Maternal heart exhibits metabolic and redox adaptations post-uncomplicated pregnancy.

Pregnancy may be a challenging period for the maternal systems and has been regarded as a stress test, as imperceptible/mild dysfunctions eventually present may be exacerbated during this period. The cardiovascular system is no exception, and several morphological and functional adaptations accompanying pregnancy have been described. However, long-term pregnancy-induced cardiac molecular alterations remain highly unexplored. The postpartum is marked by reverse remodeling of the pregnancy-induced cardiovascular adaptations, representing a possible critical period for assessing future maternal cardiovascular health. The current study explored the molecular and metabolic alterations in the cardiac tissue eight weeks after a physiological uncomplicated pregnancy. Female Sprague-Dawley rats were fed a chow diet through pregnancy, lactation, and weaning and compared to their non-pregnant counterparts. Eight weeks postpartum, increased levels of the phosphorylated form of AMPKα (Thr172) and its ratio to total AMPKα indicated possible alterations in cardiac metabolic flexibility, accompanied by increased Pparα and Hif1α transcripts levels. Additionally, postpartum hearts exhibited higher mitochondrial ATP and NADH levels without major changes in mitochondrial respiratory function. Elevated Nrf2 levels in the cardiac tissue suggested potential implications for cardiac redox balance, further supported by increased levels or activity of proteins directly regulated by Nrf2. The findings herein reported suggest that at eight weeks postpartum, molecular alterations induced by pregnancy, especially regarding redox balance, are still observed in the mothers' heart. These alterations present at late postpartum may open new avenues to understand the different risk for cardiovascular complications development after normal pregnancies.

Exercise Training Benefits Health-Related Quality of Life and Functional Capacity during Breast Cancer Chemotherapy: A Randomized Controlled Trial.

PURPOSE: To examine the effectiveness of a supervised exercise training program (SETP) on health-related quality of life (HRQoL) and functional capacity in women with breast cancer (BC) undergoing chemotherapy. METHODS: Ninety-three women with early-stage BC were randomly allocated to a SETP plus usual care (exercise, n = 47) or usual care alone (UC, n = 46). The SETP included three sessions per week, combining aerobic and resistance training, conducted concurrently over the chemotherapy. The EORTC Cancer Quality-of-Life-Questionnaire-Core-30 (QLQ-C30) and the BC-specific module (QLQ-BR23) were used to assess HRQoL. Functional capacity was analyzed by maximum voluntary handgrip strength (MVHS) and by the 30-s chair sit-to-stand test (30-s CST). These endpoints were assessed at baseline (t0); middle (t1; after 8 or 12 wk of t0); and at the end of chemotherapy (t2; after 20 wk of t0). Mean changes from baseline were assessed by an intention-to-treat approach. RESULTS: Mixed linear model analyses showed that Exercise group experienced less deterioration in several domains of QLQ-C30 at t2, including in global health status/QoL (Δ = 9.39 units; P = 0.034), QLQ-C30 summary score (Δ = 8.08 units; P < 0.001), physical (Δ = 15.14 units; P < 0.001), role ( Δ = 21.81 units; P < 0.001), cognitive (Δ = 9.16 units; P = 0.032) and social functioning (Δ = 11.67 units; P = 0.038), compared with the UC group. Similarly, Exercise group exhibited significant lower levels of fatigue (Δ = -20.19 units; P < 0.001) and appetite loss (Δ = -13.69 units; P = 0.034), compared with the UC group. Significant between-group differences were observed on MVHS of the tumor/surgery upper limb side (Δ = 2.64 kg; P < 0.001) and contralateral limb (Δ = 2.22 kg; P < 0.001), and on the 30-s CST score (Δ = 3.56repetitions; P < 0.001), favoring the Exercise group. No differences were observed on QLQ-BR23 domains. CONCLUSIONS: Exercise training was an effective complementary therapy to prevent the deterioration of HRQoL and functional capacity during chemotherapy in women with early-stage BC.

Metabolic mitochondrial alterations prevail in the female rat heart 8 weeks after exercise cessation.

