Effects of Aging, Long-Term and Lifelong Exercise on the Urinary Metabolic Footprint of Rats.

Life expectancy has risen in the past decades, resulting in an increase in the number of aged individuals. Exercise remains one of the most cost-effective treatments against disease and the physical consequences of aging. The purpose of this research was to investigate the effects of aging, long-term and lifelong exercise on the rat urinary metabolome. Thirty-six male Wistar rats were divided into four equal groups: exercise from 3 to 12 months of age (A), lifelong exercise from 3 to 21 months of age (B), no exercise (C), and exercise from 12 to 21 months of age (D). Exercise consisted in swimming for 20 min/day, 5 days/week. Urine samples collection was performed at 3, 12 and 21 months of life and their analysis was conducted by liquid chromatography-mass spectrometry. Multivariate analysis of the metabolite data did not show any discrimination between groups at any of the three aforementioned ages. However, multivariate analysis discriminated the three ages clearly when the groups were treated as one. Univariate analysis showed that training increased the levels of urinary amino acids and possibly protected against sarcopenia, as evidenced by the higher levels of creatine in the exercising groups. Aging was accompanied by decreased levels of urinary amino acids and signs of increased glycolysis. Concluding, both aging and, to a lesser degree, exercise affected the rat urinary metabolome, including metabolites related to energy metabolism, with exercise showing a potential to mitigate the consequences of aging.

Exercise in the management of obesity.

Obesity is a multifactorial disease with increasing incidence and burden on societies worldwide. Obesity can be managed through everyday behavioral changes involving energy intake and energy expenditure. Concerning the latter, there is strong evidence that regular exercise contributes to body weight and fat loss, maintenance of body weight and fat reduction, and metabolic fitness in obesity. Appropriate exercise programs should ideally combine large negative energy balance, long-term adherence, and beneficial effects on health and well-being. Endurance training appears to be the most effective in this respect, although resistance training and high-intensity interval training play distinct roles in the effectiveness of exercise interventions. With weight regain being so common, weight loss maintenance is probably the greatest challenge in the successful treatment of obesity. There is an established association between higher levels of physical activity and greater weight loss maintenance, based on the abundance of evidence from prospective observational studies and retrospective analyses. However, proving a causative relationship between exercise and weight loss maintenance is difficult at present. Exercise has the potential to alleviate the health consequences of obesity, even in the absence of weight loss. All in all, exercise constitutes an indispensable, yet often underestimated, tool in the management of obesity.

Comparison of the Serum Metabolic Fingerprint of Different Exercise Modes in Men with and without Metabolic Syndrome.

Exercise plays a beneficial role in the treatment of metabolic syndrome (MetS). Metabolomics can provide new insights and facilitate the optimization of exercise prescription. This study aimed to investigate whether the response of the human serum metabolic fingerprint to exercise depends on exercise mode or the presence of MetS. Twenty-three sedentary men (nine with MetS and fourteen healthy) completed four trials: Resting, high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE). Blood samples were collected pre-exercise, immediately after exercise, and 1 h post-exercise for targeted metabolomic analysis in serum by liquid chromatography-mass spectrometry. Time exerted the strongest differentiating effect, followed by exercise mode. The largest changes from baseline were found in the immediate post-exercise samples. RE caused the strongest responses overall, followed by HIIE, while CME had minimal effect. Unlike previous results in urine, no valid model could separate the two groups in serum. Exercise exerted a beneficial effect on prominent serum biomarkers of metabolic risks, such as branched-chain amino acids, alanine, acetylcarnitine, choline, and betaine. These findings contribute to the ongoing research efforts to map the molecular responses to exercise and to optimize exercise guidelines for individuals at cardiometabolic risk.

Metabolomics in Human Acute-Exercise Trials: Study Design and Preparation.

