Active paraplegics are protected against exercise-induced oxidative damage through the induction of antioxidant enzymes.

STUDY DESIGN: Experimental study. OBJECTIVES: Exercise improves functional capacity in spinal cord injury (SCI). However, exhaustive exercise, especially when sporadic, is linked to the production of reactive oxygen species that may have a detrimental effect on SCI. We aimed to study the effect of a single bout of exhaustive exercise on systemic oxidative stress parameters and on the expression of antioxidant enzymes in individuals with paraplegia. SETTING: The study was conducted in the Physical Therapy department and the Physical Education and Sports department of the University of Valencia. METHODS: Sixteen paraplegic subjects were submitted to a graded exercise test (GET) until volitional exhaustion. They were divided into active or non-active groups. Blood samples were drawn immediately, 1 and 2 h after the GET. We determined plasma malondialdehyde (MDA) and protein carbonylation as markers of oxidative damage. Antioxidant gene expression (catalase and glutathione peroxidase-GPx) was determined in peripheral blood mononuclear cells. RESULTS: We found a significant increase in plasma MDA and protein carbonyls immediately after the GET (P<0.05). This increment correlated significantly with the lactate levels. Active paraplegics showed lower levels of exercise-induced oxidative damage (P<0.05) and higher exercise-induced catalase (P<0.01) and GPx (P<0.05) gene expression after the GET. CONCLUSIONS: These results suggest that exercise training may be useful in SCI patients to develop systemic antioxidant defenses that may protect them against exercise-induced oxidative damage.

Allopurinol prevents cardiac and skeletal muscle damage in professional soccer players.

Xanthine oxidase (XO), a free radical-generating enzyme, is involved in tissue damage produced during exhaustive exercise. Our aim was to test whether allopurinol, a powerful inhibitor of XO, may be effective in preventing exercise-induced tissue damage in soccer players. Twelve soccer players were randomized into two experimental groups. One received allopurinol, before a match of the premier Spanish Football League, and the other placebo. Allopurinol prevented the exercise-induced increase in all the markers of skeletal muscle damage analyzed: creatine kinase, lactate dehydrogenase, aspartate aminotransferase, and myoglobin. Creatine kinase-MB isoenzyme and highly sensitive troponin T, specific biomarkers of myocardial injury, increased significantly in the placebo but not in the allopurinol-treated group after the football match. We also found that the exercise-induced lipid peroxidation, as reflected by malondialdehyde measurements, was prevented after allopurinol administration. However, inhibition of XO did not prevent the increment in the activity of alanine aminotransferase found after the match. No changes in the serum gamma glutamyltransferase activity was found after the match on either the placebo and the allopurinol groups. These two enzymes were determined as biomarkers of liver injury. Allopurinol represents an effective and inexpensive pharmacological agent to prevent tissue damage in soccer players.

Impact of exercise training on neuroplasticity-related growth factors in adolescents.

OBJECTIVES: We aimed to determine the effect of exercise training on plasma levels of brain-derived neurotrophic factor (BDNF), and serum insulin-like growth factor-1 (IGF-1) as well as cAMP response element-binding (CREB) activation in peripheral blood mononuclear cells (PBMCs) in adolescents. METHODS: Nine trained and seven sedentary male adolescents, matched in age (14.0±2.2 years), were recruited for the study. Trained boys performed higher physical activity levels (expressed both as total energy expenditure and as physical activity energy expenditure) and showed significant bradycardia when compared with sedentary ones. RESULTS: We found that BDNF and IGF-1 levels were significantly higher in trained adolescents than in sedentary ones. However, no effect of training was found in the activation of CREB in PBMCs. CONCLUSIONS: We demonstrated the increase of neuroplasticity-related proteins due to exercise training in adolescents. Our results emphasize the significance and impact of exercise in this developmental period.

Pilot study to determine the association between gut microbiota and fragility hip fracture. / Estudio piloto para determinar la asociación entre la microbiota intestinal y la fractura de cadera por fragilidad.

