Jonathan Long, Postdoctoral Faculty Sponsor
Replacing sitting with light-intensity physical activity throughout the day versus 1 bout of vigorous-intensity exercise: similar cardiometabolic health effects in multiple sclerosis. A randomised cross-over study.
Disability and rehabilitation
2023; 45 (20): 3293-3302
Persons with Multiple Sclerosis (PwMS) are physically inactive and spend more time in sedentary behaviours than healthy persons, which increases the risk of developing cardiometabolic diseases. In this randomised crossover study, the cardiometabolic health effects of replacing sitting with light-intensity physical activity (LIPA) and exercise (EX) were investigated.Twenty-eight mildly disabled PwMS performed four 4-day activity regimens in free-living conditions; CONTROL (habitual activity), SIT, LIPA, and EX. Plasma glucose and insulin (oral glucose tolerance test), plasma lipids, inflammation, resting heart rate, blood pressure, body weight, and perceived exertion were measured (clinical-trials.gov: NCT03919058).CONTROL: 9.7 h sitting/day, SIT: 13.3 h sitting/day, LIPA: 8.3 h sitting, 4.7 h standing, and 2.7 h light-intensity walking/day, and EX: 11.6 h sitting/day with 1.3 h vigorous-intensity cycling. Compared to SIT, improvements (p < 0.001) after LIPA and EX were found for insulin total area under the curve (-17 019 ± 5708 and -23 303 ± 7953 pmol/L*min), insulin sensitivity (Matsuda index +1.8 ± 0.3 and +1.9 ± 0.4) and blood lipids (triglycerides: -0.4 ± 0.1 and -0.5 ± 0.1 mmol/L; non-high-density lipoprotein cholesterol: -0.3 ± 0.1 and -0.5 ± 0.1 mmol/L), with no difference between LIPA and EX. Perceived exertion was higher after EX compared to LIPA (Borg score [6-20]: +2.6 ± 3.3, p = 0.002).Replacing sitting with LIPA throughout the day exerts similar cardiometabolic health effects as a vigorous-intensity exercise in PwMS.IMPLICATIONS FOR REHABILITATIONIncreasing light-intensity physical activity (LIPA) throughout the day improves cardiometabolic health to the same extent as one vigorous-intensity exercise sessionIncreasing LIPA induces less exertion than performing a vigorous-intensity exercise.
View details for DOI 10.1080/09638288.2022.2122601
View details for PubMedID 36190113
Carnosine synthase deficiency aggravates neuroinflammation in multiple sclerosis.
Progress in neurobiology
2023; 231: 102532
Multiple sclerosis (MS) pathology features autoimmune-driven neuroinflammation, demyelination, and failed remyelination. Carnosine is a histidine-containing dipeptide (HCD) with pluripotent homeostatic properties that is able to improve outcomes in an animal MS model (EAE) when supplied exogenously. To uncover if endogenous carnosine is involved in, and protects against, MS-related neuroinflammation, demyelination or remyelination failure, we here studied the HCD-synthesizing enzyme carnosine synthase (CARNS1) in human MS lesions and two preclinical mouse MS models (EAE, cuprizone). We demonstrate that due to its presence in oligodendrocytes, CARNS1 expression is diminished in demyelinated MS lesions and mouse models mimicking demyelination/inflammation, but returns upon remyelination. Carns1-KO mice that are devoid of endogenous HCDs display exaggerated neuroinflammation and clinical symptoms during EAE, which could be partially rescued by exogenous carnosine treatment. Worsening of the disease appears to be driven by a central, not peripheral immune-modulatory, mechanism possibly linked to impaired clearance of the reactive carbonyl acrolein in Carns1-KO mice. In contrast, CARNS1 is not required for normal oligodendrocyte precursor cell differentiation and (re)myelin to occur, and neither endogenous nor exogenous HCDs protect against cuprizone-induced demyelination. In conclusion, the loss of CARNS1 from demyelinated MS lesions can aggravate disease progression through weakening the endogenous protection against neuroinflammation.
View details for DOI 10.1016/j.pneurobio.2023.102532
View details for PubMedID 37774767
Extensive profiling of histidine-containing dipeptides reveals species- and tissue-specific distribution and metabolism in mice, rats, and humans
2023; 239 (1): e14020
Histidine-containing dipeptides (HCDs) are pleiotropic homeostatic molecules with potent antioxidative and carbonyl quenching properties linked to various inflammatory, metabolic, and neurological diseases, as well as exercise performance. However, the distribution and metabolism of HCDs across tissues and species are still unclear.Using a sensitive UHPLC-MS/MS approach and an optimized quantification method, we performed a systematic and extensive profiling of HCDs in the mouse, rat, and human body (in n = 26, n = 25, and n = 19 tissues, respectively).Our data show that tissue HCD levels are uniquely produced by carnosine synthase (CARNS1), an enzyme that was preferentially expressed by fast-twitch skeletal muscle fibres and brain oligodendrocytes. Cardiac HCD levels are remarkably low compared to other excitable tissues. Carnosine is unstable in human plasma, but is preferentially transported within red blood cells in humans but not rodents. The low abundant carnosine analogue N-acetylcarnosine is the most stable plasma HCD, and is enriched in human skeletal muscles. Here, N-acetylcarnosine is continuously secreted into the circulation, which is further induced by acute exercise in a myokine-like fashion.Collectively, we provide a novel basis to unravel tissue-specific, paracrine, and endocrine roles of HCDs in human health and disease.
