Exercise causes oxidative stress only when exhaustive. Strenuous exercise causes oxidation of glutathione, release of cytosolic enzymes, and other signs of cell damage. However, there is increasing ...evidence that reactive oxygen species (ROS) not only are toxic but also play an important role in cell signaling and in the regulation of gene expression. Xanthine oxidase is involved in the generation of superoxide associated with exhaustive exercise. Allopurinol (an inhibitor of this enzyme) prevents muscle damage after exhaustive exercise, but also modifies cell signaling pathways associated with both moderate and exhaustive exercise in rats and humans. In gastrocnemius muscle from rats, exercise caused an activation of MAP kinases. This in turn activated the NF-κB pathway and consequently the expression of important enzymes associated with defense against ROS (superoxide dismutase) and adaptation to exercise (eNOS and iNOS). All these changes were abolished when ROS production was prevented by allopurinol. Thus ROS act as signals in exercise because decreasing their formation prevents activation of important signaling pathways that cause useful adaptations in cells. Because these signals result in an upregulation of powerful antioxidant enzymes, exercise itself can be considered an antioxidant. We have found that interfering with free radical metabolism with antioxidants may hamper useful adaptations to training.
Physical exercise increases the cellular production of reactive oxygen species (ROS) in muscle, liver, and other organs. This is unlikely due to increased mitochondrial production but rather to ...extramitochondrial sources such as NADPH oxidase or xanthine oxidase. We have reported a xanthine oxidase-mediated increase in ROS production in many experimental models from isolated cells to humans. Originally, ROS were considered as detrimental and thus as a likely cause of cell damage associated with exhaustion. In the past decade, evidence showing that ROS act as signals has been gathered and thus the idea that antioxidant supplementation in exercise is always recommendable has proved incorrect. In fact, we proposed that exercise itself can be considered as an antioxidant because training increases the expression of classical antioxidant enzymes such as superoxide dismutase and glutathione peroxidase and, in general, lowering the endogenous antioxidant enzymes by administration of antioxidant supplements may not be a good strategy when training. Antioxidant enzymes are not the only ones to be activated by training. Mitochondriogenesis is an important process activated in exercise. Many redox-sensitive enzymes are involved in this process. Important signaling molecules like MAP kinases, NF-κB, PGC-1α, p53, heat shock factor, and others modulate muscle adaptation to exercise. Interventions aimed at modifying the production of ROS in exercise must be performed with care as they may be detrimental in that they may lower useful adaptations to exercise.
Regeneration of skeletal muscle is a highly synchronized process that requires muscle stem cells (satellite cells). We found that localized injuries, as experienced through exercise, activate a ...myofiber self-repair mechanism that is independent of satellite cells in mice and humans. Mouse muscle injury triggers a signaling cascade involving calcium, Cdc42, and phosphokinase C that attracts myonuclei to the damaged site via microtubules and dynein. These nuclear movements accelerate sarcomere repair and locally deliver messenger RNA (mRNA) for cellular reconstruction. Myofiber self-repair is a cell-autonomous protective mechanism and represents an alternative model for understanding the restoration of muscle architecture in health and disease.
•Low levels of physical activity are a risk factor associated with Alzheimer's disease.•Older adults who exercise are more likely to maintain cognition.•Exercise modulates amyloid β turnover, ...inflammation, synthesis, and release of neurotrophins, and cerebral blood flow.
Dementia is one of the greatest global challenges for health and social care in the 21st century. Alzheimer's disease (AD), the most common type of dementia, is by no means an inevitable consequence of growing old. Several lifestyle factors may increase, or reduce, an individual's risk of developing AD. Much has been written over the ages about the benefits of exercise and physical activity. Among the risk factors associated with AD is a low level of physical activity. The relationship between physical and mental health was established several years ago. In this review, we discuss the role of exercise (aerobic and resistance) training as a therapeutic strategy for the treatment and prevention of AD. Older adults who exercise are more likely to maintain cognition. We address the main protective mechanism on brain function modulated by physical exercise by examining both human and animal studies. We will pay especial attention to the potential role of exercise in the modulation of amyloid β turnover, inflammation, synthesis and release of neurotrophins, and improvements in cerebral blood flow. Promoting changes in lifestyle in presymptomatic and predementia disease stages may have the potential for delaying one-third of dementias worldwide. Multimodal interventions that include the adoption of an active lifestyle should be recommended for older populations.
