis is a major complication of Type 2 diabetes mellitus (T2DM), impairing myocardial deformation and, therefore, cardiac performance. It remains to be established whether abnormalities in longitudinal strain (LS) exaggerate or only occur in well-controlled T2DM, when exposed to exercise and, therefore, cardiac stress. We therefore studied left ventricular LS at rest and during exercise in T2DM patients vs. healthy controls. Methods and results Exercise echocardiography was applied with combined breath-by-breath gas exchange analyses in asymptomatic, well-controlled (HbA1c: 6.9 ± 0.7%) T2DM patients (n = 36) and healthy controls (HC, n = 23). Left ventricu-lar LS was assessed at rest and at peak exercise. Peak oxygen uptake (V̇ O 2peak) and workload (W peak) were similar between groups (p > 0.05). Diastolic (E, e' s , E/e') and systolic function (left ventricular ejection fraction) were similar at rest and during exercise between groups (p > 0.05). LS (absolute values) was significantly lower at rest and during exercise in T2DM vs. HC (17.0 ± 2.9% vs. 19.8 ± 2% and 20.8 ± 4.0% vs. 23.3 ± 3.3%, respectively, p < 0.05). The response in myocardial deformation (the change in LS from rest up to peak exercise) was similar between groups (+ 3.8 ± 0.6% vs. + 3.6 ± 0.6%, in T2DM vs. HC, respectively, p > 0.05). Multiple regression revealed that HDL-cholesterol, fasted insulin levels and exercise tolerance accounted for 30.5% of the variance in response of myocardial deformation in the T2DM group (p = 0.002). Conclusion Myocardial deformation is reduced in well-controlled T2DM and despite adequate responses, such differences persist during exercise. Trial registration NCT03299790, initially released 09/12/2017.

Background: Periodizing exercise interventions in Multiple Sclerosis (MS) shows good high intensity exercise training adherence. Whether this approach induces comparable training adaptations with respect to exercise capacity, body composition and muscle strength compared to conventional, linear progressive training programs however is not known. Methods: Thirty-one persons with MS (all phenotypes, mean EDSS 2.3?1.3) were randomized into a twelve-week periodized (MSPER, n=17) or a classic endurance (MSCLA, n=14) training program. At baseline (PRE), exercise capacity (maximal exercise test, VO2max), body composition (DEXA) and muscle strength (Biodex?) were assessed. Classic, moderate intensity endurance training (60-80% HRmax, 5 training sessions/2w, 60min/session) was performed on a stationary bicycle. Periodized exercise included 4 recurrent 3-week cycles of alternated endurance training (week 1: endurance training as described above), high intense exercise (week 2: 3 sessions/w, 3 ? 20s all-out sprints, 10min/session) and recovery weeks (week 3: one sprint session as described above). POST measurements were performed similar to baseline. Total exercise volume of both programs was expressed as total peak-effort training minutes. Results: For MSCLA, total exercise volume included 1728 total peak-effort training minutes, whereas MSPER included only 736. Despite this substantially reduced training volume, twelve weeks of periodized training significantly (p

BACKGROUND: Adults with obesity may display disturbed cardiac chronotropic responses during cardiopulmonary exercise testing, which relates to poor cardiometabolic health and an increased risk for adverse cardiovascular events. It is unknown whether cardiac chronotropic incompetence (CI) during maximal exercise is already present in obese adolescents and, if so, how that relates to cardiometabolic health. METHODS: Sixty-nine obese adolescents (body mass index standard deviation score = 2.23 ± 0.32, age = 14.1 ± 1.2 years; mean ± SD) and 29 lean adolescents (body mass index standard deviation score = –0.16 ± 0.84, age = 14.0 ± 1.5 years) performed a maximal cardiopulmonary exercise testing from which indicators for peak performance were determined. The resting heart rate and peak heart rate were used to calculate the maximal chronotropic response index. Biochemistry (lipid profile, glycemic control, inflammation, and leptin) was studied in fasted blood samples and during an oral glucose tolerance test within obese adolescents. Regression analyses were applied to examine associations between the presence of CI and blood or exercise capacity parameters, respectively, within obese adolescents. RESULTS: CI was prevalent in 32 out of 69 obese adolescents (46%) and 3 out of 29 lean adolescents (10%). C-reactive protein was significantly higher in obese adolescents with CI compared to obese adolescents without CI (p = 0.012). Furthermore, peak oxygen uptake and peak cycling power output were significantly reduced (p < 0.05) in obese adolescents with CI vs. obese adolescents without CI. The chronotropic index was independently related to blood total cholesterol (standardized coefficient β = –0.332; p = 0.012) and C-reactive protein concentration (standardized coefficient β = –0.269; p = 0.039). CONCLUSION: CI is more common in the current cohort of obese adolescents, and is related to systemic inflammation and exercise intolerance.

