Design and Evaluation of User-Centered Exergames for Patients With Multiple Sclerosis: Multilevel Usability and Feasibility Studies.

BACKGROUND: Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system. Patients with MS experience a wide range of physical and cognitive dysfunctions that affect their quality of life. A promising training approach that concurrently trains physical and cognitive functions is video game-based physical exercising (ie, exergaming). Previous studies have indicated that exergames have positive effects on balance and cognitive functions in patients with MS. However, there is still a need for specific, user-centered exergames that function as a motivating and effective therapy tool for patients with MS and studies investigating their usability and feasibility. OBJECTIVE: The aim of this interdisciplinary research project is to develop usable and feasible user-centered exergames for the pressure-sensitive plate Dividat Senso by incorporating theoretical backgrounds from movement sciences, neuropsychology, and game research as well as participatory design processes. METHODS: Focus groups (patients and therapists) were set up to define the user-centered design process. This was followed by the field testing of newly developed exergame concepts. Two sequential usability and feasibility studies were conducted on patients with MS. The first study included a single exergaming session followed by measurements. Between the first and second studies, prototypes were iterated based on the findings. The second study ran for 4 weeks (1-2 trainings per week), and measurements were taken before and after the intervention. For each study, participants answered the System Usability Scale (SUS; 10 items; 5-point Likert Scale; score range 0-100) and interview questions. In the second study, participants answered game experience-related questionnaires (Flow Short Scale [FSS]: 13 items; 7-point Likert Scale; score range 1-7; Game Flow questionnaire: 17 items; 6-point Likert Scale; score range 1-6). Mixed methods were used to analyze the quantitative and qualitative data. RESULTS: In the first study (N=16), usability was acceptable, with a median SUS score of 71.3 (IQR 58.8-80.0). In the second study (N=25), the median SUS scores were 89.7 (IQR 78.8-95.0; before) and 82.5 (IQR 77.5-90.0; after), and thus, a significant decrease was observed after training (z=-2.077; P=.04; r=0.42). Moreover, high values were observed for the overall FSS (pre: median 5.9, IQR 4.6-6.4; post: median 5.8, IQR 5.4-6.2) and overall Game Flow Questionnaire (pre: median 5.0, IQR 4.7-5.3; post: median 5.1, IQR 4.9-5.3). A significant decrease was observed in the item perceived importance (FSS: z=-2.118; P=.03; r=0.42). Interviews revealed that user-centered exergames were usable, well accepted, and enjoyable. Points of reference were identified for future research and development. CONCLUSIONS: The project revealed that the newly developed, user-centered exergames were usable and feasible for patients with MS. Furthermore, exergame elements should be considered in the development phase of user-centered exergames (for patients with MS). Future studies are needed to provide indications about the efficacy of user-centered exergames for patients with MS.

Correction: Design and Evaluation of User-Centered Exergames for Patients With Multiple Sclerosis: Multilevel Usability and Feasibility Studies.

[This corrects the article DOI: 10.2196/22826.].

Satellite cell content in Huntington's disease patients in response to endurance training.

BACKGROUND: Skeletal muscle wasting is a hallmark of Huntington's disease (HD). However, data on myocellular characteristics and myofiber remodeling in HD patients are scarce. We aimed at gaining insights into myocellular characteristics of HD patients as compared to healthy controls at rest and after a period of increased skeletal muscle turnover. METHODS: Myosin heavy chain (MyHC)-specific cross-sectional area, satellite cell content, myonuclear number, myonuclear domain, and muscle fiber type distribution were determined from vastus lateralis muscle biopsies at rest and after 26 weeks of endurance training in HD patients and healthy controls. RESULTS: At the beginning of the study, there were no differences in myocellular characteristics between HD patients and healthy controls. Satellite cell content per MyHC-1 fiber (P = 0.014) and per MyHC-1 myonucleus (P = 0.006) increased significantly in healthy controls during the endurance training intervention, whereas it remained constant in HD patients (P = 0.804 and P = 0.975 for satellite cell content per MyHC-1 fiber and myonucleus, respectively). All further variables were not altered during the training intervention in HD patients and healthy controls. CONCLUSIONS: Similar skeletal muscle characteristics between HD patients and healthy controls at baseline suggested similar potential for myofiber remodeling in response to exercise. However, the missing satellite cell response in MyHC-1 myofibers following endurance training in HD patients points to a potential dysregulation in the exercise-induced activation and/or proliferation of satellite cells. In the longer-term, impaired myonuclear turnover might be associated with the clinical observation of skeletal muscle wasting.

