Understanding graft-versus-host disease. Preliminary findings regarding the effects of exercise in affected patients

Advances in this century regarding allogeneic hematopoietic stem cell transplantation (allo-HSCT) have led to an expanding population of long-term survivors, many of whom suffer severe side effects, particularly those related to graft-versushost disease (GVHD), a potentially multi-systemic disorder caused by immunoeffector donor lymphocytes that destroy host tissues. The GVHD, especially in its chronic form (cGVHD), generates considerable morbidity and compromises the physical capacity of patients. We have reviewed the main pathophysiological aspects of the disease as well as the data available on the effects of exercise in GVHD, based on animal and human patient research. Although exercise training as an adjunct therapy to improve health outcomes after allo-HSCT shows promise (particularly, this lifestyle intervention can improve physical fitness and possibly immune function while attenuating fatigue), there is a need for more randomized control trials that focus specifically on GVHD

The Era of Smartphones: Back to Our Biological Makeup?

Physical inactivity is a major modifiable cardiovascular risk factor that has become a growing health problem in the 21st century: 83% of adolescents aged 13-15 years and approximately 1/3 of adults worldwide are inactive, that is, not meeting the minimum international physical activity (PA) recommendations (=150 minutes/week of moderate to vigorous PA) [1, 2]. Thus, the PA levels of the general population, especially of individuals at cardiovascular risk, should be routinely assessed by health care professionals, as it has been recently recommended by the American Heart Association [3]. To this end, accelerometers (usually attached to an elastic belt around the waist) allow objective quantification of PA by providing continuous recordings. At least 3 to 5 days of accelerometer monitoring (including weekend days) are required to determine habitual PA, and it is generally accepted that the device should be worn for =10 hours/day [4]. For this reason, the simple and inexpensive method of PA questionnaires is more widely used and generally better accepted. Unfortunately, the validity of self-reported PA is questionable..

Strenuous exercise worse than sedentarism?

Schnohr et al. (1) reported a U-shaped association between all-cause mortality and exercise dose in a Danish cohort. Jogging 1 to 2.4 h/week was associated with the lowest mortality, whereas jogging >3 times/week was no better than being inactive and was worse than light jogging (adjusted hazard ratio [HR]: 9.08; 95% confidence interval [CI]: 1.87 to 44.01). Furthermore, older (61.3 16.2 years) sedentary nonjoggers with cardiovascular disease (CVD) risk factors...

Genetic variants in the PPARD-PPARGC1A-NRF-TFAM mitochondriogenesis pathway are neither associated with muscle characteristics nor physical performance in elderly

We studied the influence of genetic polymorphisms involved in the PPARD-PPARGC1A-NRF-TFAM mitochondriogenesis pathway (rs6949152, rs12594956, rs2267668, rs8192678, and rs1937) on muscle phenotypes (thigh muscles’ cross-sectional, maximal handgrip-strength and 30-second chair stand-test) and Barthel index in Caucasian (Spanish) community-dwelling old people (n=75, 21 men, 54 women; 71–94 years). We found no significant genetic associations with the studied phenotypes. Multiple, com- plex gene-environment and gene-gene interactions which are yet to be determined are likely to play a more determinant role

Regular physical activity: A little is good, but is it good enough?

Ekelund et al. (1) nicely showed that physical inactivity causes an approximate twofold increase in the numbers of deaths compared with those attributable to obesity [BMI (in kg/m2) .30] in a Euro- pean cohort (n 1/4 334,161) that was followed up to 12.4 y on average. Physical activity (PA) levels were estimated by using a standardized questionnaire or in-person interviews and were found to be inversely associated with all-cause mortality at all levels of BMI and waist circumference. Another important finding from their study is that substantial survival benefits may be achieved by fairly small amounts of moderate-intensity PA: that is, ;20 min/d of brisk walking, which is below the current PA recommendations of !30 min/d on most, if not all, days of the week (or !150 min/wk). These important findings in Caucasians are in line with those recently reported in an Asiatic cohort, in whom 15 min/d or 90 min/wk of moderate-intensity PA was associated with lower all-cause mor- tality, even for persons at risk of cardiovascular diseas

Galectin-3, osteopontin and successful aging

Background: Individuals who reach exceptional longevity (100+ years of age) free of common chronic age diseases (i.e. ''dodgers'') arguably represent the paradigm of successful aging in humans. As such, identification of potential biomarkers associated with this phenomenon is of medical interest. Methods: We measured serum levels of galectin-3 and osteopontin, both of which have been shown to be linked with major chronic or aging-related disorders in younger populations, in centenarian ''dodgers'' (n=81; 40 men; 100-104 years) and healthy controls (n=41; 24 men, 70-80 years). Results: Both biomarkers showed significantly lower values (p<0.001) in the former (galectin-3: 2.4±1.7 vs. 4.8±2.8 ng/mL; osteopontin: 38.1±27.7 vs. 72.6±33.1 µg/mL). Logistic regression analysis identified the combination of these two biomarkers as a significant predictor variable associated with successful aging regardless of sex (p<0.001). The area under the curve (AUC) classified the ability of galectin-3 and osteopontin to predict the likelihood of successful aging as ''fair'' (AUC=0.75) and ''good'' (AUC=0.80), respectively. Particularly, the combination of the two biomarkers showed good discriminatory power for successful aging (AUC=0.86), with sensitivity=83% and specificity=74%. Conclusions: Lower levels of both galectin-3 and osteopontin are associated with successful aging, representing potential biomarkers of this condition. Our cross-sectional data must be however approached with caution. Further research is necessary to replicate the present preliminary results in other cohorts and to identify the potential use of galectin-3 and osteopontin as potential targets (or at least predictors) in future personalized anti-aging therapies