Exercise practitioners often take vitamin C supplements because intense muscular contractile activity can result in oxidative stress, as indicated by altered muscle and blood glutathione ...concentrations and increases in protein, DNA, and lipid peroxidation. There is, however, considerable debate regarding the beneficial health effects of vitamin C supplementation.
This study was designed to study the effect of vitamin C on training efficiency in rats and in humans.
The human study was double-blind and randomized. Fourteen men (27–36 y old) were trained for 8 wk. Five of the men were supplemented daily with an oral dose of 1 g vitamin C. In the animal study, 24 male Wistar rats were exercised under 2 different protocols for 3 and 6 wk. Twelve of the rats were treated with a daily dose of vitamin C (0.24 mg/cm2 body surface area).
The administration of vitamin C significantly (P = 0.014) hampered endurance capacity. The adverse effects of vitamin C may result from its capacity to reduce the exercise-induced expression of key transcription factors involved in mitochondrial biogenesis. These factors are peroxisome proliferator–activated receptor co-activator 1, nuclear respiratory factor 1, and mitochondrial transcription factor A. Vitamin C also prevented the exercise-induced expression of cytochrome C (a marker of mitochondrial content) and of the antioxidant enzymes superoxide dismutase and glutathione peroxidase.
Vitamin C supplementation decreases training efficiency because it prevents some cellular adaptations to exercise.
Reactive oxygen or nitrogen species (RONS) are produced during exercise due, at least in part, to the activation of xanthine
oxidase. When exercise is exhaustive they cause tissue damage; however, ...they may also act as signals inducing specific cellular
adaptations to exercise. We have tested this hypothesis by studying the effects of allopurinol-induced inhibition of RONS
production on cell signalling pathways in rats submitted to exhaustive exercise. Exercise caused an activation of mitogen-activated
protein kinases (MAPKs: p38, ERK 1 and ERK 2), which in turn activated nuclear factor κB (NF-κB) in rat gastrocnemius muscle.
This up-regulated the expression of important enzymes associated with cell defence (superoxide dismutase) and adaptation to
exercise (eNOS and iNOS). All these changes were abolished when RONS production was prevented by allopurinol. Thus we report,
for the first time, evidence that decreasing RONS formation prevents activation of important signalling pathways, predominantly
the MAPKâNF-κB pathway; consequently the practice of taking antioxidants before exercise may have to be re-evaluated.
Frailty can be an important clinical target to reduce rates of disability.
To ascertain if a supervised-facility multicomponent exercise program (MEP) when performed by frail older persons can ...reverse frailty and improve functionality; cognitive, emotional, and social networking; as well as biological biomarkers of frailty, when compared with a controlled population that received no training.
This is an interventional, controlled, simple randomized study. Researchers responsible for data gathering were blinded for this study.
Participants from 2 primary rural care centers (Sollana and Carcaixent) of the same health department in Spain were enrolled in the study between December 2013 and September 2014.
We randomized a volunteer sample of 100 men and women who were sedentary, with a gait speed lower than 0.8 meters per second and frail (met at least 3 of the frailty phenotype criteria).
Participants were randomized to a supervised-facility MEP (n = 51, age = 79.5, SD 3.9) that included proprioception, aerobic, strength, and stretching exercises for 65 minutes, 5 days per week, 24 weeks, or to a control group (n = 49, age = 80.3, SD 3.7). The intervention was performed by 8 experienced physiotherapists or nurses. Protein-calorie and vitamin D supplementation were controlled in both groups.
Our MEP reverses frailty (number needed to treat to recover robustness in subjects with attendance to ≥50% of the training sessions was 3.2) and improves functional measurements: Barthel (trained group 91.6 SD 8.0 vs 82.0 SD 11.0 control group), Lawton and Brody (trained group 6.9 SD 0.9 vs 5.7 SD 2.0 control group), Tinetti (trained group 24.5 SD 4.4 vs 21.7 SD 4.5 control group), Short Physical Performance Battery (trained group 9.5 SD 1.8 vs 7.1 SD 2.8 control group), and physical performance test (trained group 23.5 SD 5.9 vs 16.5 SD 5.1 control group) as well as cognitive, emotional, and social networking determinations: Mini-Mental State Examination (trained group 28.9 SD 3.9 vs 25.9 SD 7.3 control group), geriatric depression scale from Yesavage (trained group 2.3 SD 2.2 vs 3.2 SD 2.0 control group), EuroQol quality-of-life scale (trained group 8.2 SD 1.6 vs 7.6 SD 1.3 control group), and Duke social support (trained group 48.5 SD 9.3 vs 41.2 SD 8.5 control group). This program is unique in that it leads to a decrease in the number of visits to primary care physician (trained group 1.3 SD 1.4 vs 2.4 SD 2.9 control group) and to a significant improvement in frailty biomarkers.