View details for DOI 10.1111/apha.14020
View details for Web of Science ID 001033778700001
View details for PubMedID 37485756
Altered muscle oxidative phenotype impairs exercise tolerance but does not improve after exercise training in multiple sclerosis.
Journal of cachexia, sarcopenia and muscle
2022; 13 (5): 2537-2550
Patients with multiple sclerosis (MS) experience reduced exercise tolerance that substantially reduces quality of life. The mechanisms underpinning exercise intolerance in MS are not fully clear. This study aimed to determine the contributions of the cardiopulmonary system and peripheral muscle in MS-induced exercise intolerance before and after exercise training.Twenty-three patients with MS (13 women) and 20 age-matched and sex-matched healthy controls (13 women) performed a cardiopulmonary exercise test. Muscle fibre type composition, size, succinate dehydrogenase (SDH) activity, capillarity, and gene expression and proteins related to mitochondrial density were determined in vastus lateralis muscle biopsies. Nine MS patients (five women) were re-examined following a 12 week exercise training programme consisting of high-intensity cycling interval and resistance training.Patients with MS had lower maximal oxygen uptake compared with healthy controls (V̇O2peak , 25.0 ± 8.5 vs. 35.7 ± 6.4 mL/kg/min, P < 0.001). The lower gas exchange threshold (MS: 14.5 ± 5.5 vs. controls: 19.7 ± 2.9 mL/kg/min, P = 0.01) and slope of V̇O2 versus work rate (MS: 9.5 ± 1.7 vs. controls: 10.8 ± 1.1 mL/min/W, P = 0.01) suggested an intramuscular contribution to exercise intolerance in patients with MS. Muscle SDH activity was 22% lower in MS (P = 0.004), and strongly correlated with several indices of whole-body exercise capacity in MS patients (e.g. V̇O2peak , Spearman's ρ = 0.81, P = 0.002), but not healthy controls (ρ = 0.24, P = 0.38). In addition, protein levels of mitochondrial OXPHOS complexes I (-40%, P = 0.047) and II (-45%, P = 0.026) were lower in MS patients versus controls. Muscle capillary/fibre ratio correlated with V̇O2peak in healthy controls (ρ = 0.86, P < 0.001) but not in MS (ρ = 0.35, P = 0.22), and did not differ between groups (1.41 ± 0.30 vs. 1.47 ± 0.38, P = 0.65). Expression of genes involved in mitochondrial function, such as PPARA, PPARG, and TFAM, was markedly reduced in muscle tissue samples of MS patients (all P < 0.05). No differences in muscle fibre type composition or size were observed between groups (all P > 0.05). V̇O2peak increased by 23% following exercise training in MS (P < 0.001); however, no changes in muscle capillarity, SDH activity, gene or protein expression were observed (all P > 0.05).Skeletal muscle oxidative phenotype (mitochondrial complex I and II content, SDH activity) is lower in patients with MS, contributing to reduced exercise tolerance. However, skeletal muscle mitochondria appeared resistant to the beneficial effects of exercise training, suggesting that other physiological systems, at least in part, drive the improvements in exercise capacity following exercise training in MS.
View details for DOI 10.1002/jcsm.13050
View details for PubMedID 35929063
View details for PubMedCentralID PMC9530506
Carnosine quenches the reactive carbonyl acrolein in the central nervous system and attenuates autoimmune neuroinflammation.