INTRODUCTION: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. MATERIAL AND METHODS: Observational, analytical, case-control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. RESULTS: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. CONCLUSIONS: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.

[Translated article] Pilot study to determine the association between gut microbiota and fragility hip fracture.

INTRODUCTION: Hip fractures are the most common cause of hospital admission to orthopaedic departments in Europe and they generate a major health problem. Therefore, it is of great interest to identify additional risk factors that will help us to better understand the pathophysiology of these fractures and improve our preventive capacity. There is sufficient data to support the theory of modulation of bone mass by gut microbiota (osteomicrobiology); however, there is a lack of human clinical studies directly linking microbiota to hip fracture risk. MATERIAL AND METHODS: Observational, analytical, case-control study. The sample consisted of 50 patients and it was distributed as follows: 25 elderly patients with fragility hip fracture and 25 subjects without fracture. The intestinal microbiota was determined by DNA extraction from stool samples and 16S ribosomal DNA sequencing after generation of gene libraries. RESULTS: Alpha diversity revealed an elevation of the estimators for the taxonomic class level in the hip fracture group. The orders Bacteroidales, Oscillospirales, Lachnospirales, Peptostreptococcales-Tissierellales and Enterobacterales were the dominant orders in both groups. In patients with fracture, a significant percentage increase in the orders Bacteroidales (p<.001) and Peptostreptococcales-Tissierellales (p<.005) was observed, as well as a decrease in the orders Lachnospirales (p<.001) compared to controls. CONCLUSIONS: This study has found an association between a specific microbiota in elderly patients with fragility hip fracture. These findings open the door to new strategies to prevent hip fractures. Modification of the microbiota through probiotics may prove to be an effective method to reduce the risk of hip fracture.

Increased average longevity among the "Tour de France" cyclists.

It is widely held among the general population and even among health professionals that moderate exercise is a healthy practice but long term high intensity exercise is not. The specific amount of physical activity necessary for good health remains unclear. To date, longevity studies of elite athletes have been relatively sparse and the results are somewhat conflicting. The Tour de France is among the most gruelling sport events in the world, during which highly trained professional cyclists undertake high intensity exercise for a full 3 weeks. Consequently we set out to determine the longevity of the participants in the Tour de France, compared with that of the general population. We studied the longevity of 834 cyclists from France (n=465), Italy (n=196) and Belgium (n=173) who rode the Tour de France between the years 1930 and 1964. Dates of birth and death of the cyclists were obtained on December 31 (st) 2007. We calculated the percentage of survivors for each age and compared them with the values for the pooled general population of France, Italy and Belgium for the appropriate age cohorts. We found a very significant increase in average longevity (17%) of the cyclists when compared with the general population. The age at which 50% of the general population died was 73.5 vs. 81.5 years in Tour de France participants. Our major finding is that repeated very intense exercise prolongs life span in well trained practitioners. Our findings underpin the importance of exercising without the fear that becoming exhausted might be bad for one's health.

Effect of xanthine oxidase-generated extracellular superoxide on skeletal muscle force generation.

Skeletal muscle contractions increase superoxide anion in skeletal muscle extracellular space. We tested the hypotheses that 1) after an isometric contraction protocol, xanthine oxidase (XO) activity is a source of superoxide anion in the extracellular space of skeletal muscle and 2) the increase in XO-derived extracellular superoxide anion during contractions affects skeletal muscle contractile function. Superoxide anion was monitored in the extracellular space of mouse gastrocnemius muscles by following the reduction of cytochrome c in muscle microdialysates. A 15-min protocol of nondamaging isometric contractions increased the reduction of cytochrome c in microdialysates, indicating an increase in superoxide anion. Mice treated with the XO inhibitor oxypurinol showed a smaller increase in superoxide anions in muscle microdialysates following contractions than in microdialysates from muscles of vehicle-treated mice. Intact extensor digitorum longus (EDL) and soleus muscles from mice were also incubated in vitro with oxypurinol or polyethylene glycol-tagged Cu,Zn-SOD. Oxypurinol decreased the maximum tetanic force produced by EDL and soleus muscles, and polyethylene glycol-tagged Cu,Zn-SOD decreased the maximum force production by the EDL muscles. Neither agent influenced the rate of decline in force production when EDL or soleus muscles were repeatedly electrically stimulated using a 5-min fatiguing protocol (stimulation at 40 Hz for 0.1 s every 5 s). Thus these studies indicate that XO activity contributes to the increased superoxide anion detected within the extracellular space of skeletal muscles during nondamaging contractile activity and that XO-derived superoxide anion or derivatives of this radical have a positive effect on muscle force generation during isometric contractions of mouse skeletal muscles.