A Transcriptomic Approach to Search for Novel Phenotypic Regulators in McArdle Disease

McArdle disease is caused by lack of glycogen phosphorylase (GP) activity in skeletal muscle. Patients experience exercise intolerance, presenting as early fatigue and contractures. In this study, we investigated the effects produced by a lack of GP on several genes and proteins of skeletal muscle in McArdle patients. Muscle tissue of 35 patients and 7 healthy controls were used to identify abnormalities in the patients' transcriptomic profile using low-density arrays. Gene expression was analyzed for the influence of variables such as sex and clinical severity. Differences in protein expression were studied by immunoblotting and 2D electrophoresis analysis, and protein complexes were examined by two-dimensional, blue native gel electrophoresis (BN-PAGE). A number of genes including those encoding acetyl-coA carboxylase beta, m-cadherin, calpain III, creatine kinase, glycogen synthase (GS), and sarcoplasmic reticulum calcium ATPase 1 (SERCA1), were found to be downregulated in patients. Specifically, compared to controls, GS and SERCA1 proteins were reduced by 50% and 75% respectively; also, unphosphorylated GS and SERCA1 were highly downregulated. On BN-PAGE analysis, GP was present with GS in two muscle protein complexes. Our findings revealed some issues that could be important in understanding the physiological consequences of McArdle disease: (i) SERCA1 downregulation in patients could result in impaired calcium transport in type II (fast-twitch) muscle fibers, leading to early fatigability during exercise tasks involving type II fibers (which mostly use glycolytic metabolism), i.e. isometric exercise, lifting weights or intense dynamic exercise (stair climbing, bicycling, walking at a very brisk pace), (ii) GP and GS were found together in two protein complexes, which suggests a new regulatory mechanism in the activity of these glycogen enzymes

Experimental evaluation of vibrotactile training mappings for dual-joystick directional guidance

Two joystick-based teleoperation is a common method for controlling a remote machine or a robot. Their use could be counter-intuitive and could require a heavy mental workload. The goal of this paper is to investigate whether vibrotactile prompts could be used to trigger dual-joystick responses quickly and intuitively, so to possibly employ them for training. In particular, we investigate the effects of: (1) stimuli delivered either on the palm or on the back of the hand, (2) with attractive and repulsive mappings, (3) with single and sequential stimuli. We find that 38 participants responded quicker and more accurately when stimuli were delivered on the back of the hand, preferred to move towards the vibration. Sequential stimuli led to intermediate responses in terms of speed and accuracy

Low aerobic capacity in McArdle disease: A role for mitochondrial network impairment?

[Background]: McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO2peak)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. [Methods]: We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO2peak in patients (both sexes, N = 145) and healthy controls (N = 133). [Results]: Besides corroborating very poor VO2peak values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. [Conclusions]: In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses.The present study was funded by grants received from the Fondo de Investigaciones Sanitarias (FIS, PI17/02052, PI18/00139, PI19/01313, and PI20/00645) and cofunded by ‘Fondos FEDER’. Gisela Nogales-Gadea and Carmen Fiuza-Luces are supported by the Miguel Servet research contracts (ISCIII CD14/00032 and CP18/00034, respectively and cofounded by Fondos FEDER′). Research by Pedro L. Valenzuela is funded by a postdoctoral contract granted by Instituto de Salud Carlos III (Sara Borrell, CD21/00138). Monica Villarreal Salazar is supported by the Mexican National Council for Science and Technology (CONACYT)

Low aerobic capacity in McArdle disease : A role for mitochondrial network impairment?

McArdle disease is caused by myophosphorylase deficiency and results in complete inability for muscle glycogen breakdown. A hallmark of this condition is muscle oxidation impairment (e.g., low peak oxygen uptake (VO)), a phenomenon traditionally attributed to reduced glycolytic flux and Krebs cycle anaplerosis. Here we hypothesized an additional role for muscle mitochondrial network alterations associated with massive intracellular glycogen accumulation. We analyzed in depth mitochondrial characteristics-content, biogenesis, ultrastructure-and network integrity in skeletal-muscle from McArdle/control mice and two patients. We also determined VO in patients (both sexes, N = 145) and healthy controls (N = 133). Besides corroborating very poor VO values in patients and impairment in muscle glycolytic flux, we found that, in McArdle muscle: (a) damaged fibers are likely those with a higher mitochondrial and glycogen content, which show major disruption of the three main cytoskeleton components-actin microfilaments, microtubules and intermediate filaments-thereby contributing to mitochondrial network disruption in skeletal muscle fibers; (b) there was an altered subcellular localization of mitochondrial fission/fusion proteins and of the sarcoplasmic reticulum protein calsequestrin-with subsequent alteration in mitochondrial dynamics/function; impairment in mitochondrial content/biogenesis; and (c) several OXPHOS-related complex proteins/activities were also affected. In McArdle disease, severe muscle oxidative capacity impairment could also be explained by a disruption of the mitochondrial network, at least in those fibers with a higher capacity for glycogen accumulation. Our findings might pave the way for future research addressing the potential involvement of mitochondrial network alterations in the pathophysiology of other glycogenoses