Increased capillary tortuosity and pericapillary basement membrane thinning in skeletal muscle of mice undergoing running wheel training.

To work out which microvascular remodeling processes occur in murine skeletal muscle during endurance exercise, we subjected C57BL/6 mice to voluntary running wheel training for 1 week (1 wk-t) or 6 weeks (6 wks-t). By means of morphometry, the capillarity as well as the compartmental and sub-compartmental structure of the capillaries were quantitatively described at the light microscopy level and at the electron microscopy level, respectively, in the plantaris (PLNT) muscle of the exercising mice in comparison to untrained littermates. In the early phase of the training (1 wk-t), angiogenesis [32% higher capillary/fiber (C/F) ratio; P<0.05] in PLNT muscle was accompanied by a tendency for capillary lumen enlargement (30%; P=0.06) and a reduction of the pericapillary basement membrane thickness [(CBMT) 12.7%; P=0.09] as well as a 21% shortening of intraluminal protrusion length (P<0.05), all compared with controls. After long-term training (6 wks-t), when the mice reached a steady state in running activity, additional angiogenesis (C/F ratio: 76%; P<0.05) and a 16.3% increase in capillary tortuosity (P<0.05) were established, accompanied by reversal of the lumen expansion (23%; P>0.05), further reduction of the CBMT (16.5%; P<0.05) and additional shortening of the intraluminal protrusion length (23%; P<0.05), all compared with controls. Other structural indicators, such as capillary profile sizes, profile area densities, perimeters of the capillary compartments and concentrations of endothelium-pericyte peg-socket junctions, were not significantly different between the mouse groups. Besides angiogenesis, increase of capillary tortuosity and reduction of CBMT represent the most striking microvascular remodeling processes in skeletal muscle of mice that undergo running wheel training.

Effects of endurance training on skeletal muscle mitochondrial function in Huntington disease patients.

BACKGROUND: Mitochondrial dysfunction may represent a pathogenic factor in Huntington disease (HD). Physical exercise leads to enhanced mitochondrial function in healthy participants. However, data on effects of physical exercise on HD skeletal muscle remains scarce. We aimed at investigating adaptations of the skeletal muscle mitochondria to endurance training in HD patients. METHODS: Thirteen HD patients and 11 healthy controls completed 26 weeks of endurance training. Before and after the training phase muscle biopsies were obtained from M. vastus lateralis. Mitochondrial respiratory chain complex activities, mitochondrial respiratory capacity, capillarization, and muscle fiber type distribution were determined from muscle samples. RESULTS: Citrate synthase activity increased during the training intervention in the whole cohort (P = 0.006). There was no group x time interaction for citrate synthase activity during the training intervention (P = 0.522). Complex III (P = 0.008), Complex V (P = 0.043), and succinate cytochrome c reductase (P = 0.008) activities increased in HD patients and controls by endurance training. An increase in mass-specific mitochondrial respiratory capacity was present in HD patients during the endurance training intervention. Overall capillary-to-fiber ratio increased in HD patients by 8.4% and in healthy controls by 6.4% during the endurance training intervention. CONCLUSIONS: Skeletal muscle mitochondria of HD patients are equally responsive to an endurance-training stimulus as in healthy controls. Endurance training is a safe and feasible option to enhance indices of energy metabolism in skeletal muscle of HD patients and may represent a potential therapeutic approach to delay the onset and/or progression of muscular dysfunction. TRIAL REGISTRATION: ClinicalTrials.gov NCT01879267 . Registered May 24, 2012.

Exercise effects in Huntington disease.

