Long-term voluntary running modifies the levels of proteins of the excitatory/inhibitory system and reduces reactive astrogliosis in the brain of Ts65Dn mouse model for Down syndrome.

We showed previously that voluntary long-term running improved cognition and motor skills, but in an age-dependent manner, in the Ts65Dn mouse model for Down syndrome (DS). Presently, we investigated the effect of running on the levels of some key proteins of the excitatory/inhibitory system, which is impaired in the trisomic brain, and on astroglia, a vital component of this system. Ts65Dn mice had free access to a running wheel for 9-13 months either from weaning or from the age of 7 months. Sedentary Ts65Dn mice served as controls. We found that running modified the levels of four of the seven proteins we tested that are associated with the glutamatergic/GABA-ergic system. Thus, Ts65Dn runners demonstrated increased levels of glutamine synthetase and metabotropic glutamate receptor 1 and decreased levels of glutamate transporter 1 and glutamic acid decarboxylase 65 (GAD65) versus sedentary mice, but of metabotropic glutamate receptor 1 and GAD65 only in the post-weaning cohort. GAD67, ionotropic N-methyl-D-aspartate type receptor subunit 1, and GABAAα5 receptors' levels were similar in runners and sedentary animals. The number of glial fibrillary acidic protein (GFAP)-positive astrocytes and the levels of GFAP were significantly reduced in runners relative to sedentary mice. Our study provides new insight into the mechanisms underlying the beneficial effect of voluntary, sustained running on function of the trisomic brain by identifying the involvement of proteins associated with glutamatergic and GABAergic systems and reduction in reactive astrogliosis.

Astrocyte remodeling in the beneficial effects of long-term voluntary exercise in Alzheimer's disease.

BACKGROUND: Increased physical exercise improves cognitive function and reduces pathology associated with Alzheimer's disease (AD). However, the mechanisms underlying the beneficial effects of exercise in AD on the level of specific brain cell types remain poorly investigated. The involvement of astrocytes in AD pathology is widely described, but their exact role in exercise-mediated neuroprotection warrant further investigation. Here, we investigated the effect of long-term voluntary physical exercise on the modulation of the astrocyte state. METHODS: Male 5xFAD mice and their wild-type littermates had free access to a running wheel from 1.5 to 7 months of age. A battery of behavioral tests was used to assess the effects of voluntary exercise on cognition and learning. Neuronal loss, impairment in neurogenesis, beta-amyloid (Aß) deposition, and inflammation were evaluated using a variety of histological and biochemical measurements. Sophisticated morphological analyses were performed to delineate the specific involvement of astrocytes in exercise-induced neuroprotection in the 5xFAD mice. RESULTS: Long-term voluntary physical exercise reversed cognitive impairment in 7-month-old 5xFAD mice without affecting neurogenesis, neuronal loss, Aß plaque deposition, or microglia activation. Exercise increased glial fibrillary acid protein (GFAP) immunoreactivity and the number of GFAP-positive astrocytes in 5xFAD hippocampi. GFAP-positive astrocytes in hippocampi of the exercised 5xFAD mice displayed increases in the numbers of primary branches and in the soma area. In general, astrocytes distant from Aß plaques were smaller in size and possessed simplified processes in comparison to plaque-associated GFAP-positive astrocytes. Morphological alterations of GFAP-positive astrocytes occurred concomitantly with increased astrocytic brain-derived neurotrophic factor (BDNF) and restoration of postsynaptic protein PSD-95. CONCLUSIONS: Voluntary physical exercise modulates the reactive astrocyte state, which could be linked via astrocytic BDNF and PSD-95 to improved cognition in 5xFAD hippocampi. The molecular pathways involved in this modulation could potentially be targeted for benefit against AD.

Taurine with combined aerobic and resistance exercise training alleviates myocardium apoptosis in STZ-induced diabetes rats via Akt signaling pathway.

