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The health benefits of exercise training in a cancer setting are increasingly acknowledged; however, the underlying molecular mechanisms remain poorly understood. It has been suggested that extracellular vesicles (EVs) released from contracting skeletal muscles play a key role in mediating the systemic benefits of exercise by transporting bioactive molecules, including myokines. Nevertheless, skeletal muscle-derived vesicles account for only about 5% of plasma EVs, with the immune cells making the largest contribution. Moreover, it remains unclear whether the contribution of skeletal muscle-derived EVs increases after physical exercise or how muscle contraction modulates the secretory activity of other tissues and thus influences the content and profile of circulating EVs. Furthermore, the destination of EVs after exercise is unknown, and it depends on their molecular composition, particularly adhesion proteins. The cargo of EVs is influenced by the training program, with acute training sessions having a greater impact than chronic adaptations. Indeed, there are numerous questions regarding the role of EVs in mediating the effects of exercise, the clarification of which is critical for tailoring exercise training prescriptions and designing exercise mimetics for patients unable to engage in exercise programs. This review critically analyzes the current knowledge on the effects of exercise on the content and molecular composition of circulating EVs and their impact on cancer progression. [ABSTRACT FROM AUTHOR]

This work aimed to understand how lifelong exercise training promotes the remodelling of the immune system and prostate signalome in a rat model of PCa. Fifty-five male Wistar rats were divided into four groups: control sedentary, control exercised, induced PCa sedentary and induced PCa exercised. Exercised animals were trained in a treadmill for 53 weeks. Pca induction consisted on the sequential administration of flutamide, N-methyl-N-nitrosourea and testosterone propionate implants. Serum concentrations of C-reactive protein (CRP) and tumor necrosis factor (TNF)-like weak inducer of apoptosis (TWEAK) were not different among groups. Peripheral levels of γδ T cells were higher in Pca exercised group than in the PCa sedentary group (p < 0.05). Exercise training also induced Oestrogen Receptor (ESR1) upregulation and Mitogen-activated Protein Kinase 13 (MAPK13) downregulation, changed the content of the phosphorylated (at Ser-104) form of this receptor (coded by the gene ESR1) and seemed to increase Erα phosphorylation and activity in exercised PCa rats when compared with sedentary PCa rats. Our data highlight the exercise-induced remodelling of peripheral lymphocyte subpopulations and lymphocyte infiltration in prostate tissue. Moreover, exercise training promotes the remodelling prostate signalome in this rat model of prostate carcinogenesis. [ABSTRACT FROM AUTHOR]

Background: Inflammation is widely recognized as the driving force of cachexia induced by chronic diseases; however, therapies targeting inflammation do not always reverse cachexia. Thus, whether inflammation per se plays an important role in the clinical course of cachectic patients is still a matter of debate. Aims: To give new insights into cachexia's pathogenesis and diagnosis, we performed a comprehensive literature search on the contribution of inflammatory markers to this syndrome, focusing on the noncommunicable diseases cancer and cardiovascular diseases. Methods: A systematic review was performed in PubMed using the keywords ("cancer" OR "cardiac" cachexia AND "human" OR "patient" AND "plasma" or "serum"). A total of 744 studies were retrieved and, from these, 206 were selected for full-text screening. In the end, 98 papers focusing on circulating biomarkers of cachexia were identified, which resulted in a list of 113 different mediators. Results: Data collected from the literature highlight the contribution of interleukin-6 (IL-6) and C-reactive protein (CRP) to cachexia, independently of the underlying condition. Despite not being specific, once the diagnosis of cachexia is established, CRP might help to monitor the effectiveness of anti-cachexia therapies. In cardiac diseases, B-type natriuretic peptide (BNP), renin, and obestatin might be putative markers of body wasting, whereas in cancer, growth differentiation factor (GDF) 15, transforming growth factor (TGF)-β1 and vascular endothelial growth factor (VEGF) C seem to be better markers of this syndrome. Independently of the circulating mediators, NF-κB and JAK/STAT signaling pathways play a key role in bridging inflammation with muscle wasting; however, therapies targeting these pathways were not proven effective for all cachectic patients. Conclusion: The critical and integrative analysis performed herein will certainly feed future research focused on the better comprehension of cachexia pathogenesis toward the improvement of its diagnosis and the development of personalized therapies targeting specific cachexia phenotypes. [ABSTRACT FROM AUTHOR]