Huntington disease (HD) is a relentlessly progressive neurodegenerative disorder with symptoms across a wide range of neurological domains, including cognitive and motor dysfunction. There is still no causative treatment for HD but environmental factors such as passive lifestyle may modulate disease onset and progression. In humans, multidisciplinary rehabilitation has a positive impact on cognitive functions. However, a specific role for exercise as a component of an environmental enrichment effect has been difficult to demonstrate. We aimed at investigating whether endurance training (ET) stabilizes the progression of motor and cognitive dysfunction and ameliorates cardiovascular function in HD patients. Twelve male HD patients (mean ± SD, 54.8 ± 7.1 years) and twelve male controls (49.1 ± 6.8 years) completed 26 weeks of endurance training. Before and after the training intervention, clinical assessments, exercise physiological tests, and a body composition measurement were conducted and a muscle biopsy was taken from M. vastus lateralis. To examine the natural course of the disease, HD patients were additionally assessed 6 months prior to ET. During the ET period, there was a motor deficit stabilization as indicated by the Unified Huntington's Disease Rating Scale motor section score in HD patients (baseline: 18.6 ± 9.2, pre-training: 26.0 ± 13.7, post-training: 26.8 ± 16.4). Peak oxygen uptake ([Formula: see text]) significantly increased in HD patients (∆[Formula: see text] = +0.33 ± 0.28 l) and controls (∆[Formula: see text] = +0.29 ± 0.41 l). No adverse effects of the training intervention were reported. Our results confirm that HD patients are amenable to a specific exercise-induced therapeutic strategy indicated by an increased cardiovascular function and a stabilization of motor function.

Altered skeletal muscle (mitochondrial) properties in patients with mitochondrial DNA single deletion myopathy.

BACKGROUND: Mitochondrial myopathy severely affects skeletal muscle structure and function resulting in defective oxidative phosphorylation. However, the major pathomechanisms and therewith effective treatment approaches remain elusive. Therefore, the aim of the present study was to investigate disease-related impairments in skeletal muscle properties in patients with mitochondrial myopathy. Accordingly, skeletal muscle biopsies were obtained from six patients with moleculargenetically diagnosed mitochondrial myopathy (one male and five females, 53 ± 9 years) and eight age- and gender-matched healthy controls (two males and six females, 58 ± 14 years) to determine mitochondrial respiratory capacity of complex I-V, mitochondrial volume density and fiber type distribution. RESULTS: Mitochondrial volume density (4.0 ± 0.5 vs. 5.1 ± 0.8 %) as well as respiratory capacity of complex I-V were lower (P < 0.05) in mitochondrial myopathy and associated with a higher (P < 0.001) proportion of type II fibers (65.2 ± 3.6 vs. 44.3 ± 5.9 %). Additionally, mitochondrial volume density and maximal oxidative phosphorylation capacity correlated positively (P < 0.05) to peak oxygen uptake. CONCLUSION: Mitochondrial myopathy leads to impaired mitochondrial quantity and quality and a shift towards a more glycolytic skeletal muscle phenotype.

Angiogenesis-related ultrastructural changes to capillaries in human skeletal muscle in response to endurance exercise.