BACKGROUND: The consumption of high-caloric diets strongly contributes to the development of non-communicable diseases (NCDs), including cardiovascular disease, the leading cause of mortality worldwide. Exercise (along with diet intervention) is one of the primary non-pharmacological approaches to promote a healthier lifestyle and counteract the rampant prevalence of NCDs. The present study evaluated the effects of exercise cessation after a short period training on the cardiac metabolic and mitochondrial function of female rats. METHODS: Seven-week-old female Sprague-Dawley rats were fed a control or a high-fat, high-sugar (HFHS) diet and, after 7 weeks, the animals were kept on a sedentary lifestyle or submitted to endurance exercise for 3 weeks (6 days per week, 20-60 min/day). The cardiac samples were analysed 8 weeks after exercise cessation. RESULTS: The consumption of the HFHS diet triggered impaired glucose tolerance, whereas the HFHS diet and physical exercise resulted in different responses in plasma adiponectin and leptin levels. Cardiac mitochondrial respiration efficiency was decreased by the HFHS diet consumption, which led to reduced ATP and increased NAD(P)H mitochondrial levels, which remained prevented by exercise 8 weeks after cessation. Exercise training-induced cardiac adaptations in redox balance, namely increased relative expression of Nrf2 and downstream antioxidant enzymes persist after an eight-week exercise cessation period. CONCLUSIONS: Endurance exercise modulated cardiac redox balance and mitochondrial efficiency in female rats fed a HFHS diet. These findings suggest that exercise may elicit cardiac adaptations crucial for its role as a non-pharmacological intervention for individuals at risk of developing NCDs.

Effects of exercise training on cardiac toxicity markers in women with breast cancer undergoing chemotherapy with anthracyclines: a randomized controlled trial.

AIMS: Exercise training has been suggested to prevent anthracycline-related cardiac dysfunction, but clinicalbased evidence is scarce. We investigated the effects of a supervised exercise training programme (SETP) on cardiac toxicity markers in women with breast cancer (BC) receiving anthracycline-containing chemotherapy. METHODS AND RESULTS: Ninety-three women with early-stage breast cancer were randomly allocated to a supervised exercise training programme (SETP) plus usual care group (Exercise, n = 47) or usual care alone group (UC, n = 46). The SETP consisted of three sessions per week, combining aerobic and resistance training, conducted concurrently across the anthracycline-containing chemotherapy length. The primary endpoint was the change in left ventricular ejection fraction (LVEF) from baseline to the end of anthracycline cycles. Secondary endpoints included global longitudinal strain (GLS) and other conventional echocardiographic parameters, cardiorespiratory fitness (estimated peak VO2), circulating biomarkers (NT-proBNP, hs-TnT), and safety of the SETP. The study endpoints were also assessed 3 months after the end of anthracycline cycles. All patients were prescribed four cycles of doxorubicin plus cyclophosphamide (AC). No significant between-group differences in LVEF change were seen at the end of AC [mean difference: 0.7%; 95% confidence interval (CI): -0.8, 2.3; P = 0.349] and 3 months after AC (1.1%; 95% CI: -0.5, 2.6; P = 0.196). Compared to the usual care (UC) group, the estimated peak VO2 increased in the Exercise group at the end of AC (1.6 mL O2·kg-1·min-1; 95% CI: 0.06, 3.1; P = 0.041) and 3 months after AC (3.1 mL O2·kg-1·min-1; 95% CI: 1.4, 4.7; P < 0.001). No between-group differences were found in the remaining secondary endpoints. No serious adverse events were observed during SETP. CONCLUSION: Exercise training was safe during chemotherapy and significantly improved cardiorespiratory fitness. No significant effects were seen on cardiac toxicity markers (LVEF or GLS) as compared to the usual care. TRIAL REGISTRATION: Mama Move Gaia on treatment trial ISRCTN32617901.

Breast cancer patients are often treated with chemotherapy. Despite the clinical benefit, some of these drugs increase the risk of cardiac toxicity and impair patients' cardiorespiratory fitness. Exercise training has been proposed as a preventive approach, but clinical-based evidence is scarce. The results of this trial showed that an exercise training programme, combining aerobic training and resistance training, conducted during chemotherapy, did not significantly attenuate the decline in conventional cardiac function parameters when compared to usual care. However, the results of this trial showed that the training programme was safe and significantly improved cardiorespiratory fitness.

Gestational Exercise Antagonises the Impact of Maternal High-Fat High-Sucrose Diet on Liver Mitochondrial Alterations and Quality Control Signalling in Male Offspring.

Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are relevant modulators of the intrauterine environment, increasing the risk of liver metabolic alterations in mothers and offspring. In contrast, as a non-pharmacological approach against metabolic disorders, exercise is highly recommended in GDM treatment. We analysed whether gestational exercise (GE) protects mothers from diet-induced GDM metabolic consequences and mitigates liver mitochondrial deleterious alterations in their 6-week-old male offspring. Female Sprague Dawley rats were fed with control or high-fat high-sucrose (HFHS) diet and kept sedentary or submitted to GE. Male offspring were sedentary and fed with control diet. Sedentary HFHS mothers and their offspring showed impaired hepatic mitochondrial biogenesis and morphological evidence of mitochondrial remodelling. In contrast, GE-related beneficial effects were demonstrated by upregulation of mitochondrial biogenesis signalling markers and mitochondrial fusion proteins and downregulation of mitochondrial fission protein. Alterations in miR-34a, miR-130b, and miR-494, associated with epigenetic regulation of mitochondrial biogenesis, suggested that GE is a more critical modulator of intergenerational changes in miRs expression than the maternal diet. Our data showed that GE positively modulated the altered hepatic mitochondrial biogenesis and dynamics markers and quality control signalling associated with maternal HFHS-diet-related GDM in mothers and offspring.

Adding protein to a carbohydrate pre-exercise beverage does not influence running performance and metabolism.

BACKGROUND: To analyze whether pre-exercise CHO+PRO vs. CHO intake distinctly influences running performance and metabolic biomarkers along a various of exercise intensities. METHODS: In a randomized, double blind, counterbalanced, crossover and placebo control design, 10 middle distance runners were tested in 3 occasions. After 10 h of fasting, participants ingested isovolumic beverages (0.75+0.25g·BW-1 of CHO+PRO, 1.0g·BW-1 of CHO and placebo control) 30 min before a treadmill running incremental protocol of 4 min steps until exhaustion. Venous blood was collected at fasting, 30 min after beverage ingestion and after the 3rd and 7th running steps. Oxygen uptake-related variables, including respiratory exchange ratio, heart rate, plasma glucose, insulin, glucagon, free fatty acids, blood lactate concentrations, gastrointestinal discomfort and rate of perceived exertion were measured. RESULTS: The addition of PRO to CHO had no influence on the measured variables, which did not differ between conditions along all incremental protocol intensities. The intake of CHO+PRO (compared to CHO) tended to decrease glycemia (106.5±21.3 vs. 113.6±26.5) and to increase insulinemia (14.4±15.1 vs. 12.7±10.8) at intensities close to maximum oxygen uptake. CONCLUSIONS: The addition of PRO to a pre-exercise CHO beverage had no impact on running performance and related metabolic variables at a wide spectrum of exercise intensities.

Recreational futsal provides broad-spectrum fitness and health benefits but no blood pressure effects in men with treated hypertension - a randomised controlled trial.

We determined the coadjuvant effect of a recreational futsal (RF) programme versus standard care alone (CON) in men with treated arterial hypertension (TAHT). Thirty-nine men with TAHT were randomised to RF (N = 20; 48 ± 8 years; systolic blood pressure [SBP]: 122 ± 14 mmHg) with 2-3 one-hour sessions/week for 3 months, or to CON (N = 19; 51 ± 6 years; SBP: 126 ± 13 mmHg). Participants were assessed at baseline, at 3 months, and after 1 month of training cessation (4 months). Mean training attendance was 60 ± 23%. At 3-months, there were no between-group differences in BP parameters (SBP: 0.44 mmHg; 95% CI: -5.79, 6.67). However, compared to CON, RF was effective for peak oxygen uptake (2.76 mL.min-1.kg-1; 95% CI: 0.26, 5.26), time to exhaustion (1.15 min; 95% CI: 0.59, 1.69), Yo-Yo IE1 performance (365 m; 95% CI: 175, 556), resting heart rate (RHR; -5 b.min-1; 95% CI: -10, -1), glycated haemoglobin (-0.52 mmol/L; 95% CI: -0.84, -0.19), blood glucose (-0.25 mmol/L; 95% CI: -0.44, -0.06), left femur bone mineral content (1.96 g; 95% CI: 0.29, 3.65), and postural balance (-2.3 falls; 95% CI: -3.9, -0.6). Similar findings were observed after 1-month of training cessation, except for RHR and blood glucose that returned to baseline levels in the RF group. In conclusion, RF provides broad-spectrum fitness and health benefits but no BP effects in men with TAHT.

Exercise performed during pregnancy positively modulates liver metabolism and promotes mitochondrial biogenesis of female offspring in a rat model of diet-induced gestational diabetes.