High-intensity concurrent training positively affects cardiovascular risk factors. Because this was never investigated in multiple sclerosis, the present pilot study explored the impact of this training on cardiovascular risk factors in this population.Before and after 12 weeks of high-intense concurrent training (interval and strength training, 5 sessions per 2 weeks, n = 16) body composition, resting blood pressure and heart rate, 2-h oral glucose tolerance (insulin sensitivity, glycosylated hemoglobin, blood glucose and insulin concentrations), blood lipids (high- and low-density lipoprotein, total cholesterol, triglyceride levels) and C-reactive protein were analyzed.Twelve weeks of high-intense concurrent training significantly improved resting heart rate (-6%), 2-h blood glucose concentrations (-13%) and insulin sensitivity (-24%). Blood pressure, body composition, blood lipids and C-reactive protein did not seem to be affected.Under the conditions of this pilot study, 12 weeks of concurrent high-intense interval and strength training improved resting heart rate, 2-h glucose and insulin sensitivity in multiple sclerosis but did not affect blood C-reactive protein levels, blood pressure, body composition and blood lipid profiles. Further, larger and controlled research investigating the effects of high-intense concurrent training on cardiovascular risk factors in multiple sclerosis is warranted. Implications for rehabilitation High-intensity concurrent training improves cardiovascular fitness. This pilot study explores the impact of this training on cardiovascular risk factors in multiple sclerosis. Despite the lack of a control group, high-intense concurrent training does not seem to improve cardiovascular risk factors in multiple sclerosis.

Introduction Although high intensity exercise therapy (HIT) in Multiple Sclerosis (MS) induces substantial effects, longer term compliance to such a training program is not evident. When embedded in a periodized, home-based training strategy, high intensity exercise therapy adherence may improve. This is explored first in mildly affected persons with MS. Methods Exercise capacity (maximal exercise test) and body composition (DEXA) of healthy controls (n = 22) and persons with MS (n = 23, EDSS: 1.9 ± 1.1) were assessed at baseline (PRE). Next and within the context of an MS awareness project (climbing the Mont Ventoux, France), all participants were enrolled in a 6 m home-based periodized HIT oriented cycling program with remote (Polar® M200 activity tracker) supervision. Hereafter, POST measurements were performed similar to baseline. Results Six months of periodized and home-based HIT oriented training induced improvements in body weight (−3%, p = 0.008), BMI (−3%, p = 0.01), total mass (−2%, p = 0.023), VO2max (+ 5%, p = 0.016), workload (+ 11%, p = 0.001), time until exhaustion (+ 14%, p = 0.001), recovery heart rate (+ 4%, p = 0.04), lactate peak (+ 16%, p = 0.03) and RER (+ 4%, p = 0.04) in MS. Furthermore, all persons with MS safely reached the top of the Mont Ventoux, except for two. Conclusion The applied 6 m periodized, home-based and HIT-oriented cycling program provided good therapy adherence with similar improvements in exercise capacity compared to healthy controls. Furthermore, this exercise regimen trained mildly-affected persons with MS adequately to climb the Mont Ventoux.