Journal of neuroinflammation
2021; 18 (1): 255
Multiple sclerosis (MS) is a chronic autoimmune disease driven by sustained inflammation in the central nervous system. One of the pathological hallmarks of MS is extensive free radical production. However, the subsequent generation, potential pathological role, and detoxification of different lipid peroxidation-derived reactive carbonyl species during neuroinflammation are unclear, as are the therapeutic benefits of carbonyl quenchers. Here, we investigated the reactive carbonyl acrolein and (the therapeutic effect of) acrolein quenching by carnosine during neuroinflammation.The abundance and localization of acrolein was investigated in inflammatory lesions of MS patients and experimental autoimmune encephalomyelitis (EAE) mice. In addition, we analysed carnosine levels and acrolein quenching by endogenous and exogenous carnosine in EAE. Finally, the therapeutic effect of exogenous carnosine was assessed in vivo (EAE) and in vitro (primary mouse microglia, macrophages, astrocytes).Acrolein was substantially increased in inflammatory lesions of MS patients and EAE mice. Levels of the dipeptide carnosine (β-alanyl-L-histidine), an endogenous carbonyl quencher particularly reactive towards acrolein, and the carnosine-acrolein adduct (carnosine-propanal) were ~ twofold lower within EAE spinal cord tissue. Oral carnosine treatment augmented spinal cord carnosine levels (up to > tenfold), increased carnosine-acrolein quenching, reduced acrolein-protein adduct formation, suppressed inflammatory activity, and alleviated clinical disease severity in EAE. In vivo and in vitro studies indicate that pro-inflammatory microglia/macrophages generate acrolein, which can be efficiently quenched by increasing carnosine availability, resulting in suppressed inflammatory activity. Other properties of carnosine (antioxidant, nitric oxide scavenging) may also contribute to the therapeutic effects.Our results identify carbonyl (particularly acrolein) quenching by carnosine as a therapeutic strategy to counter inflammation and macromolecular damage in MS.
View details for DOI 10.1186/s12974-021-02306-9
View details for PubMedID 34740381
View details for PubMedCentralID PMC8571880
Carnosine and skeletal muscle dysfunction in a rodent multiple sclerosis model.
2021; 53 (11): 1749-1761
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.
View details for DOI 10.1007/s00726-021-03086-5
View details for PubMedID 34642824
Lifestyle interventions to reduce sedentary behaviour in clinical populations: A systematic review and meta-analysis of different strategies and effects on cardiometabolic health.
2021; 148: 106593
Cardiometabolic comorbidities are highly prevalent in clinical populations, and have been associated (partly) with their sedentary lifestyle. Although lifestyle interventions targeting sedentary behaviour (SB) have been studied extensively in the general population, the effect of such strategies in clinical populations is not yet clear. Therefore, this systematic review and meta-analysis evaluated the effect of different lifestyle interventions on SB and cardiometabolic health in clinical populations. Randomised controlled trials were collected from five bibliographic databases (PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials, and Scopus). Studies were eligible for inclusion if they evaluated a lifestyle intervention to reduce objectively measured SB, in comparison with a control intervention among persons with a clinical condition. Data were pooled using a random-effects meta-analysis. In total, 7094 studies were identified. Eighteen studies met the inclusion criteria and were categorised in five population groups: overweight/obesity, type 2 diabetes mellitus, cardiovascular, neurological/cognitive and musculoskeletal diseases. Participants reduced their SB by 64 min/day (95%CI: [-91, -38] min/day; p < 0.001), with larger within-group differences of multicomponent behavioural interventions including motivational counselling, self-monitoring, social facilitation and technologies (-89 min/day; 95%CI: [-132, -46] min/day; p < 0.001). Blood glycated haemoglobin concentration (-0.17%; 95% CI: [-0.30, -0.04]%; p = 0.01), fat percentage (-0.66%; 95% CI: [-1.26, -0.06]%, p = 0.03) and waist circumference (-1.52 cm; 95%CI: [-2.84, -0.21] cm; p = 0.02) were significantly reduced in the intervention groups compared to control groups. Behavioural lifestyle interventions reduce SB among clinical populations and improve cardiometabolic risk markers such as waist circumference, fat percentage, and glycaemic control. Sedentary behaviour, Cardiometabolic health, Clinical populations.
View details for DOI 10.1016/j.ypmed.2021.106593
View details for PubMedID 33930434
Oxidative stress and impaired oligodendrocyte precursor cell differentiation in neurological disorders.
Cellular and molecular life sciences : CMLS
2021; 78 (10): 4615-4637
Oligodendrocyte precursor cells (OPCs) account for 5% of the resident parenchymal central nervous system glial cells. OPCs are not only a back-up for the loss of oligodendrocytes that occurs due to brain injury or inflammation-induced demyelination (remyelination) but are also pivotal in plastic processes such as learning and memory (adaptive myelination). OPC differentiation into mature myelinating oligodendrocytes is controlled by a complex transcriptional network and depends on high metabolic and mitochondrial demand. Mounting evidence shows that OPC dysfunction, culminating in the lack of OPC differentiation, mediates the progression of neurodegenerative disorders such as multiple sclerosis, Alzheimer's disease and Parkinson's disease. Importantly, neurodegeneration is characterised by oxidative and carbonyl stress, which may primarily affect OPC plasticity due to the high metabolic demand and a limited antioxidant capacity associated with this cell type. The underlying mechanisms of how oxidative/carbonyl stress disrupt OPC differentiation remain enigmatic and a focus of current research efforts. This review proposes a role for oxidative/carbonyl stress in interfering with the transcriptional and metabolic changes required for OPC differentiation. In particular, oligodendrocyte (epi)genetics, cellular defence and repair responses, mitochondrial signalling and respiration, and lipid metabolism represent key mechanisms how oxidative/carbonyl stress may hamper OPC differentiation in neurodegenerative disorders. Understanding how oxidative/carbonyl stress impacts OPC function may pave the way for future OPC-targeted treatment strategies in neurodegenerative disorders.