Gestational diabetes mellitus (GDM) is associated with a high-risk for metabolic complications in offspring. However, exercise is recognized as a non-pharmacological strategy against metabolic disorders and is recommended in GDM treatment. This study aimed to investigate whether gestational exercise (GE) could modulate maternal high-fat high-sucrose (HFHS) diet-related hepatic metabolic and mitochondrial outcomes in female offspring of mothers with HFHS-induced GDM. Female Sprague-Dawley rats were fed with control or HFHS diet and kept sedentary or submitted to GE. Their female offspring were fed with control diet and kept sedentary. Hepatic lipid accumulation, lipid metabolism regulators, mitochondrial biogenesis and dynamics markers, and microRNAs associated to the regulation of these markers were evaluated. Female offspring of GDM mothers showed increased body weight at early age, whereas GE prevented this effect of maternal HFHS-feeding and reduced hepatic lipid accumulation. GE stimulated hepatic mRNA transcription and protein expression of mitochondrial biogenesis markers (peroxisome proliferator-activated receptor-gamma co-activator-1alpha and mitochondrial transcription factor A) and mRNA transcription of mitochondrial dynamics markers (mitofusin-1, mitofusin-2, and dynamin-related protein-1) that were altered by maternal GDM, while mitochondrial dynamics markers protein expression was not affected by maternal diet/GE except for optic atrophy-1. MicroRNAs associated with these processes (miR-122, miR-34a, miR-130b, miR-494), and the expression of auto/mitophagy- and apoptosis-related proteins were not substantially influenced by altered intrauterine environment. Our findings suggest that GE is an important regulator of the intrauterine environment positively affecting liver metabolism and promoting liver mitochondrial biogenesis in female offspring despite eventual effects of maternal HFHS-feeding and related GDM.

Gestational Exercise Increases Male Offspring's Maximal Workload Capacity Early in Life.

Mothers' antenatal strategies to improve the intrauterine environment can positively decrease pregnancy-derived intercurrences. By challenging the mother-fetus unit, gestational exercise (GE) favorably modulates deleterious stimuli, such as high-fat, high-sucrose (HFHS) diet-induced adverse consequences for offspring. We aimed to analyze whether GE alters maternal HFHS-consumption effects on male offspring's maximal workload performance (MWP) and in some skeletal muscle (the soleus-SOL and the tibialis anterior-TA) biomarkers associated with mitochondrial biogenesis and oxidative fitness. Infant male Sprague-Dawley rats were divided into experimental groups according to mothers' dietary and/or exercise conditions: offspring of sedentary control diet-fed or HFHS-fed mothers (C-S or HFHS-S, respectively) and of exercised HFHS-fed mothers (HFHS-E). Although maternal HFHS did not significantly alter MWP, offspring from GE dams exhibited increased MWP. Lower SOL AMPk levels in HFHS-S were reverted by GE. SOL PGC-1α, OXPHOS C-I and C-IV subunits remained unaltered by maternal diet, although increased in HFHS-E offspring. Additionally, GE prevented maternal diet-related SOL miR-378a overexpression, while upregulated miR-34a expression. Decreased TA C-IV subunit expression in HFHS-S was reverted in HFHS-E, concomitantly with the downregulation of miR-338. In conclusion, GE in HFHS-fed dams increases the offspring's MWP, which seems to be associated with the intrauterine modulation of SM mitochondrial density and functional markers.

Physical exercise positively modulates nonalcoholic steatohepatitis-related hepatic endoplasmic reticulum stress.

Obesity is a predictive factor for the development of nonalcoholic steatohepatitis (NASH). Although some of the mechanisms associated with NASH development are still elusive, its pathogenesis relies on a complex broad spectrum of (interconnected) metabolic-based disorders. We analyzed the effects of voluntary physical activity (VPA) and endurance training (ET), as preventive and therapeutic nonpharmacological strategies, respectively, against hepatic endoplasmic reticulum (ER) stress, ER-related proapoptotic signaling, and oxidative stress in an animal model of high-fat diet (HFD)-induced NASH. Adult male Sprague-Dawley rats were divided into standard control liquid diet (SCLD) or HFD groups, with sedentary, VPA, and ET subgroups in both (sedentary animals with access to SCLD [SS], voluntarily physically active animals with access to SCLD [SV], and endurance-trained animals with access to SCLD [ST] in the former and sedentary animals with access to liquid HFD [HS], voluntarily physically active animals with access to liquid HFD [HV], and endurance-trained animals with access to liquid HFD [HT] in the latter, respectively). Hepatic ER stress and ER-related proapoptotic signaling were evaluated by Western blot and reverse transcriptase-polymerase chain reaction; redox status was evaluated through quantification of lipid peroxidation, protein carbonyls groups, and glutathione levels as well as antioxidant enzymes activity. In SCLD-treated animals, VPA significantly decreased eukaryotic initiation factor-2 alpha (eIF2α). In HFD-treated animals, VPA significantly decreased eIF2α and phospho-inositol requiring enzyme-1 alpha (IRE1α) but ET significantly decreased eIF2α and significantly increased both spliced X-box binding protein 1 (sXBP1) and unspliced X-box binding protein 1; a significant increase of phosphorylated-eIF2α (p-eIF2α) to eIF2α ratio occurred in ET versus VPA. HS compared to SS disclosed a significant increase of total and reduced glutathione, HV compared to SV a significant increase of oxidized glutathione, HT compared to ST a significant increase of p-eIF2α to eIF2α ratio and sXBP1. Physical exercise counteracts NASH-related ER stress and its associated deleterious consequences through a positive and dynamical modulation of the hepatic IRE1α-X-box binding protein 1 pathway.