Metabolomics can be of great value in the study of exercise metabolism. However, because of the high intraindividual and interindividual biological variability of the human metabolome, special considerations should be taken into account when designing an acute-exercise metabolomic study. To study different exercise parameters, e.g., different exercise modes, intensities, etc., a crossover study design, where each participant acts as their own control, is preferable to a parallel design, one involving different groups of participants. Moreover, the study should include a no exercise, control trial. Before each trial, participants should follow carefully designed preparatory steps to control for possible confounding factors, i.e., maintain repeatable and constant conditions for all individual trials of the study to minimize variation due to factors other than the one(s) being studied. This chapter focuses on the design of human metabolomic studies, where the intervention is an acute metabolic challenge, such as an exercise bout or a test meal, and presents some basic steps for screening potential participants, performing preliminary tests, preparing for the trial day, and performing the trial.

Physiology of Activins/Follistatins: Associations With Metabolic and Anthropometric Variables and Response to Exercise.

Context: Clinical trials are evaluating the efficacy of inhibitors of the myostatin pathway in neuromuscular and metabolic diseases. Activins and follistatins are major regulators of the myostatin pathway, but their physiology in relation to metabolic and anthropometric variables and in response to exercise remains to be fully elucidated in humans. Objective: We investigated whether concentrations of circulating activin A, activin B, follistatin, and follistatin-like 3 (FSTL3) are associated with anthropometric and metabolic variables and whether they are affected by exercise. Design: Activin A, activin B, follistatin, and FSTL3 were measured in (1) 80 subjects divided according to age (young vs old) and fitness status (active vs sedentary) before and after exercise at 70% maximal oxygen consumption (VO2max), followed by 90% of VO2max until exhaustion; and (2) 23 subjects [9 healthy and 14 with metabolic syndrome (MetS)] who completed four sessions: no exercise, high-intensity interval exercise, continuous moderate-intensity exercise, and resistance exercise for up to 45 minutes. Results: At baseline, follistatin and FSTL3 concentrations were positively associated with age, fat percentage, and body mass index (P < 0.001). Follistatin was positively associated with serum cholesterol (P = 0.005), low-density lipoprotein cholesterol (P = 0.01), triglycerides (P = 0.033), and blood pressure (P = 0.019), whereas activin A and activin B were higher in physically active participants (P = 0.056 and 0.029, respectively). All exercise types increased the levels of all hormones ∼10% to 21% (P = 0.034 for activin B, P < 0.001 for the others) independent of the presence of MetS. Conclusion: Concentrations of circulating activins and follistatins are associated with metabolic parameters and increase after 45 minutes of exercise.

Propranolol and Oxandrolone Therapy Accelerated Muscle Recovery in Burned Children.

INTRODUCTION: Severe burns result in prolonged hypermetabolism and skeletal muscle catabolism. Rehabilitative exercise training (RET) programs improved muscle mass and strength in severely burned children. The combination of RET with ß-blockade or testosterone analogs showed improved exercise-induced benefits on body composition and muscle function. However, the effect of RET combined with multiple drug therapy on muscle mass, strength, cardiorespiratory fitness, and protein turnover are unknown. In this placebo-controlled randomized trial, we hypothesize that RET combined with oxandrolone and propranolol (Oxprop) will improve muscle mass and function and protein turnover in severely burned children compared with burned children undergoing the same RET with a placebo. METHODS: We studied 42 severely burned children (7-17 yr) with severe burns over 30% of the total body surface area. Patients were randomized to placebo (22 control) or to Oxprop (20) and began drug administration within 96 h of admission. All patients began RET at hospital discharge as part of their standardized care. Muscle strength (N·m), power (W), V˙O2peak, body composition, and protein fractional synthetic rate and fractional breakdown rate were measured pre-RET (PRE) and post-RET (POST). RESULTS: Muscle strength and power, lean body mass, and V˙O2peak increased with RET in both groups (P < 0.01). The increase in strength and power was significantly greater in Oxprop versus control (P < 0.01), and strength and power was greater in Oxprop over control POST (P < 0.05). Fractional synthetic rate was significantly higher in Oxprop than control POST (P < 0.01), resulting in improved protein net balance POST (P < 0.05). CONCLUSIONS: Rehabilitative exercise training improves body composition, muscle function, and cardiorespiratory fitness in children recovering from severe burns. Oxprop therapy augments RET-mediated improvements in muscle strength, power, and protein turnover.