AIM: The aim of this study was considering the effects of taurine supplementation with combined aerobic and resistance training (CARE) on myocardial apoptosis and Protein Kinase B (akt) level changes in diabetic rat. MAIN METHODS: Forty male Wistar rats were randomly divided in to 5 groups of 8 animals in each: 1) control, 2) Diabetes Mellitus (DM), 3) DM with taurine supplementation (DM/T), 4) DM with CARE (DM/CARE), and 5) DM with combination of taurine and CARE (DM/T/CARE). DM was induced by injection of streptozotocin (STZ) and nicotine amid (NA) for 2, 3, 4 and 5 groups. Supplement groups received taurine in gavage, 100 mg/kg of body weight, 6 day per weeks, 8 weeks. CARE was performed at maximal speed and 1RM (40-60% of maximum for both). KEY FINDINGS: The results of this study showed that DM significantly increased blood glucose and caspase 3, caspase 9 expressions and apoptosis cells in heart tissue and reduced Akt expression (p < 0.001). However, taurine and CARE interventions significantly decreased apoptosis markers (caspase 3 and caspase 9) and significantly increased Akt in heart of diabetic rats compare to DM groups (p < 0.05). The highest improvement observed in DM/T/CARE group (p < 0.05). SIGNIFICANCE: Based on these results, it seems that the use of taurine with combined aerobic and exercise training minimize the cardiac damage caused by diabetes (especially apoptosis) trough increasing protein kinase Akt expression. This could improve cardiac remodeling after diabetes. However, more research is needed, especially on the human samples.

Review of basic trends in cryotherapy applications for horse injuries / Revisão das tendências básicas em aplicações de crioterapia em lesões em cavalos

While solving the problem of sport horses' pathologies it is important to choose safe and environmentally friendly methods, including cryotherapy, which is the topic of our research. The use of cryotherapy is a promising means of treatment of primary injury, rehabilitation in post-traumatic conditions and in chronic injuries. Prospects of cryotherapy applications in horse breeding, in particular in sports and prize areas, were researched. It was found out that modern sport horses training and their involvement in competitions is associated with serious stress on their locomotor system and maximum mobilization of all body systems, which overstrains certain muscle groups, determines increased probability and severity of injury incidence, reduction of sport longevity and worse performance in competitions.(AU)

Na resolução do problema das patologias dos cavalos esportivos é importante escolher métodos seguros e ecológicos, incluindo a crioterapia, que é o tópico desta pesquisa. O uso da crioterapia é um meio promissor no tratamento de lesões primárias, reabilitação em condições pós-traumáticas e lesões crônicas. Foram pesquisadas as perspectivas de aplicações da crioterapia na criação de cavalos, particularmente em esportes e prêmios. Verificou-se que o treinamento moderno de cavalos esportivos e seu envolvimento em competições está associado com severo estresse sobre seu sistema locomotor e mobilização máxima de todos os sistemas corporais, que sobrecarregam certos grupos musculares, determinam maior probabilidade e severidade da incidência de lesões, e reduzem a longevidade no esporte e pior desempenho em competições.(AU)

Physical exercise modifies behavioral and molecular parameters related to opioid addiction regardless of training time.

Addiction is a devastating worldwide disorder that requires effective and innovative therapies. Physical exercise could be useful in addiction treatment because it shares a common neural circuit with addictive drugs. Based on this, molecular adaptations consequent to time of exercise in opioid exposed animals were evaluated. Rats were designed as sedentary (SED) or exercised (EXE). This last group was separated to perform three different periods of swimming: short-term (S-EXE), medium-term (M-EXE) and long-term (L-EXE) for 14, 28 and 42 days, respectively. On the last exercising week, one-half of the animals from SED and all animals from S-, M- and l-EXE were concomitantly exposed to morphine-conditioned place preference (CPP) paradigm and y-maze task for behavioral assessments followed by molecular assays in both Nucleus accumbens (NAc) and hippocampus. Between SED groups, morphine conditioning showed drug-CPP and increased dopamine transporter (DAT), dopamine receptor type-1 (D1R), type-2 (D2R) and glucocorticoid receptor (GR) in both brain areas in relation to saline group. Besides the small morphine-CPP in relation to SED group, all periods decreased DAT, D1R, and GR immunoreactivity in NAc, DAT and D1R in hippocampus, while D2R in both brain areas and GR in hippocampus were primarily decreased by L-EXE. Our findings show that even a short-term exercise modifies behaviors related to drug withdrawal, changing DA targets and GR, which are closely linked to addiction. Therefore, our outcomes involving physical exercise are interesting to perform a possible clinical trial, thus expanding the knowledge about drug addiction.