Fit mothers for a healthy future: Breaking the intergenerational cycle of non-alcoholic fatty liver disease with maternal exercise.

SPECIAL ISSUE: 'FOIEGRAS-Bioenergetic Remodelling in the Pathophysiology and Treatment of Non-Alcoholic Fatty Liver Disease'. BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) emerges as significant health burden worldwide. Lifestyle changes, unhealthy dietary habits and physical inactivity, can trigger NAFLD development. Persisting on these habits during pregnancy affects in utero environment and prompts a specific metabolic response in foetus resulting in offspring metabolic maladjustments potentially critical for developing NAFLD later in life. The increasing prevalence of NAFLD, particularly in children, has shifted the research focus towards preventive and therapeutic strategies. Yet, designing effective approaches that can break the NAFLD intergenerational cycle becomes even more complicated. Regular physical exercise (PE) is a powerful non-pharmacological strategy known to counteract deleterious metabolic outcomes. In this narrative review, we aimed to briefly describe NAFLD pathogenesis focusing on maternal nutritional challenge and foetal programming, and to provide potential mechanisms behind the putative intergenerational effect of PE against metabolic diseases, including liver diseases. METHODS: Following detailed electronic database search, recent existing evidence about NAFLD development, intergenerational programming and gestational exercise effects was critically analysed and discussed. RESULTS: PE during pregnancy could have a great potential to counteract intergenerational transmission of metabolic burden. The interplay between different PE roles-metabolic, endocrine and epigenetic-could offer a more stable in utero environment to the foetus, thus rescuing offspring vulnerability to metabolic disturbances. CONCLUSIONS: The better understanding of maternal PE beneficial consequences on offspring metabolism could reinforce the importance of PE during pregnancy as an indispensable strategy in improving offspring health.

Technical match actions and plasma stress markers in elite female football players during an official FIFA Tournament.

This study analyzed the impact of performing four consecutive football matches separated by 48-72 hours during a FIFA tournament on physical load, technical performance and plasma markers of redox state, muscle damage and inflammation in elite female players. Forty-eight players from three national teams were evaluated at seven time points: before (baseline) and throughout the tournament (after each match and before two training sessions). Only data from players who played all matches were included in the analyses (N = 13). The players were divided into high-rank (N = 6) and low-rank (N = 7) team players according to FIFA standards. Plasma creatine kinase (CK), C-reactive protein (CRP), total antioxidant status (TAS), and uric acid (UA) were analyzed at the selected time points. Technical performance and physical load were also quantified according to team rank. Players from low-rank teams played significantly more time than high-rank players (85 ± 10 vs 67 ± 15 minutes; P = .02; d = 1.51). Low-rank team players presented higher values in technical performance actions than the high-rank team players, but most of the differences were explained by the longer match time played. UA content differed across the matches, increasing from baseline (F(4,40)  = 3.90; P = .01) and more in the high-rank team players (F(1,10)  = 20.46; P = .001), while CRP only differed across the matches (F(4,36)  = 2.66; P = .05), also increasing from baseline. A large time effect was shown for UA only in the high-rank players (η2 p  = 0.50; P = .02). Four consecutive matches did not result in considerable alterations in plasma stress markers, physical load, and technical performance in elite female football players from distinct rank levels.

Building-up fit muscles for the future: Transgenerational programming of skeletal muscle through physical exercise.

'Special issue - In Utero and Early Life Programming of Aging and Disease'. Skeletal muscle (SM) adaptations to physical exercise (PE) have been extensively studied due, not only to the relevance of its in situ plasticity, but also to the SM endocrine-like effects in noncontractile tissues, such as brain, liver or adipocytes. Regular PE has been considered a pleiotropic nonpharmacological strategy to prevent and counteract the deleterious consequences of several metabolic, cardiovascular, oncological and neurodegenerative disorders. Additionally, PE performed by parents seems to have a direct impact in the offspring through the transgenerational programming of different tissues, such as SM. In fact, SM offspring programming mechanisms seems to be orchestrated, at least in part, by epigenetic machinery conditioning transcriptional or post-transcriptional processes. Ultimately, PE performed in the early in life is also a critical window of opportunity to positively modulate the juvenile and adult phenotype. Parental PE has a positive impact in several health-related offspring outcomes, such as SM metabolism, differentiation, morphology and ultimately in offspring exercise volition and endurance. Also, early-life PE counteracts conceptional-related adverse effects and induces long-lasting healthy benefits throughout adulthood. Additionally, epigenetics mechanisms seem to play a key role in the PE-induced SM adaptations. Despite the undoubtedly positive role of parental and early-life PE on SM phenotype, a strong research effort is still needed to better understand the mechanisms that positively regulate PE-induced SM programming.

