The complexity of human DNA has been affected by aerobic metabolism, including endurance exercise and oxygen toxicity. Aerobic endurance exercise could play an important role in the evolution of Homo sapiens, and oxygen was not important just for survival, but it was crucial to redox-mediated adaptation. The metabolic challenge during physical exercise results in an elevated generation of reactive oxygen species (ROS) that are important modulators of muscle contraction, antioxidant protection, and oxidative damage repair, which at moderate levels generate physiological responses. Several factors of mitochondrial biogenesis, such as peroxisome proliferator-activated receptor-c coactivator 1a (PGC-1a), mitogen-activated protein kinase, and SIRT1, are modulated by exercise-associated changes in the redox milieu. PGC-1a activation could result in decreased oxidative challenge, either by upregulation of antioxidant enzymes and/or by an increased number of mitochondria that allows lower levels of respiratory activity for the same degree of ATP generation. Endogenous thiol antioxidants glutathione and thioredoxin are modulated with high oxygen consumption and ROS generation during physical exercise, controlling cellular function through redox-sensitive signaling and proteinprotein interactions. Endurance exercise-related angiogenesis, up to a significant degree, is regulated by ROSmediated activation of hypoxia-inducible factor 1a. Moreover, the exercise-associated ROS production could be important to DNA methylation and post-translation modifications of histone residues, which create heritable adaptive conditions based on epigenetic features of chromosomes. Accumulating data indicate that exercise with moderate intensity has systemic and complex health-promoting effects, which undoubtedly involve regulation of redox homeostasis and signaling. Antioxid. Redox Signal. 18, 1208Signal. 18, -1246

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Silent information regulators are potent NAD + -dependent protein deacetylases, which have been shown to regulate gene silencing, muscle differentiation and DNA damage repair. Here, changes in the level and activity of sirtuin 1 (SIRT1) in response to exercise in groups of young and old rats were studied. There was an age-related increase in SIRT1 level, while exercise training significantly increased the relative activity of SIRT1. A strong inverse correlation was found between the nuclear activity of SIRT1 and the level of acetylated proteins. Exercise training induced SIRT1 activity due to the positive effect of exercise on the activity of nicotinamide phosphoribosyltransferase (NAMPT) and thereby the production of sirtuin-fueling NAD + . Exercise training normalized the age-associated shift in redox balance, since exercised animals had significantly lower levels of carbonylated proteins, expression of hypoxia-inducible factor-1alpha and vascular endothelial growth factor. The ageassociated increase in the level of SIRT6 was attenuated by exercise training. On the other hand, aging did not significantly increase the level of DNA damage, which was in line with the activity of 8-oxoguanine DNA glycosylase, while exercise training increased the level of this enzyme. Regular exercise decelerates the deleterious effects of the aging process via SIRT1-dependent pathways through the stimulation of NAD + biosynthesis by NAMPT.

According to our hypothesis, delayed onset muscle soreness (DOMS) is an acute compression axonopathy of the nerve endings in the muscle spindle. It is caused by the superposition of compression when repetitive eccentric contractions are executed under cognitive demand. The acute compression axonopathy could coincide with microinjury of the surrounding tissues and is enhanced by immune-mediated inflammation. DOMS is masked by sympathetic nervous system activity at initiation, but once it subsides, a safety mode comes into play to prevent further injury. DOMS becomes manifest when the microinjured non-nociceptive sensory fibers of the muscle spindle stop inhibiting the effects of the microinjured, hyperexcited nociceptive sensory fibers, therefore providing the ‘open gate’ in the dorsal horn to hyperalgesia. Reactive oxygen species and nitric oxide play a cross-talking role in the parallel, interlinked degeneration–regeneration mechanisms of these injured tissues. We propose that the mitochondrial electron transport chain generated free radical involvement in the acute compression axonopathy. ‘Closed gate exercises’ could be of nonpharmacological therapeutic importance, because they reduce neuropathic pain in addition to having an anti-inflammatory effect. Finally, DOMS could have an important ontogenetical role by not just enhancing ability to escape danger to survive in the wild, but also triggering muscle growth.

Alzheimer's disease (AD) is a progressive neurodegenerative disorder affecting the elderly population. It is predicted that the incidence of AD will be increased in the future making this disease one of the greatest medical, social, and economic challenges for individuals, families, and the health care system worldwide. The etiology of AD is multifactorial. It features increased oxidative state and deposition of amyloid plaques and neurofibrillary tangles of protein tau in the central cortex and limbic system of the brain. Here we provide an overview of the positive impacts of exercise on this challenging disease. Regular physical activity increases the endurance of cells and tissues to oxidative stress, vascularization, energy metabolism, and neurotrophin synthesis, all important in neurogenesis, memory improvement, and brain plasticity. Although extensive studies are required to understand the mechanism, it is clear that physical exercise is beneficial in the prevention of AD and other age-associated neurodegenerative disorders.