The ultrastructure of capillaries in skeletal muscle was morphometrically assessed in vastus lateralis muscle (VL) biopsies taken before and after exercise from 22 participants of two training studies. In study 1 (8 wk of ergometer training), light microscopy revealed capillary-fiber (C/F) ratio (+27%) and capillary density (+16%) to be higher (P ≤ 0.05) in postexercise biopsies than in preexercise biopsies from all 10 participants. In study 2 (6 mo of moderate running), C/F ratio and capillary density were increased (+23% and +20%; respectively, P ≤ 0.05) in VL biopsies from 6 angiogenesis responders (AR) after training, whereas 6 nonangiogenesis responders (NR) showed nonsignificant changes in these structural indicators (-4%/-4%, respectively). Forty capillary profiles per participant were evaluated by point and intersection counting on cross sections after transmission electron microscopy. In study 1, volume density (Vv) and mean arithmetic thickness (T) of endothelial cells (ECs; +19%/+17%, respectively) and pericytes (PCs; +20%/+21%, respectively) were higher (P ≤ 0.05), whereas Vv and T of the pericapillary basement membrane (BM) were -23%/-22% lower (P ≤ 0.05), respectively, in posttraining biopsies. In study 2, exercise-related differences between AR and NR-groups were found for Vv and T of PCs (AR, +26%/+22%, respectively, both P ≤ 0.05; NR, +1%/-3%, respectively, both P > 0.05) and BM (AR, -14%/-13%, respectively, both P ≤ 0.05; NR, -9%/-11%, respectively, P = 0.07/0.10). Vv and T of ECs were higher (AR, +16%/+18%, respectively; NR, +6%/+6%, respectively; all P ≤ 0.05) in both groups. The PC coverage was higher (+13%, P ≤ 0.05) in VL biopsies of individuals in the AR group but nonsignificantly altered (+3%, P > 0.05) in those of the NR group after training. Our study suggests that intensified PC mobilization and BM thinning are related to exercise-induced angiogenesis in human skeletal muscle, whereas training per se induces EC-thickening.

Long-Term Endurance Exercise in Humans Stimulates Cell Fusion of Myoblasts along with Fusogenic Endogenous Retroviral Genes In Vivo.

Myogenesis is defined as growth, differentiation and repair of muscles where cell fusion of myoblasts to multinucleated myofibers is one major characteristic. Other cell fusion events in humans are found with bone resorbing osteoclasts and placental syncytiotrophoblasts. No unifying gene regulation for natural cell fusions has been found. We analyzed skeletal muscle biopsies of competitive cyclists for muscle-specific attributes and expression of human endogenous retrovirus (ERV) envelope genes due to their involvement in cell fusion of osteoclasts and syncytiotrophoblasts. Comparing muscle biopsies from post- with the pre-competitive seasons a significant 2.25-fold increase of myonuclei/mm fiber, a 2.38-fold decrease of fiber area/nucleus and a 3.1-fold decrease of satellite cells (SCs) occurred. We propose that during the pre-competitive season SC proliferation occurred following with increased cell fusion during the competitive season. Expression of twenty-two envelope genes of muscle biopsies demonstrated a significant increase of putative muscle-cell fusogenic genes Syncytin-1 and Syncytin-3, but also for the non-fusogenic erv3. Immunohistochemistry analyses showed that Syncytin-1 mainly localized to the sarcolemma of myofibers positive for myosin heavy-chain isotypes. Cellular receptors SLC1A4 and SLC1A5 of Syncytin-1 showed significant decrease of expression in post-competitive muscles compared with the pre-competitive season, but only SLC1A4 protein expression localized throughout the myofiber. Erv3 protein was strongly expressed throughout the myofiber, whereas envK1-7 localized to SC nuclei and myonuclei. Syncytin-1 transcription factors, PPARγ and RXRα, showed no protein expression in the myofiber, whereas the pCREB-Ser133 activator of Syncytin-1 was enriched to SC nuclei and myonuclei. Syncytin-1, Syncytin-3, SLC1A4 and PAX7 gene regulations along with MyoD1 and myogenin were verified during proliferating or actively-fusing human primary myoblast cell cultures, resembling muscle biopsies of cyclists. Myoblast treatment with anti-Synycytin-1 abrogated cell fusion in vitro. Our findings support functional roles for ERV envelope proteins, especially Syncytin-1, contributing to cell fusion of myotubes.

High-load resistance exercise with superimposed vibration and vascular occlusion increases critical power, capillaries and lean mass in endurance-trained men.