We have designed a multicomponent exercise intervention that reverses frailty and improves cognition, emotional, and social networking in a controlled population of community-dwelling frail older adults.
ClinicalTrials.gov. Identifier: NCT02331459.
Mitochondrial biogenesis (MB) is the essential mechanism by which cells control the number of mitochondria. Cells respond to different physiologic, metabolic, and pathologic changes by regulating ...this organelle with high morphological and functional adaptability. A considerable number of proteins, transcription factors, upstream regulatory proteins and secondary mechanisms are involved in MB and the stabilization of new mitochondrial DNA. These MB activators and regulators, including the main participating proteins (e.g. PGC-1α and mtTFA), are candidates for therapeutic intervention in diverse diseases, like neurodegenerative disorders, metabolic syndrome, sarcopenia, cardiac pathophysiology and physiological processes like aging. In this review, we analyze the implication of MB in several diseases in which the MB pathway is affected. Furthermore, we describe therapeutical interventions on MB targets to boost MB for the prevention and treatment of human diseases. Furthermore, evidence based results and the knowledge gained during last years for some of these drugs aim us hypothesize about the value of a given treatment involved in the activation of MB.
Mice models of Alzheimer's disease (APP/PS1) typically experience cognitive decline with age. G6PD overexpressing mice (G6PD-Tg) exhibit better protection from age-associated functional decline ...including improvements in metabolic and muscle functions as well as reduced frailty compared to their wild-type counterparts. Importantly G6PD-Tg mice show diminished accumulation of DNA oxidation in the brain at different ages in both males and females. To further explore the potential benefits of modulating the G6PD activity in neurodegenerative diseases, triple transgenic mice (3xTg G6PD) were generated, overexpressing APP, PSEN1, and G6PD genes. The cognitive decline characteristic of APP/PS1 mice was prevented in 3xTg G6PD mice, despite similar amyloid-β (Aβ) levels in the hippocampus. This challenges the dominant hypothesis in Alzheimer's disease (AD) etiology and the majority of therapeutic efforts in the field, based on the notion that Aβ is pivotal in cognitive preservation.
Notably, the antioxidant properties of G6PD led to a decrease in oxidative stress parameters, such as improved GSH/GSSG and GSH/CysSSG ratios, without major changes in oxidative damage markers. Additionally, metabolic changes in 3xTg G6PD mice increased brain energy status, countering the hypometabolism observed in Alzheimer's models. Remarkably, a higher respiratory exchange ratio suggested increased carbohydrate utilization. The relative failures of Aβ-targeted clinical trials have raised significant skepticism on the amyloid cascade hypothesis and whether the development of Alzheimer's drugs has followed the correct path. Our findings highlight the significance of targeting glucose-metabolizing enzymes rather than solely focusing on Aβ in Alzheimer's research, advocating for a deeper exploration of glucose metabolism's role in cognitive preservation.
The beneficial effects of exercise have been well recognized for over half a century. Dr Jeremy Morris's pioneering studies in the fifties showed a striking difference in cardiovascular disease ...between the drivers and conductors on the double‐decker buses in London. These studies sparked off a vast amount of research on the effects of exercise in health, and the general consensus is that exercise contributes to improved outcomes and treatment for several diseases including osteoporosis, diabetes, depression and atherosclerosis. Evidence of the beneficial effects of exercise is reviewed here. One way of highlighting the impact of exercise on disease is to consider it from the perspective of good practice. However, the intensity, duration, frequency (dosage) and counter indications of the exercise should be taken into consideration to individually tailor the exercise programme. An important case of the beneficial effect of exercise is that of ageing. Ageing is characterized by a loss of homeostatic mechanisms, on many occasions leading to the development of frailty, and hence frailty is one of the major geriatric syndromes and exercise is very useful to mitigate, or at least delay, it. Since exercise is so effective in reducing frailty, we would like to propose that exercise be considered as a supplement to other treatments. People all over the world have been taking nutritional supplements in the hopes of improving their health. We would like to think of exercise as a physiological supplement not only for treating diseases, but also for improving healthy ageing.
Exercise is a physiological supplement not only for treating diseases but also for improving healthy ageing.
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