Pulmonary arterial hypertension (PAH) is a progressive and fatal vascular disease in which high blood pressure in the pulmonary artery and remodeling of the pulmonary vasculature ensues. This disorder is characterized by the presence of thrombotic lesions, resulting from chronic platelet, coagulation factors, and endothelium activation, which translate into platelet aggregation, vasoconstriction, and medial thickening. Neutrophil extracellular traps (NETs), a network of chromatin and cytoplasmatic enzymes (myeloperoxidase and neutrophil elastase) forming after neutrophil programmed cell death, were described in multiple cardiovascular diseases as thrombotic mediators, by creating a scaffold or by surface receptor interaction. In this review, we analyze the possible involvement of NETs in PAH, to enlighten future studies to explore this hypothesis. NETs may have a determining role in pulmonary hypertension through activation of platelets and endothelial cells. Simultaneously, NETosis may be induced by endothelial signaling and/or cell–cell interaction between platelets and primed neutrophils, creating a positive feedback loop. Confirming its role in the pathophysiology and prognosis of PAH may represent a new opportunity to explore new therapeutic options. Key messages: Thrombosis and innate immunity are relevant axes in PAH. Patients with PAH display elevated levels of NETs. NETs could activate platelets/endothelium with proliferative and thrombotic effects. Activated platelets and endothelium could contribute to NETosis. NETs could open new therapy research avenues. [ABSTRACT FROM AUTHOR]

Conventional treatments for heart failure have failed to improve survival in heart failure with preserved ejection fraction (HFpEF). The current therapy recommendations highlight the importance of symptom management and improvement of patient's well-being or other health-related outcomes. Physical activity/exercise training might be an adjuvant treatment option, since several studies in HFpEF patients reported beneficial effects on exercise intolerance, which is the main symptom associated with this disease. In addition, exercise training was shown to improve quality of life and, in some studies, to improve cardiac function. However, the mechanisms behind these effects are not completely known. The objective of this narrative review is to summarize the main clinical findings regarding the role of physical activity/exercise training in several outcomes, such as hospitalization and mortality, exercise capacity, quality of life, and cardiac function and remodeling. In addition, we will briefly discuss the findings provided by pre-clinical studies. In conclusion, while the impact of physical activity/exercise training on exercise intolerance and quality of life is already well known, its effect on mortality and hospitalization is not well documented, and whether it benefits diastolic function needs further investigation. Some clinical studies showed that exercise training can improve diastolic function, and evidences from pre-clinical studies suggest that this effect is mediated through reduced myocardial stiffness. [ABSTRACT FROM AUTHOR]

Heart failure with preserved ejection fraction (HFpEF) is currently lacking an effective pharmacological treatment with impact on major outcomes such as hospitalization and mortality. Exercise training (EXT) is recognized as an important nonpharmacological tool, capable of improving exercise capacity and quality of life, and has even been associated with a reduction in hospitalization and cardiovascular mortality risk. However, this positive impact largely lacks a physiological explanation. The aim of this narrative review was to provide an overview of the available data supporting the hypothesis that the beneficial role of EXT in HFpEF might be due to its effects on targeting the inflammatory paradigm described for this disease. A comprehensive literature search was conducted using the PubMed-NCBI database. We reviewed the effects of EXT throughout each step of the pathophysiological pathway leading to HFpEF and found clinical and/or preclinical evidence supporting the reduction of systemic inflammation, endothelial dysfunction, microvascular rarefaction, and myocardial stiffness. We also highlighted some gaps in the knowledge or topics that deserve further clarification in future studies. In conclusion, despite the scarcity of clinical studies in this population, there is compelling evidence suggesting that EXT modulates crucial aspects of the inflammatory pathway described for HFpEF and future investigation on cellular and molecular mechanisms are encouraged. [ABSTRACT FROM AUTHOR]

Sexual dimorphism greatly influences adipose tissue remodeling, which is characterized by changes in the activity, number, and/or size of adipocytes in response to distinct stimuli, including lifestyle and anti-obesity drugs. This sex dependence seems to be due to the anatomical and endocrine disparities between men and women. At the molecular level, sex hormones are believed to mediate such differences and involve estrogen and androgen receptor-induced gene expression. The signaling pathways that regulate adipose tissue metabolism and function include peroxisome proliferator-activated receptor gamma, uncoupling protein 1 (UCP1), 5' adenosine monophosphate-activated protein kinase (AMPK), and mitochondrial oxidative phosphorylation (OXPHOS), among other molecular players. Sex hormone-related pathways also interplay with adrenergic signaling, probably the most well-characterized molecular mechanism implicated in the remodeling of white adipose tissue. This review overviews and integrates the signaling pathways behind sexual dimorphism in adipose tissue remodeling, hoping to increase the knowledge on the pathogenesis of diseases, such as obesity and related comorbidities, and consequently, to drive future studies to investigate the regulation of this tissue homeostasis, either in men or women. [ABSTRACT FROM AUTHOR]