Activity-Based Training Reverses Spinal Cord Injury-Induced Changes in Kidney Receptor Densities and Membrane Proteins.

Complications in upper and lower urinary function arise after spinal cord injury (SCI), which creates a significant impact on quality of life for those affected. One upper urinary complication is SCI-induced polyuria, or the overproduction of urine, of which the underlying mechanisms have yet to be elucidated. Activity-based training (ABT) has been utilized in both animal and clinical settings as a rehabilitative therapy to improve many issues that arise after SCI, including more recently urogenital function. The goal of the current study was to identify potential mechanisms contributing to previously identified improvements in polyuria with ABT, using a male rat moderate-severe spinal contusion model. Although ABT had no significant effect on reversing injury-induced alterations of serum arginine vasopressin and urinary atrial natriuretic peptide levels, there was a dramatic effect upon the receptors of these fluid balance hormones (vasopressin receptor 2 and natriuretic peptide A receptor), as well as kidney aquaporin 2 and sodium channels. ABT changes in densities of key receptors and kidney membrane proteins involved in fluid balance after chronic SCI support the likelihood of multiple mechanisms through which exercise can positively influence urinary tract function after SCI. By understanding the mechanisms, amount, and timing regarding how ABT improves different aspects of urinary function, more targeted training strategies can be developed to optimize the functional gains within the SCI population.

Inhaled molecular hydrogen attenuates intense acute exercise-induced hippocampal inflammation in sedentary rats.

Physical exercise-induced inflammation may be beneficial when exercise is regular but it may be harmful when exercise is intense and performed by unaccustomed individuals/rats. Molecular hydrogen (H2) has recently emerged as a powerful anti-inflammatory, antioxidant and anti-apoptotic molecule in a number of pathological conditions, but little is known about its putative role under physiological conditions such as physical exercise. Therefore, we tested the hypothesis that H2 decreases intense acute exercise-induced inflammation in the hippocampus, since it is a brain region particularly susceptible to inflammation. Moreover, we also assessed hippocampus oxidative status. Rats ran on a sealed treadmill inhaling either the H2 (2% H2, 21% O2, balanced with N2) or the control gas (0% H2, 21% O2, balanced with N2) and hippocampal samples were collected immediately or 3 h after exercise. We measured hippocampal levels of cytokines [tumor necrosis factor-α (TNF-α), interleukin (IL)-1ß, IL-6 and IL-10] and oxidative markers [superoxide dismutase (SOD), thiobarbituric acid reactive species (TBARS) and nitrite/nitrate (NOx)]. Exercise increased TNF-α, IL-6 and IL-10 immediately after the session, whereas no change in IL-1ß levels was observed. Conversely, exercise did not cause any change in SOD activity, TBARS and NOx levels. H2 inhibited the exercise-induced surges in TNF-α and IL-6, and potentiated the IL-10 surge, immediately after the exercise. Moreover, no change in IL1-ß levels of rats inhaling H2 was observed. Regarding the oxidative stress markers, H2 failed to cause any change in SOD activity, TBARS and NOx levels. No significant change was observed in any of the assessed parameters 3 h after the exercise bout. These data are consistent with the notion that H2 acts as a powerful anti-inflammatory agent not only down-modulating pro-inflammatory cytokines (TNF-α and IL-6) but also upregulating an anti-inflammatory cytokine (IL-10) production without affecting the local oxidative stress status. These data indicate that H2 effectively decreases exercise-induced inflammation in the hippocampus, despite the fact that this region is particularly prone to inflammatory insults.

Four-month treadmill exercise prevents the decline in spatial learning and memory abilities and the loss of spinophilin-immunoreactive puncta in the hippocampus of APP/PS1 transgenic mice.