Desmopresssin and hemodilution: implications in doping.

Blood doping improves physical performance in sport. This is the reason why the antidoping authorities subject athletes to blood tests. Plasma volume expanders are prohibited agents used to reduce an artificial increase in hematological values using different illegal practices. The aim of our study was to test whether desmopressin (DDAVP)-induced hemodilution would alter the concentration of hematological parameters used to detect blood doping in sports. This was an intra-subject crossover study. Venous blood samples were obtained from eight physically active males on two occasions. On the first occasion the subjects ingested 1.5 L of mineral water and 4.3 microg/kg of DDAVP. On the second occasion the subjects ingested 1.5 L of mineral water. The samples were analyzed for hematocrit, hemoglobin, reticulocytes, OFF Hr-Score, glucose, albumin, creatinine and total proteins. After treatment with DDAVP we found a significant decrease in the hematocrit, hemoglobin and in the OFF Hr-Score values. We also found a significant decrease in glucose, albumin, creatinine and total proteins concentration; however, in this case, all the values were significantly below the physiological levels. Treatment with DDAVP has a very effective hemodilution effect. We consider that this substance should be included in the WADA's prohibited list.

Redox modulation of muscle mass and function.

Muscle mass and strength are very important for exercise performance. Training-induced musculoskeletal injuries usually require periods of complete immobilization to prevent any muscle contraction of the affected muscle groups. Disuse muscle wasting will likely affect every sport practitioner in his or her lifetime. Even short periods of disuse results in significant declines in muscle size, fiber cross sectional area, and strength. To understand the molecular signaling pathways involved in disuse muscle atrophy is of the utmost importance to develop more effective countermeasures in sport science research. We have divided our review in four different sections. In the first one we discuss the molecular mechanisms involved in muscle atrophy including the main protein synthesis and protein breakdown signaling pathways. In the second section of the review we deal with the main cellular, animal, and human atrophy models. The sources of reactive oxygen species in disuse muscle atrophy and the mechanism through which they regulate protein synthesis and proteolysis are reviewed in the third section of this review. The last section is devoted to the potential interventions to prevent muscle disuse atrophy with especial consideration to studies on which the levels of endogenous antioxidants enzymes or dietary antioxidants have been tested.

Sarcopenia, frailty and their prevention by exercise.

Sarcopenia is a major component of the frailty syndrome, both being considered as strong predictors of morbidity, disability, and death in older people. In this review, we explore the definitions of sarcopenia and frailty and summarize the current knowledge on their relationship with oxidative stress and the possible therapeutic interventions to prevent or treat them, including exercise-based interventions and multimodal strategies. We highlight the relevance of the impairment of the nervous system and of the anabolic response (protein synthesis) in muscle aging leading to frailty and sarcopenia. We also discuss the importance of malnutrition and physical inactivity in these geriatric syndromes. Finally, we propose multimodal interventions, including exercise programs and nutritional supplementation, as the strategies to prevent and treat both sarcopenia and frailty.

Reversal of age-associated frailty by controlled physical exercise: The pre-clinical and clinical evidences.