PURPOSE: It is a widely accepted premise in the scientific community and by athletes alike, that adding resistance exercise to a regular regimen of endurance training increases endurance performance in endurance-trained men. However, critical power (CP), capillarization, and myofiber size remain unaffected by this addition. Therefore, we tested whether the superimposition of resistance exercise with whole-body vibration and vascular occlusion (vibroX) would improve these variables in endurance-trained males relative to resistance exercise alone. METHODS: Twenty-one young, endurance-trained males were randomly assigned either to a vibroX (n = 11) or resistance (n = 10) training group. Both groups trained in a progressive mode twice a week for 8 weeks. Pre and post training, histochemical muscle characteristics, thigh muscle size, endurance and strength parameters were determined. RESULTS: vibroX increased CP (P = 0.001), overall capillary-to-fiber ratio (P = 0.001) and thigh lean mass (P < 0.001), while these parameters were unaffected by resistance training. The gain in CP by vibroX was positively correlated with the gain in capillarization (R(2) = 0.605, P = 0.008), and the gain in thigh lean mass was paralleled by increases in MyHC-1 and MyHC-2 fiber cross-sectional areas and strength. Maximum voluntary torque and the finite work capacity above CP (W') increased significantly only following resistance training. CONCLUSIONS: We achieved a proof of concept by demonstrating that modification of resistance exercise by superimposing side-alternating whole-body vibration and sustained vascular occlusion induced further improvements in CP, capillarization and hypertrophy, all of which were not observed with resistance training alone.

Multiday acute sodium bicarbonate intake improves endurance capacity and reduces acidosis in men.

BACKGROUND: The purpose was to investigate the effects of one dose of NaHCO3 per day for five consecutive days on cycling time-to-exhaustion (Tlim) at 'Critical Power' (CP) and acid-base parameters in endurance athletes. METHODS: Eight trained male cyclists and triathletes completed two exercise periods in a randomized, placebo-controlled, double-blind interventional crossover investigation. Before each period, CP was determined. Afterwards, participants completed five constant-load cycling trials at CP until volitional exhaustion on five consecutive days, either after a dose of NaHCO3 (0.3 g·kg-1 body mass) or placebo (0.045 g·kg-1 body mass NaCl). RESULTS: Average Tlim increased by 23.5% with NaHCO3 supplementation as compared to placebo (826.5 ± 180.1 vs. 669.0 ± 167.2 s; P = 0.001). However, there was no time effect for Tlim (P = 0.375). [HCO3-] showed a main effect for condition (NaHCO3: 32.5 ± 2.2 mmol·l-1; placebo: 26.2 ± 1.4 mmol·l-1; P < 0.001) but not for time (P = 0.835). NaHCO3 supplementation resulted in an expansion of plasma volume relative to placebo (P = 0.003). CONCLUSIONS: The increase in Tlim was accompanied by an increase in [HCO3-], suggesting that acidosis might be a limiting factor for exercise at CP. Prolonged NaHCO3 supplementation did not lead to a further increase in [HCO3-] due to the concurrent elevation in plasma volume. This may explain why Tlim remained unaltered despite the prolonged NaHCO3 supplementation period. Ingestion of one single NaHCO3 dose per day before the competition during multiday competitions or tournaments might be a valuable strategy for performance enhancement. TRIAL REGISTRATION: Trial registration: ClinicalTrials.gov Identifier NCT01621074.

Accelerated aging phenotype in mice with conditional deficiency for mitochondrial superoxide dismutase in the connective tissue.

The free radical theory of aging postulates that the production of mitochondrial reactive oxygen species is the major determinant of aging and lifespan. Its role in aging of the connective tissue has not yet been established, even though the incidence of aging-related disorders in connective tissue-rich organs is high, causing major disability in the elderly. We have now addressed this question experimentally by creating mice with conditional deficiency of the mitochondrial manganese superoxide dismutase in fibroblasts and other mesenchyme-derived cells of connective tissues in all organs. Here, we have shown for the first time that the connective tissue-specific lack of superoxide anion detoxification in the mitochondria results in reduced lifespan and premature onset of aging-related phenotypes such as weight loss, skin atrophy, kyphosis (curvature of the spine), osteoporosis and muscle degeneration in mutant mice. Increase in p16(INK4a) , a robust in vivo marker for fibroblast aging, may contribute to the observed phenotype. This novel model is particularly suited to decipher the underlying mechanisms and to develop hopefully novel connective tissue-specific anti-aging strategies.