Effects of Different Exercise Modes on the Urinary Metabolic Fingerprint of Men with and without Metabolic Syndrome.

Exercise is important in the prevention and treatment of the metabolic syndrome (MetS), a cluster of risk factors that raises morbidity. Metabolomics can facilitate the optimization of exercise prescription. This study aimed to investigate whether the response of the human urinary metabolic fingerprint to exercise depends on the presence of MetS or exercise mode. Twenty-three sedentary men (MetS, n = 9, and Healthy, n = 14) completed four trials: resting, high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE). Urine samples were collected pre-exercise and at 2, 4, and 24 h for targeted analysis by liquid chromatography-mass spectrometry. Time exerted the strongest differentiating effect, followed by exercise mode and health status. The greatest changes were observed in the first post-exercise samples, with a gradual return to baseline at 24 h. RE caused the greatest responses overall, followed by HIIE, while CME had minimal effect. The metabolic fingerprints of the two groups were separated at 2 h, after HIIE and RE; and at 4 h, after HIIE, with evidence of blunted response to exercise in MetS. Our findings show diverse responses of the urinary metabolic fingerprint to different exercise modes in men with and without metabolic syndrome.

Irisin in response to exercise in humans with and without metabolic syndrome.

CONTEXT: Irisin is a recently identified exercise-induced myokine. However, the circulating levels of irisin in response to different types of exercise in subjects with metabolic syndrome are unknown. OBJECTIVE: This study aimed to study the levels of irisin in healthy males and subjects with metabolic syndrome at baseline and in response to exercise. DESIGN: Each individual completed high-intensity interval exercise (HIIE), continuous moderate-intensity exercise (CME), and resistance exercise (RE) sessions in a random, crossover design. Percentage change in circulating irisin levels was examined. Two different irisin assays were used to compare the results of the RE study. RESULTS: Circulating irisin increased immediately after HIIE, CME, and RE and declined 1 hour later. The increase was greater in response to resistance compared with either high-intensity intermittent exercise or CME. Change in irisin in response to exercise did not differ between individuals with and without metabolic syndrome. CONCLUSIONS: Exercise is able to increase circulating irisin levels in individuals with the metabolic syndrome as well as healthy individuals. Whether this increase may contribute to the beneficial effects of exercise on patients with the metabolic syndrome remains to be studied further.

Exercise-induced irisin secretion is independent of age or fitness level and increased irisin may directly modulate muscle metabolism through AMPK activation.

CONTEXT: Irisin has been proposed to be a myokine mediating the effect of exercise on adipocyte browning. The physiology of irisin in humans is not completely understood. OBJECTIVE: To study the physiology of irisin in healthy individuals with different age and fitness levels and to explore the direct effects of irisin on muscle metabolism. DESIGN, SETTING, AND SUBJECTS: Treadmill exercise studies were conducted to measure circulating irisin at baseline and in response to exercise among old and young, physically active and sedentary individuals. Also, high- and moderate-intensity swimming was performed in adolescent men and women to study the effect of exercise intensity and the time course of irisin induction by acute bouts of exercise. Human myotubes were treated with recombinant irisin, and the effect on gene expression, cell signaling, and metabolism was examined. RESULTS: Baseline circulating irisin was lower in old (vs young) and physically active (vs sedentary) subjects. Despite differences in basal levels, the percentage increase of irisin by acute bouts of exercise was not related to age or fitness level. The time course study revealed that circulating irisin increased immediately after high-intensity interval exercise and declined 1 hour thereafter. In vitro experiments showed that irisin facilitates glucose and lipid metabolism in human muscle through AMP kinase phosphorylation. CONCLUSIONS: Despite the differences in basal irisin levels, exercise-induced irisin secretion is independent of age or fitness level. Increased irisin can directly modulate muscle metabolism through AMP kinase activation.