Maternal high-fat high-sucrose diet and gestational exercise modulate hepatic fat accumulation and liver mitochondrial respiratory capacity in mothers and male offspring.

BACKGROUND: Maternal high-caloric nutrition and related gestational diabetes mellitus (GDM) are associated with a high-risk for developing metabolic complications later in life and in their offspring. In contrast, exercise is recognized as a non-pharmacological strategy against metabolic dysfunctions associated to lifestyle disorders. Therefore, we investigated whether gestational exercise delays the development of metabolic alterations in GDM mothers later in life, but also protects 6-week-old male offspring from adverse effects of maternal diet. METHODS: Female Sprague-Dawley rats were fed with either control (C) or high-fat high-sucrose (HFHS) diet to induce GDM and submitted to gestational exercise during the 3 weeks of pregnancy. Male offspring were sedentary and fed with C-diet. RESULTS: Sedentary HFHS-fed dams exhibited increased gestational body weight gain (p < 0.01) and glucose intolerance (p < 0.01), characteristic of GDM. Their offspring had normal glucose metabolism, but increased early-age body weight, which was reverted by gestational exercise. Gestational exercise also reduced offspring hepatic triglycerides accumulation (p < 0.05) and improved liver mitochondrial respiration capacity (p < 0.05), contributing to the recovery of liver bioenergetics compromised by maternal HFHS diet. Interestingly, liver mitochondrial respiration remained increased by gestational exercise in HFHS-fed dams despite prolonged HFHS consumption and exercise cessation. CONCLUSIONS: Gestational exercise can result in liver mitochondrial adaptations in GDM animals, which can be preserved even after the exercise program cessation. Exposure to maternal GDM programs liver metabolic setting of male offspring, whereas gestational exercise appears as an important preventive tool against maternal diet-induced metabolic alterations.

Preventive and Therapeutic Potential of Physical Exercise in Neurodegenerative Diseases.

Significance: The prevalence and incidence of age-related neurodegenerative diseases (NDDs) tend to increase along with the enhanced average of the world life expectancy. NDDs are a major cause of morbidity and disability, affecting the health care, social and economic systems with a significant impact. Critical Issues and Recent Advances: Despite the worldwide burden of NDDs and the ongoing research efforts to increase the underlying molecular mechanisms involved in NDD pathophysiologies, pharmacological therapies have been presenting merely narrow benefits. On the contrary, absent of detrimental side effects but growing merits, regular physical exercise (PE) has been considered a prone pleiotropic nonpharmacological alternative able to modulate brain structure and function, thereby stimulating a healthier and "fitness" neurological phenotype. Future Directions: This review summarizes the state of the art of some peripheral and central-related mechanisms that underlie the impact of PE on brain plasticity as well as its relevance for the prevention and/or treatment of NDDs. Nevertheless, further studies are needed to better clarify the molecular signaling pathways associated with muscle contractions-related myokines release and its plausible positive effects in the brain. In addition, particular focus of research should address the role of PE in the modulation of mitochondrial metabolism and oxidative stress in the context of NDDs.

Physical exercise and liver "fitness": Role of mitochondrial function and epigenetics-related mechanisms in non-alcoholic fatty liver disease.

BACKGROUND: Modern lifestyles, especially high-caloric intake and physical inactivity, contribute to the increased prevalence of non-alcoholic fatty liver disease (NAFLD), which becomes a significant health problem worldwide. Lifestyle changes, however, affect not only parental generation, but also their offspring, reinforcing the need for efficient preventive approaches to deal with this disease. This transgenerational influence of phenotypes dependent on parents (particularly maternal) behaviours may open additional research avenues. Despite persistent attempts to design an effective pharmacological therapy against NAFLD, physical activity, as a non-pharmacological approach, emerges as an exciting strategy. SCOPE OF REVIEW: Here we briefly review the effect of physical exercise on liver mitochondria adaptations in NAFLD, highlighting the importance of mitochondrial metabolism and transgenerational and epigenetic mechanisms in liver diseases. MAJOR CONCLUSIONS: A deeper look into cellular mechanisms sheds a light on possible effects of physical activity in the prevention and treatment of NAFLD through modulation of function and structure of particular organelles, namely mitochondria. Additionally, despite of increasing evidence regarding the contribution of epigenetic mechanisms in the pathogenesis of different diseases, the role of microRNAs, DNA methylation, and histone modification in NAFLD pathogenesis still needs to be elucidated.