Demographic aging is one of the most serious challenges facing our society. Although we live longer, we do not live better because it is considered that approximately 16-20% of our life is spent in late-life morbidity. Older people have the greatest risk of developing frailty increasing the risk of presenting various adverse health events such as low quality of life, disability, hospitalization and even death. Frail men and women over 65 years old have lower muscle quality and muscle mass and higher percentage of body fat than non-frail people of the same age. In this review we will address the main physiological changes in the muscular and nervous system associated to aging. More specifically we will review the changes in muscle mass, quality, and strength relating them with the decrease in capillarization and muscular oxidative capacity as well as with the alterations in protein synthesis in the muscle with aging. The last section of the manuscript will be devoted to the animal models of frailty and the indexes developed to measure frailty in these models. We will finally address the importance of exercise training as an intervention to delay or even reverse frailty.

Acute exercise activates nuclear factor (NF)-kappaB signaling pathway in rat skeletal muscle.

Two studies were performed to investigate the effects of an acute bout of physical exercise on the nuclear protein kappaB (NF-kappaB) signaling pathway in rat skeletal muscle. In Study 1, a group of rats (n=6) was run on the treadmill at 25 m/min, 5% grade, for 1 h or until exhaustion (Ex), and compared with a second group (n=6) injected with two doses of pyrrolidine dithiocarbamate (PDTC, 100 mg/kg, i.p.) 24 and 1 h prior to the acute exercise bout. Three additional groups of rats (n=6) were injected with either 8 mg/kg (i.p.) of lipopolysaccharide (LPS), 1 mmol/kg (i.p.) t-butylhydroperoxide (tBHP), or saline (C) and killed at resting condition. Ex rats showed higher levels of NF-kappaB binding and P50 protein content in muscle nuclear extracts compared with C rats. Cytosolic IkappaBalpha and IkappaB kinase (IKK) contents were decreased, whereas phospho-IkappaBalpha and phospho-IKK contents were increased, comparing Ex vs. C. The exercise-induced activation of NF-kappaB signaling cascade was partially abolished by PDTC treatment. LPS, but not tBHP, treatment mimicked and exaggerated the effects observed in Ex rats. In Study 2, the time course of exercise-induced NF-kappaB activation was examined. Highest levels of NF-kappaB binding were observed at 2 h postexercise. Decreased cytosolic IkappaBalpha and increased phosphor-IkappaBalpha content were found 0-1 h postexercise whereas P65 reached peak levels at 2-4 h. These data suggest that the NF-kappaB signaling pathway can be activated in a redox-sensitive manner during muscular contraction, presumably due to increased oxidant production. The cascade of intracellular events may be the overture to elevated gene expression of manganese superoxide dismutase reported earlier (Pfluegers Arch. 442, 426-434, 2001).

Properties of Resveratrol: In Vitro and In Vivo Studies about Metabolism, Bioavailability, and Biological Effects in Animal Models and Humans.

Plants containing resveratrol have been used effectively in traditional medicine for over 2000 years. It can be found in some plants, fruits, and derivatives, such as red wine. Therefore, it can be administered by either consuming these natural products or intaking nutraceutical pills. Resveratrol exhibits a wide range of beneficial properties, and this may be due to its molecular structure, which endow resveratrol with the ability to bind to many biomolecules. Among these properties its activity as an anticancer agent, a platelet antiaggregation agent, and an antioxidant, as well as its antiaging, antifrailty, anti-inflammatory, antiallergenic, and so forth activities, is worth highlighting. These beneficial biological properties have been extensively studied in humans and animal models, both in vitro and in vivo. The issue of bioavailability of resveratrol is of paramount importance and is determined by its rapid elimination and the fact that its absorption is highly effective, but the first hepatic step leaves little free resveratrol. Clarifying aspects like stability and pharmacokinetics of resveratrol metabolites would be fundamental to understand and apply the therapeutic properties of resveratrol.

Growth hormone replacement therapy prevents sarcopenia by a dual mechanism: improvement of protein balance and of antioxidant defenses.