Circulating irisin in healthy, young individuals: day-night rhythm, effects of food intake and exercise, and associations with gender, physical activity, diet, and body composition.

CONTEXT: The myokine irisin may increase energy expenditure and affect metabolism. OBJECTIVE: The objective of the study was to elucidate predictors of irisin and study whether circulating irisin may have day-night rhythm in humans. DESIGN: This was an observational, cross-sectional study with an additional 24-hour prospective observational arm (day-night rhythm substudy) and two prospective interventional arms (mixed meal substudy and exercise substudy). SETTING: The study was conducted at the Hellenic Military School of Medicine (Thessaloniki, Greece). PATIENTS AND INTERVENTIONS: One hundred twenty-two healthy, young individuals were subjected to anthropometric and body composition measurements, and their eating and exercise behavior profiles were assessed with validated questionnaires. Subgroups were subjected to day-night rhythm, standardized meal ingestion, and 30-minute aerobic exercise studies. MAIN OUTCOME MEASURES: Circulating irisin levels were measured. RESULTS: Ιrisin levels were lower in males than females (P = .02) after adjustment for lean body mass, which was its major determinant. Irisin levels followed a day-night rhythm (P < .001) with peak at 9:00 pm. Irisin levels were increased at the end of exercise (84.1 ± 10.0 vs 105.8 ± 14.3 ng/mL; P < .001). Irisin levels were not affected by intake of a standardized meal and were not associated with caloric intake or diet quality. CONCLUSIONS: In healthy, young individuals, circulating irisin displays a day-night rhythm, is correlated with lean body mass, and increases acutely after exercise.

Acute effects of exercise and calorie restriction on triglyceride metabolism in women.

PURPOSE: The mechanisms by which exercise reduces fasting plasma triglyceride (TG) concentrations in women and the effect of negative energy balance independent of muscular contraction are not known.The aim of this study was to evaluate the effects of equivalent energy deficits induced by exercise or calorie restriction on basal VLDL-TG metabolism in women. METHODS: Eleven healthy women (age = 23.5 ± 2.7 yr, body mass index = 21.6 ± 1.4 kg·m-2; mean ± SD) underwent a stable isotopically labeled tracer infusion study to determine basal VLDL-TG kinetics after performing, in random order, three experimental trials on the previous day: (i) a single exercise bout (brisk walking at 60% of peak oxygen consumption for 123 ± 18 min, with a net energy expenditure of 2.06 ± 0.39 MJ, ∼500 kcal), (ii) dietary energy restriction of 2.10 ± 0.41 MJ, and (iii) a control day of isocaloric feeding and rest (zero energy balance). RESULTS: Fasting plasma VLDL-TG concentration was approximately 30% lower after the exercise trial compared with the control trial (P < 0.001), whereas no significant change was detected after the calorie restriction trial (P = 0.297 vs control). Relative to the control condition, exercise increased the plasma clearance rate of VLDL-TG by 22% (P = 0.001) and reduced hepatic VLDL-TG secretion rate by approximately 17% (P = 0.042), whereas hypocaloric diet had no effect on VLDL-TG kinetics (P > 0.2). CONCLUSION: (i) Exercise-induced hypotriglyceridemia in women manifests through a different mechanism (increased clearance and decreased secretion of VLDL-TG) than that previously described in men (increased clearance of VLDL-TG only), and (ii) exercise affects TG homeostasis by eliciting changes in VLDL-TG kinetics that cannot be reproduced by an equivalent diet-induced energy deficit, indicating that these changes are independent of the exercise-induced negative energy balance but instead are specific to muscular contraction.