Aerobic exercise training induces a unique cardioprotective phenotype, but it is becoming clear that it does not promote the same structural, functional, and molecular adaptations in both ventricles. In the present study, we aimed to better characterize and compare the molecular pathways involved in the exercise-induced remodeling of both ventricles. Female Sprague-Dawley rats were randomly assigned to control and exercise groups. Animals in the exercise group were submitted to low-intensity treadmill exercise for 54 weeks. After the experimental period, biventricular hemodynamic analysis was performed and right and left ventricles were harvested for morphological and biochemical analyses. Data showed that long-term low-intensity exercise training improves cardiac function, especially left ventricular diastolic function; however, the expression of connexin-43, CCAAT-enhancer binding protein β, and c-kit did not change in none of the ventricles. In the right ventricle, long-term exercise training induced an increase of manganese superoxide dismutase and sirtuin 3 protein expression, suggestive of improved antioxidant capacity. Our results also support that long-term aerobic exercise training imposes greater metabolic remodeling to the right ventricle, mainly by increasing mitochondrial ability to produce ATP, with no association to estrogen-related receptor α regulation. [ABSTRACT FROM AUTHOR]

Findings on experimental animals show that ovarian failure is accompanied by a decrease in motor activity. As mechanical loading has a vital role in the maintenance of skeletal health, our aim was to determine to what extent this decrease in motor activity contributes to ovariectomy-induced bone loss. Thirty-two female Wistar rats were ovariectomized or sham-operated and housed in standard cages or with access to running wheels for 36 weeks with their running distance monitored. Markers of bone turnover were assayed in the serum, and bone geometry, trabecular and cortical bone microarchitecture, mineralization degree, and biomechanical properties were assessed in the femur. Differences between groups were determined by one-way ANOVA. Although reduced motor activity and sex steroid deficiency both resulted in decreases in trabecular bone volume, trabecular number decreases were mostly associated with sex steroid deficiency, whereas trabecular thickness decreases were mostly associated with sedentary behavior. Cortical bone appeared to be more sensitive to variations in motor activity, whereas bone turnover rate and bone tissue mineralization degree seemed to be primarily affected by sex steroid deficiency, even though they were further aggravated by sedentary behavior. Increases in femur length were mostly a consequence of sex steroid deficiency, whereas femoral neck length was also influenced by sedentary behavior. Differences in mechanical properties resulted mostly from differences in physical activity. Both the direct effect of sex steroid deficiency and the indirect effect of motor activity changes are implicated in bone loss following ovariectomy. [ABSTRACT FROM AUTHOR]

Clinical studies suggest that aerobic exercise can exert beneficial effects in pulmonary arterial hypertension (PAH), but the underlying mechanisms are largely unknown. We compared the impact of early or late aerobic exercise training on right ventricular function, remodeling and survival in experimental PAH. Male Wistar rats were submitted to normal cage activity (SED), exercise training in early (EarlyEX) and in late stage (LateEX) of PAH induced by monocrotaline (MCT, 60 mg/kg). Both exercise interventions resulted in improved cardiac function despite persistent right pressure-overload, increased exercise tolerance and survival, with greater benefits in EarlyEX+MCT. This was accompanied by improvements in the markers of cardiac remodeling (SERCA2a), neurohumoral activation (lower endothelin-1, brain natriuretic peptide and preserved vascular endothelial growth factor mRNA), metabolism and mitochondrial oxidative stress in both exercise interventions. EarlyEX+MCT provided additional improvements in fibrosis, tumor necrosis factor-alpha/interleukin-10 and brain natriuretic peptide mRNA, and beta/alpha myosin heavy chain protein expression. The present study demonstrates important cardioprotective effects of aerobic exercise in experimental PAH, with greater benefits obtained when exercise training is initiated at an early stage of the disease. [ABSTRACT FROM AUTHOR]