Physical exercise mitigates behavioral impairments in a rat model of sporadic Alzheimer's disease.

Physical exercise has proven to be beneficial to mitigate several deleterious effects associated with neurodegenerative diseases, including Alzheimer's Disease (AD). Here, we investigated the role of long-term exercise as a preventive and therapeutic tool against AD cognitive and behavioral impairments using a sporadic AD-like rat model, established through the administration of streptozotocin (STZ) inside both cerebral ventricles (icv). Six-weeks-old Wistar male rats (56) were divided into groups (either saline or STZ): sedentary (Sed), voluntary physical activity (VPA), VPA + endurance treadmill training (VPA + ET) and VPA + ET only after the injection (VPA + ET-post). Surgeries occurred at 16wks and the animals were sacrificed at 28 wks. VPA, VPA + ET, and VPA + ET-post had continuous access to the running wheels during the entire experimental protocol. VPA + ET (entire protocol) and VPA + ET-post (only after surgical procedure) ran 60 min/d, 25 m/min, 5d/wk in a treadmill. Both ET regimens led to significant improvements in the compromised spatial learning and long-term memory of STZ-infused animals that were not observed neither in the saline Sed nor in VPA STZ groups. General activity patterns and exploration habits were also ameliorated with chronic-exercise in STZ treated animals, while freezing patterns were decreased in these groups. these results were further. Positive alterations were seen in mitochondrial oxygen consumption endpoints (synaptosomal and non-synaptosomal brain mitochondria) that might underlie the neurobehavioral improvements observed. Data suggest that VPA alone was not able to counteract the AD-related deleterious consequences, although when accompanied by endurance training (either lifelong or later-life) may be able to prevent and reverse cognitive and phenotypic impairments associated with AD.

Impact of exercise training on cardiotoxicity and cardiac health outcomes in women with breast cancer anthracycline chemotherapy: a study protocol for a randomized controlled trial.

BACKGROUND: Anthracyclines are chemotherapeutic agents frequently used in breast cancer (BC) treatment. Although it improves disease-free and overall survival, the use of anthracyclines is associated with a cumulative risk of cardiac toxicity. Preventive strategies to optimize cardiac health are needed and exercise is proposed as a potential non-pharmacological approach for counteracting anthracycline-related cardiotoxicity (ARC). Most of the data on the effects of exercise to reduce ACT are from animal studies, with only a few studies in a limited number of patients indicating beneficial effects. To better understand the effectiveness of exercise in the mitigation of ARC, clinical, real-world trials claim require a larger sample size and more accurate and valuable clinical biomarkers. In this study, we intend to include a large sample and investigate cardiac function through serial measures of biomarkers and imaging techniques. METHODS: This protocol describes a two-arm, prospective, randomized controlled trial that will explore the cardioprotective effect of a structured exercise program in women with BC undergoing anthracycline-containing chemotherapy (ACT). Ninety adult women with early BC and recommended to receive ACT will be randomly assigned (1:1) to an intervention group or a control group. Patients allocated to the intervention group will perform a supervised exercise program three times per week, consisting of a combination of aerobic and resistance training with progressive intensity and volume, during the time period they receive ACT. The control group will receive standard BC care. Primary outcomes related to cardiac (dys)function will be circulating N-terminal pro-brain natriuretic peptide (NT-proBNP) levels, resting left ventricular (LV) longitudinal strain, and resting LV ejection fraction. Secondary outcomes will include the assessment of resting blood pressure, resting heart rate (HR), resting HR variability (HRV), recovery HR, physical function outcomes, self-reported physical activity level, health-related quality of life, and fatigue. Data will be obtained at baseline (t0), after the end of anthracycline-treatment (t2), and 3 months after t2 (t3). Additionally, NT-proBNP will be measured 1-24 h prior to each anthracycline-treatment cycle (t1). DISCUSSION: The implementation of the present study design, using novel clinical biomarkers, will determine the effect of structured exercise interventions at mitigating ARC, with the overall aim of finding means to further improve BC care. TRIAL REGISTRATION: ISRCTN, ISRCTN32617901 . Registered on 24 October 2018. Last updated on 11 January 2019.