View details for DOI 10.1007/s00018-021-03802-0
View details for PubMedID 33751149
View details for PubMedCentralID PMC8195802
Can consumer wearable activity tracker-based interventions improve physical activity and cardiometabolic health in patients with chronic diseases? A systematic review and meta-analysis of randomised controlled trials.
The international journal of behavioral nutrition and physical activity
2020; 17 (1): 57
To date, it is unclear if consumer wearable activity trackers (CWATs), with or without behaviour multi-component strategies, effectively improve adherence to physical activity and health outcomes under free living conditions in populations with chronic diseases. Therefore, we systematically evaluated the efficacy of CWAT-based interventions to promote physical activity levels and cardiometabolic health in populations with chronic diseases.Randomised controlled trials were collected from five bibliographic databases (PubMed, Embase, Web of Science, The Cochrane Central Register of Controlled Trials and CINAHL). Studies were eligible for inclusion if they evaluated a CWAT-based counselling intervention versus control intervention among patients with chronic respiratory diseases, type 2 diabetes mellitus, cardiovascular diseases, overweight/obesity, cognitive disorders, or sedentary older adults. Data were pooled using a random-effects model.After deduplication 8147 were identified of which 35 studies met inclusion criteria (chronic respiratory diseases: 7, type 2 diabetes mellitus: 12, cardiovascular diseases: 6, overweight/obesity: 3, cognitive disorders: 1, sedentary older adults: 6). Compared to control groups, CWAT-based interventions significantly increased physical activity by 2123 steps per day (95% confidence interval [CI], [1605-2641]; p < 0.001). In addition, CWAT-based interventions in these populations significantly decreased systolic blood pressure (- 3.79 mm Hg; 95% CI: [- 4.53, - 3.04] mm Hg; p < 0.001), waist circumference (- 0.99 cm; 95% CI: [- 1.48, - 0.50] cm; p < 0.001) and low-density lipoprotein cholesterol concentration (- 5.70 mg/dl; 95% CI: [- 9.24, - 2.15] mg/dl; p = 0.002).CWAT-based interventions increase physical activity and have beneficial effects on important health-related outcomes such as systolic blood pressure, waist circumference and LDL cholesterol concentration in patients with chronic diseases.
View details for DOI 10.1186/s12966-020-00955-2
View details for PubMedID 32393357
View details for PubMedCentralID PMC7216601
Intensity-dependent clinical effects of an individualized technology-supported task-oriented upper limb training program in Multiple Sclerosis: A pilot randomized controlled trial.
Multiple sclerosis and related disorders
2019; 34: 119-127
Task-oriented training promotes functional recovery in Multiple Sclerosis (MS). Know-how to determine an individualized training intensity and intensity-dependent effects are, however, unknown. The objective of the study was to investigate the feasibility and the clinical effects of a task-oriented upper limb training program at different individualized training intensities with conventional occupational therapy.People with MS (n = 20, EDSS range 4-8) were divided into three groups, receiving task-oriented training at 100% (n = 7) or 50% (n = 8) of their individual maximal number of repetitions, or conventional occupational therapy (n = 5). Effects were evaluated using different upper limb capacity and perceived performance measures on activity level, and measures on body functions and structures level.Mixed model analyses revealed significant improvements (p < 0.05) over time on the Box and block test (BBT), Action Research Arm Test and the Manual Ability Measure-36. Significant interaction effects (group*time) in favor of the task-oriented group training at the highest intensity were found for BBT and static fatigue index during a maximal sustained handgrip strength test.All participants were able to perform the task-oriented training at their individualized intensity without any adverse effects. Several improvements over time were found for all intervention groups, however the results suggest a superiority of task-oriented training at 100%. CLINICAL TRIAL REGISTRATION NUMBER ON CLINICALTRIALS.GOV: = NCT02688231.
View details for DOI 10.1016/j.msard.2019.06.014
View details for PubMedID 31255988
Periodized home-based training: A new strategy to improve high intensity exercise therapy adherence in mildly affected patients with Multiple Sclerosis.
Multiple sclerosis and related disorders
2019; 28: 91-97
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.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.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.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.
View details for DOI 10.1016/j.msard.2018.12.018
View details for PubMedID 30576848