Exercise training is a well-known non-pharmacological strategy for the prevention and treatment of cardiovascular diseases. Despite the established phenotypic knowledge, the molecular signature of exercise-induced cardiac remodeling remains poorly characterized. The great majority of studies dedicated to this topic use conventional reductionist methods, which only allow analyzing individual protein candidates. Nowadays, several methodologies based on mass spectrometry are available and have been successfully applied for the characterization of heart proteome, representing an attractive approach for the wide characterization of the complex molecular networks that underlie exercise-induced cardiac remodeling. Still, few studies have used these methodologies to understand the impact of exercise training on the remodeling of cardiac proteome. The present study analyzes the few available data obtained from mass spectrometry (MS)-based proteomic studies assessing the impact of distinct types of exercise training on the protein profile of heart (left ventricle and isolated mitochondria) and the potential cross-tolerance between exercise training and diseases as myocardial infarction and obesity. Network analysis was performed with bioinformatics to integrate data from distinct research papers, based on distinct exercise training protocols, animal models and methodological approaches applied in the characterization of heart proteome. The analysis revealed that exercise training confers a unique proteome signature characterized by the up-regulation of lipid and organic metabolic processes, vasculogenesis and tissue regeneration. Data retrieved from this analysis also suggested that cardiac mitochondrial proteome is highly dynamic in response to exercise training due, in part, to the action of specific kinases as PKA and PKG. Regarding to the type of exercise, treadmill training seems to have a greater effect on the modulation of cardiac proteome than swimming. Data from the present review will certainly open new perspectives on cardiac proteomics and will help to envisage future studies targeting the identification of the regulatory mechanisms underlying cardiac adaptive and maladaptive remodeling. [ABSTRACT FROM AUTHOR]

Bone fragility is a major health concern, as the increased risk of bone fractures has devastating outcomes in terms of mortality, decreased autonomy, and healthcare costs. Efforts made to address this problem have considerably increased our knowledge about the mechanisms that regulate bone formation and resorption. In particular, we now have a much better understanding of the cellular events that are triggered when bones are mechanically stimulated and how these events can lead to improvements in bone mass. Despite these findings at the molecular level, most exercise intervention studies reveal either no effects or only minor benefits of exercise programs in improving bone mineral density (BMD) in osteoporotic patients. Nevertheless, and despite that BMD is the gold standard for diagnosing osteoporosis, this measure is only able to provide insights regarding the quantity of bone tissue. In this article, we review the complex structure of bone tissue and highlight the concept that its mechanical strength stems from the interaction of several different features. We revisited the available data showing that bone mineralization degree, hydroxyapatite crystal size and heterogeneity, collagen properties, osteocyte density, trabecular and cortical microarchitecture, as well as whole bone geometry, are determinants of bone strength and that each one of these properties may independently contribute to the increased or decreased risk of fracture, even without meaningful changes in aBMD. Based on these findings, we emphasize that while osteoporosis (almost) always causes bone fragility, bone fragility is not always caused just by osteoporosis, as other important variables also play a major role in this etiology. Furthermore, the results of several studies showing compelling data that physical exercise has the potential to improve bone quality and to decrease fracture risk by influencing each one of these determinants are also reviewed. These findings have meaningful clinical repercussions as they emphasize the fact that, even without leading to improvements in BMD, exercise interventions in patients with osteoporosis may be beneficial by improving other determinants of bone strength. [ABSTRACT FROM AUTHOR]

Bone strength depends on several material and structural properties, but findings concerning the best predictors of bone mechanical performance are conflicting. The aim of this study was to investigate how a broad set of bone properties in the proximal femur are influenced by age and hormonal status, and how these properties together determine bone strength. Twenty-five Wistar rats were ovariectomized (OVX, n = 13) or sham operated (SHAM, n = 12) at 5 months of age, and killed after 9 months. Another group of rats was killed at 5 months as baseline control (BSL, n = 7). At sacrifice, serum 17β-estradiol and bone turnover marker concentrations were determined in the serum. Both femurs were collected for assessment of trabecular microarchitecture, femoral neck geometry, radiographic absorptiometry, calcium and phosphate content, and biomechanical properties. While stiffness was mostly associated with proximal femur trabecular microarchitecture and mineralization degree, bone strength was mostly linked to bone size and femoral neck geometry, which predicted almost 50% of its variance. Despite the decrease in cortical and trabecular bone as well as in mineralization degree following estrogen loss, bone strength was not reduced in OVX animals compared to BSL or sham-operated rats. This was due to a change in femoral neck geometry as well as to an increase in femur size in OVX, which apparently compensated their lower bone volume and mineral content, thereby preserving bone strength. Estrogen loss leads to a deterioration of bone tissue quality, but bone strength was preserved at the expense of geometric adaptations. [ABSTRACT FROM AUTHOR]