The aim of our study was to elucidate the role of growth hormone (GH) replacement therapy in three of the main mechanisms involved in sarcopenia: alterations in mitochondrial biogenesis, increase in oxidative stress, and alterations in protein balance. We used young and old Wistar rats that received either placebo or low doses of GH to reach normal insulin-like growth factor-1 values observed in the young group. We found an increase in lean body mass and plasma and hepatic insulin-like growth factor-1 levels in the old animals treated with GH. We also found a lowering of age-associated oxidative damage and an induction of antioxidant enzymes in the skeletal muscle of the treated animals. GH replacement therapy resulted in an increase in the skeletal muscle protein synthesis and mitochondrial biogenesis pathways. This was paralleled by a lowering of inhibitory factors in skeletal muscle regeneration and in protein degradation. GH replacement therapy prevents sarcopenia by acting as a double-edged sword, antioxidant and hypertrophic.

Exercise acts as a drug; the pharmacological benefits of exercise.

The beneficial effects of regular exercise for the promotion of health and cure of diseases have been clearly shown. In this review, we would like to postulate the idea that exercise can be considered as a drug. Exercise causes a myriad of beneficial effects for health, including the promotion of health and lifespan, and these are reviewed in the first section of this paper. Then we deal with the dosing of exercise. As with many drugs, dosing is extremely important to get the beneficial effects of exercise. To this end, the organism adapts to exercise. We review the molecular signalling pathways involved in these adaptations because understanding them is of great importance to be able to prescribe exercise in an appropriate manner. Special attention must be paid to the psychological effects of exercise. These are so powerful that we would like to propose that exercise may be considered as a psychoactive drug. In moderate doses, it causes very pronounced relaxing effects on the majority of the population, but some persons may even become addicted to exercise. Finally, there may be some contraindications to exercise that arise when people are severely ill, and these are described in the final section of the review. Our general conclusion is that exercise is so effective that it should be considered as a drug, but that more attention should be paid to the dosing and to individual variations between patients.

Epigenetic biomarkers: A new perspective in laboratory diagnostics.

Epigenetics comprises the study of chemical modifications in the DNA and histones that regulates the gene expression or cellular phenotype. However, during the last decade this term has evolved after the elucidation of different mechanisms (microRNAs and nuclear organization of the chromosomes) involved in regulating gene expression. Epigenetics and the new designed technologies capable to analyze epigenetic changes (e.g., methylated DNA, miRNAs expression, post-translational modifications on histones among others) have disclosed an appealing scenario that will offer for the biomedical sciences new biomarkers for the study of neurodegenerative diseases, multifactorial complex diseases, rare diseases and cancer. Moreover, new technologies adapted for epigenetic studies will offer promising applications that in the next years will be common technologies in clinical laboratories. In this review we discuss epigenetic modifications used as possible biomarkers in several diseases. We also present the potential of methodologies to purify histones, and high throughput technologies as candidates to be set in clinical laboratories for their high potential analyzing epigenetic processes.

Effects of chronic exercise on myocardial refractoriness: a study on isolated rabbit heart.

AIM: To determine whether chronic physical training increases atrial and ventricular refractoriness in isolated rabbit heart. METHODS: Trained rabbits were submitted to a protocol of treadmill running. The electrophysiological parameters of refractoriness investigated in an isolated heart preparation were: (1) atrial effective refractory period (AERP) and atrial functional refractory period and ventricular effective and functional refractory periods (VERP and VFRP) using the extrastimulus technique at four different pacing cycle lengths; (2) the dominant frequency (DF) of ventricular fibrillation (VF). A multi-electrode plaque containing 256 electrodes and a spectral method were used to obtain the mean, maximum and minimum DF of VF. Sinus cycle length of the isolated hearts was determined as an electrophysiological parameter of training. In vivo heart rate, myocardial heat shock proteins (HSP60) and inducible nitric oxide synthase were also determined in some animals as electrophysiological and biochemical markers of training respectively. RESULTS: VERP and VFRP were longer in the trained group than in the control group. The mean DF of VF was lower in the trained group than in the control group. Despite the fact that training did not significantly modify the AERP, it tended to be longer in the trained group (P = 0.09). CONCLUSION: Training seems to increase the electrical stability of ventricular myocardium. As the electrophysiological modifications were exhibited in hearts not submitted to extrinsic nervous system or humoral influences, they are, at least in part, intrinsic modifications. These electrophysiological data also suggest that training could protect against reentrant ventricular arrhythmias.