Objective: To examine the acute effect of exercise on cytokines and adipokines during relapse and the remitting phase of multiple sclerosis (MS). Methods: Thirty women with MS in the relapsing or remitting phase were matched with fifteen healthy controls. Participants performed a single-bout of aerobic exercise at 60-70% maximal heart rate. Furthermore, five women in the relapsing phase were enrolled (control relapse) and did not receive any intervention. Blood samples were taken before, immediately after, 1-h and 6-h after the exercise. Results: Levels of IL-10 and TNF-alpha in response to exercise were similar in healthy and MS remitting subjects. Compared to baseline, TNF-alpha levels in relapsing subjects were significantly decreased immediately after exercise. Immediately following exercise, leptin levels significantly decreased in relapsing subjects. Adiponectin and IL-6 showed no significant difference between groups. Conclusion: After relapse, exercise does not induce inflammatory cytokine response and temporarily improves both cytokine and adipokine balance. (C) 2018 Elsevier Ltd. All rights reserved. This project was supported by the grant (No: pht-9431) from Musculoskeletal Rehabilitation Research Center, Ahvaz Jundishapur University of Medical Science, Ahvaz, Iran and financial support was provided by the vice chancellor for research affairs, Ahvaz Jundishapur University of Medical Sciences. The authors would like to thank Dr. Mustafa Atalay, Dr. Matthew Watson, Dr. Ali-Akbar Alizade, Dr. Tabassom Ghanavati and Dr. Shahin Goharpay for their contribution and other individuals who participated in the study.

During incremental exercise tests, chronotropic incompetence (CI), which is the inability of the heart rate (HR) to rise in proportion to an increase in metabolic demand, is often observed in patients with type 2 diabetes mellitus (T2DM). Despite the fact that CI is associated with exercise intolerance and elevated risks of development of cardiovascular disease and premature death, this clinical anomaly is often ignored or overlooked by clinicians and physiologists. CI is, however, a significant clinical abnormality that deserves further attention, examination and treatment. The aetiology of CI in T2DM remains poorly understood and is complex. Certain T2DM-related co-morbidities or physiological anomalies may contribute to development of CI, such as altered blood catecholamine and/or potassium levels during exercise, structural myocardial abnormalities, ventricular and/or arterial stiffness, impaired baroreflex sensitivity and cardiovascular autonomic neuropathy. Clinicians should thus be aware of the potential presence of yet undetected anomalies or diseases in T2DM patients who experience CI during exercise testing. However, an effective treatment for CI in T2DM is yet to be developed. Exercise training programmes seem to be the only potentially effective and feasible interventions for partial restoration of the chronotropic response in T2DM, but it remains poorly understood how these interventions lead to restoration of the chronotropic response. Studies are thus warranted to elucidate the aetiology of CI and develop an effective treatment for CI in T2DM. In particular, the impact of (different) exercise interventions on CI in T2DM deserves greater attention in future studies.

Background: Muscle carnosine is related to contractile function (Ca+ + handling) and buffering of exercise-induced acidosis. As these muscular functions are altered in Multiple Sclerosis (MS) it is relevant to understand muscle carnosine levels in MS. Methods: Tibialis anterior muscle carnosine was measured in an animal MS model (EAE, experimental autoimmune encephalomyelitis, n = 40) and controls (CONEX, n = 40) before and after exercise training (EAE(EX), CONEX, 10d, 1 h/d, 24 m/min treadmill running) or sedentary conditions (EAE(SED), CONSED). Human m. vastus lateralis carnosine of healthy controls (HC, n = 22) and MS patients (n = 24) was measured. Results: EAE muscle carnosine levels were decreased (p < .0001) by similar to 40% to similar to 64% at 10d and 17d following EAE induction (respectively) regardless of exercise (p = .823). Similarly, human MS muscle carnosine levels were decreased (- 25%, p = .03). Conclusion: Muscle carnosine concentrations in an animal MS model and MS patients are substantially reduced. In EAE exercise therapy does not restore this.

Patients with chronic obstructive pulmonary disease (COPD), asthma and interstitial lung diseases (ILD) frequently suffer from cardiovascular comorbidities (CVC). Exercise training is a cornerstone intervention for the management of these conditions, however recommendations on tailoring programmes to patients suffering from respiratory diseases and CVC are scarce. This systematic review aimed to identify the eligibility criteria used to select patients with COPD, asthma or ILD and CVC to exercise programmes; assess the impact of exercise on cardiovascular outcomes; and identify how exercise programmes were tailored to CVC. PubMed, Scopus, Web of Science and Cochrane were searched. Three reviewers extracted the data and two reviewers independently assessed the quality of studies with the Quality Assessment Tool for Quantitative Studies. MetaXL 5.3 was used to calculate the individual and pooled effect sizes (ES). Most studies (58.9%) excluded patients with both stable and unstable CVC. In total, 26/42 studies reported cardiovascular outcomes. Resting heart rate was the most reported outcome measure (n = 13) and a small statistically significant effect (ES = −0.23) of exercise training on resting heart rate of patients with COPD was found. No specific adjustments to exercise prescription were described. Few studies have included patients with CVC. There was a lack of tailoring of exercise programmes and limited effects were found. Future studies should explore the effect of tailored exercise programmes on relevant outcome measures in respiratory patients with CVC.