Chronic pressure-overload and diabetes mellitus are two frequent disorders affecting the heart. We aimed to characterize myocardial structural and functional changes induced by both conditions. Pressure-overload was established in Wistar-han male rats by supra-renal aortic banding. Six-weeks later, diabetes was induced by streptozotocin (65 mg/kg,ip), resulting in four groups: SHAM, banding (BA), diabetic (DM) and diabetic-banding (DB). Six-weeks later, pressure-volume loops were obtained and left ventricular samples were collected to evaluate alterations in insulin signalling pathways, extracellular matrix as well as myofilament function and phosphorylation. Pressure-overload increased cardiomyocyte diameter (BA 22.0 ± 0.4 μm, SHAM 18.2 ± 0.3 μm) and myofilament maximal force (BA 25.7 ± 3.6 kN/m, SHAM 18.6 ± 1.4 kN/m), Ca sensitivity (BA 5.56 ± 0.02, SHAM 5.50 ± 0.02) as well as MyBP-C, Akt and Erk phosphorylation, while decreasing rate of force redevelopment ( K; BA 14.9 ± 1.1 s, SHAM 25.2 ± 1.5 s). At the extracellular matrix level, fibrosis (BA 10.8 ± 0.9%, SHAM 5.3 ± 0.6%), pro-MMP-2 and MMP-9 activities increased and, in vivo, relaxation was impaired ( τ; BA 14.0 ± 0.9 ms, SHAM 12.9 ± 0.4 ms). Diabetes increased cardiomyocyte diameter, fibrosis (DM 21.4 ± 0.4 μm, 13.9 ± 1.8%, DB 20.6 ± 0.4 μm, 13.8 ± 0.8%, respectively), myofilament Casensitivity (DM 5.57 ± 0.02, DB 5.57 ± 0.01), advanced glycation end-product deposition (DM 4.9 ± 0.6 score/mm, DB 5.1 ± 0.4 score/mm, SHAM 2.1 ± 0.3 score/mm), and apoptosis, while decreasing K (DM 13.5 ± 1.9 s, DB 15.2 ± 1.4 s), Akt phosphorylation and MMP-9/TIMP-1 and MMP-1/TIMP-1 ratios. Diabetic hearts were stiffer (higher end-diastolic-pressure: DM 7.0 ± 1.2 mmHg, DB 6.7 ± 0.7 mmHg, SHAM 5.3 ± 0.4 mmHg, steeper end-diastolic-pressure-volume relation: DM 0.59 ± 0.18, DB 0.83 ± 0.17, SHAM 0.41 ± 0.10), and hypo-contractile (decreased end-systolic-pressure-volume-relation). DB animals presented further pulmonary congestion (Lungs/body-weight: DB 5.23 ± 0.21 g/kg, SHAM 3.80 ± 0.14 g/kg) as this group combined overload-induced relaxation abnormalities and diabetes-induced stiffness. Diabetes mellitus and pressure overload led to distinct diastolic dysfunction phenotypes: while diabetes promoted myocardial stiffening, pressure overload impaired relaxation. The association of these damages accelerates the progression of diastolic heart failure progression in diabetic-banded animals. [ABSTRACT FROM AUTHOR]

Osteocytes are recognized as having a pivotal role in bone tissue homeostasis, and stimuli that increase osteocyte death result in decreased bone tissue quality. Previous in vitro studies have shown that mechanical stimulation prevents osteocyte death; however, in vivo evidence of this protective effect is limited. The aim of this study was to investigate if mechanical stimulation provided by voluntary exercise reduces osteocyte death caused by estrogen deficiency. Thirty-two female Wistar rats (5 months old) were either sacrificed as baseline controls (BSL, n = 7), ovariectomized or sham-operated and housed in cages with a voluntary running wheel (OVXEX, n = 7; SHAMEX, n = 6), or ovariectomized or sham-operated and housed in standard cages of equivalent size (OVXSED, n = 6; SHAMSED, n = 6) and sacrificed at age 14 months. Histomorphometric analysis of femur mid-diaphysis cortical bone revealed a significantly higher osteocyte number (N.Ot) and lower empty lacunae number (N.Lc) in both the OVXEX and SHAMEX groups compared to their SED counterparts. Intracortical porosity (Po.Ar) was also lower in both EX groups compared to their SED counterparts and significantly correlated with N.Lc ( r = 0.616; P < 0.001). Three-point bending testing showed a significantly higher Young's modulus and ultimate stress in OVXEX compared to OVXSED and significant correlations between N.Lc and both yield stress ( r = −0.376, P < 0.05) and ultimate stress ( r = −0.369, P < 0.05) and between intracortical porosity and bone ultimate stress ( r = −0.451, P < 0.05). Our results show that voluntary exercise prevented osteocyte death and that this protective effect was associated with increases in femur ultimate stress, which could be partially explained by decreases in Po.Ar. [ABSTRACT FROM AUTHOR]