Physical exercise positively modulates DOX-induced hepatic oxidative stress, mitochondrial dysfunction and quality control signaling.

Doxorubicin (DOX), a widely used and efficient antineoplastic agent, is mainly limited by cardiotoxicity, although other tissues including liver are also affected. The effects of exercise to cope with DOX side-effects has already been studied in the heart and brain, demonstrating successful results. However, the benefits of this non-pharmacological strategy have not been so extensively checked in the liver. We here aimed to ascertain whether exercise could mitigate DOX-induced liver harmful effects using mitochondria as a model for evaluating toxicity. Twenty-four male rats were divided into four groups: SED + SAL (sedentary with saline administration), SED + DOX (sedentary with DOX administration), ET + DOX (endurance-trained with DOX administration) and VPA + DOX (voluntary physical activity with DOX administration). Isolated liver mitochondria were obtained for evaluation of their respiratory activity and transmembrane electrical potential endpoints. Molecular markers of oxidative damage (carbonyls, MDA, aconitase, MnSOD), mitochondrial dynamics (PGC-1α, TFAM, OPA1, DRP1, MFN1) and auto(mito)phagy signaling (p62, LC3, Beclin1, Bcl-2, PINK, Parkin) were measured. Transmission electron microscopy evaluation was used to analyze mitochondrial morphological alterations. When compared to SED + SAL, respiratory function of SED + DOX was compromised. Decreased SOD and aconitase activities and increased MDA content, decreases in PGC-1α, TFAM, OPA1 and MFN1 expressions, and increases in DRP1 and LC3II/LC3I ratio were also observed after DOX administration. However, these alterations were reverted or mitigated in the ET + DOX group. Semi-quantitative and qualitative analyses from microphotographs showed that liver mitochondria of SED + DOX animals were more circular and had lower density, whereas the animals with exercise showed a tendency to revert this phenotype and increase the mitochondrial density. Taken together, our results suggest that physical exercise, particularly ET, positively reversed the deleterious effects caused by DOX administration, such as oxidative damage, mitochondrial dysfunction, and altered mitochondrial dynamics toward fission, thus contributing to increase liver resistance against DOX administration.

Self-Paced Free-Running Wheel Mimics High-Intensity Interval Training Impact on Rats' Functional, Physiological, Biochemical, and Morphological Features.

Free-running wheel (FRW) is an animal exercise model that relies on high-intensity interval moments interspersed with low-intensity or pauses apparently similar to those performed in high-intensity interval training (HIIT). Therefore, this study, conducted over a 12-weeks period, aimed to compare functional, thermographic, biochemical and morphological skeletal and cardiac muscle adaptations induced by FRW and HIIT. Twenty-four male Wistar rats were assigned into three groups: sedentary rats (SED), rats that voluntarily exercise in free wheels (FRW) and rats submitted to a daily HIIT. Functional tests revealed that compared to SED both FRW and HIIT increased the ability to perform maximal workload tests (MWT-cm/s) (45 ± 1 vs. 55 ± 2 and vs. 65 ± 2). Regarding thermographic assays, FRW and HIIT increased the ability to lose heat through the tail during MWT. Histochemical analyzes performed in tibialis anterior (TA) and soleus (SOL) muscles showed a general adaptation toward a more oxidative phenotype in both FRW and HIIT. Exercise increased the percentage of fast oxidative glycolytic (FOG) in medial fields of TA (29.7 ± 2.3 vs. 44.9 ± 4.4 and vs. 45.2 ± 5.3) and slow oxidative (SO) in SOL (73.4 ± 5.7 vs. 99.5 ± 0.5 and vs. 96.4 ± 1.2). HITT decreased fiber cross-sectional area (FCSA-µm2) of SO (4350 ± 286.9 vs. 4893 ± 325 and vs. 3621 ± 237.3) in SOL. Fast glycolytic fibers were bigger across all the TA muscle in FRW and HIIT groups. The FCSA decrease in FOG fibers was accompanied by a circularity decrease of SO from SOL fibers (0.840 ± 0.005 vs. 0.783 ± 0.016 and vs. 0.788 ± 0.010), and a fiber and global field capillarization increase in both FRW and HIIT protocols. Moreover, FRW and HIIT animals exhibited increased cardiac mitochondrial respiratory control ratio with complex I-driven substrates (3.89 ± 0.14 vs. 5.20 ± 0.25 and vs. 5.42 ± 0.37). Data suggest that FRW induces significant functional, physiological, and biochemical adaptations similar to those obtained under an intermittent forced exercise regimen, such as HIIT.