Background Multiple sclerosis (MS) is associated with elevated cardiovascular mortality. To prevent this a better understanding of their CVD risk factors and interrelations is necessary. Methods MS patients (n = 52) and healthy controls (HC, n = 24) were matched for age, height, weight, body mass index and physical activity. Body composition, resting blood pressure (BP), resting heart rate (HR), glucose tolerance, HbA1c, blood lipids (HDL, LDL, total cholesterol, triglyceride concentrations) and c-reactive protein concentrations were analyzed. Regression analyses identified independent CVD risk factors and their interrelations in MS. Results In MS and compared to HC, fat mass (25.1 ± 1.2 kg vs. 17.9 ± 1 kg), fat percentage (33.8 ± 1.2% vs. 28.4 ± 1.5%), systolic (130 ± 1.8 mmHg vs. 120 ± 2.9 mmHg) and diastolic (79 ± 1.1 mmHg vs. 71 ± 1.9 mmHg) BP, resting HR (72 ± 1.4 bpm vs. 60 ± 2 bpm), blood triglycerides (113.8 ± 8.6 mg/dl vs. 98.2 ± 17.4 mg/dl), fasting (13.5 ± 2.9 mU/l vs. 7.2 ± 0.8 mU/l) and 2 h insulin (71.9 ± 12.5 mU/l vs. 35.8 ± 8.1 mU/l), 2 h glucose (6.3 ± 0.5 mmol/l vs. 4.8 ± 0.5 mmol/l) and HOMA index (3.7 ± 1.1 vs. 1.7 ± 0.2) were significantly (p < 0.05) elevated. Total cholesterol, blood HDL and LDL concentrations did nog differ between groups (p < 0.05). Regression analyses indicated that MS is independently associated with elevated fat mass/percentage, systolic and diastolic BP and HR and in MS fat mass appears to be an independent contributor of the other measured CVD risk factors in MS. Conclusion Persons with MS have an increased risk for CVD and fat mass appears to be an important risk factor. Therefore, normalizing whole body fat should be an essential part of MS treatment. We thank the MS Liga Flanders (MS Liga Steunfonds 2014) for partly funding this project.

BACKGROUND AND PURPOSE: Brain derived neurotrophic factor (BDNF) is suggested to play a neuroprotective role in multiple sclerosis (MS). However, the BDNF response to long-term exercise in MS remains unknown. Our objective was to compare resting BDNF profiles of healthy controls (HCs) and persons with relapsing-remitting MS (RRMS) and to investigate the impact of a 24-week exercise intervention on serum BDNF release in MS.METHODS: At baseline, blood BDNF levels were assessed in MS (n = 22, mean Expanded Disability Status Scale 2.6 ± 0.2, mean age 43 ± 2 years) and HCs (n = 19, mean age 47 ± 1 year). Next, persons with MS were randomized to an exercise intervention group (EX, n = 15) or a sedentary control group (SED, n = 7) completing a 24-week randomized controlled trial. In persons with MS, muscle strength, exercise tolerance and body composition were assessed, as compliance measures, at baseline and after 24 weeks.RESULTS: At baseline, the BDNF concentration of persons with RRMS was 21% lower than HCs. Following 24 weeks of intervention, changes in BDNF concentrations differed significantly between EX and SED. In particular, within EX BDNF concentrations increased 13.9% ± 8.8%, whereas it decreased 10.5% ± 4.1% within SED. Furthermore, 24 weeks of exercise induced changes in the compliance measures between EX and SED. In addition, within EX muscle strength, exercise tolerance and lean tissue mass improved, whereas these remained stable within SED.CONCLUSION: In conclusion, BDNF concentration of persons with RRMS was lower compared to HCs and increased after 24 weeks of exercise in persons with MS, compared to the non-exercise MS control group.