BACKGROUND: Previous studies have reported that exercise could improve the plasticity of hippocampal synapses. However, the effects of exercise on synapses in the hippocampus in Alzheimer's disease (AD) are not completely known. METHODS: In this study, thirty 12-month-old male APP/PS1 double transgenic mice were randomly divided into a sedentary group (n = 15) and a running group (n = 15). Fifteen 12-month-old male wild-type littermates were assigned to the control group (n = 15). While running mice were assigned to treadmill running for four months, the control mice and sedentary mice did not run during the study period. After Morris water maze testing, five mice in each group were randomly selected for a stereological assessment of spinophilin-immunoreactive puncta in the CA1, CA2-3 and dentate gyrus (DG) of the hippocampus. RESULTS: Morris water maze testing revealed that while the learning and memory abilities in sedentary APP/PS1 mice were significantly worse than those in wild-type control mice, the learning and memory abilities in running APP/PS1 mice were significantly better than those in sedentary APP/PS1 mice. The stereological results showed that the spinophilin-immunoreactive puncta numbers of the CA1, CA2-3 and DG in the hippocampus of sedentary APP/PS1 mice were significantly lower than those of wild-type control mice and that the numbers of these spines in the CA1, CA2-3 and DG in the hippocampus of running APP/PS1 mice were significantly higher than those of sedentary APP/PS1 mice. Moreover, a running-induced improvement in spatial learning and memory abilities was significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus. CONCLUSIONS: Four-month treadmill exercise induced a significant improvement in spatial learning and memory abilities and a significant increase in the number of spinophilin-immunoreactive puncta of the CA1, CA2-3 and DG in the hippocampus of APP/PS1 mice. Running-induced improvements in spatial learning and memory abilities were significantly correlated with running-induced increases in the spinophilin-immunoreactive puncta numbers in the CA1 and DG of the hippocampus.

Exercise and retinal health.

Many ocular diseases (such as glaucoma, diabetic retinopathy, age-related macular degeneration, and traumatic eye injuries) can result in the degeneration of retinal cells and the subsequent loss of vision. Some kinds of treatments, such as drugs, stem cell transplantation and surgery are reported to be effective in certain patients. However, no confirmatively effective, convenient and low-price intervention has been available so far. Physical exercise has been reported to exert neuroprotective effects on several neurodegenerative diseases, including Parkinson's disease and Alzheimer's disease. Studies investigating the potential impacts of exercise on retinal diseases are rapidly emerging. Here we review these up-to-date findings from both human and animal studies, and discuss the possible mechanisms underlying exercise-elicited protection on retina.

Cardioprotective effect of a moderate and prolonged exercise training involves sirtuin pathway.

AIM: To investigate the cardioprotective effects of prolonged and moderate exercise training on cellular and molecular events early after myocardial infarction. MATERIALS AND METHODS: Male Wistar rats were divided in sedentary or exercised group; both groups underwent to a myocardial infarction. All the molecular and immunohistochemical analyses on hearts of sedentary and exercised rats were performed 48 h after surgical procedure. SIRT1 and SIRT3 expression were measured and two of the pathways activated by sirtuins, p53-induced apoptosis and Forkhead boxO (FOXO)3a-induced oxidative stress, were investigated. All the experiments were performed also in presence of the SIRT inhibitor, EX527. KEY FINDINGS: Fourty-eight hours post myocardial infarction, exercise training induced the activation of SIRT1 and SIRT3 pathway reducing cardiomyocytes apoptosis and oxidative damage. Molecular data were confirmed by immunohistochemical evaluations. These effects are more evident in border infarcted zone than in the remote myocardium. SIGNIFICANCE: Exercise training is a non-pharmacological prevention strategy in cardiovascular diseases and the sirtuins family seems to be as novel and attractive target in cardioprotection.

The mechanisms involved in the increased adiposity induced by interruption of regular physical exercise practice.

AIMS: We investigated the effects of physical detraining on lipogenesis/lipolysis and cellularity (apoptosis/adipogenesis) in rat subcutaneous (inguinal; SC) and visceral (retroperitoneal; RP) white adipose depots. MAIN METHODS: Three groups of male Wistar rats (6-wk old) were studied: (1) (T) trained for 12 weeks; (2) (D) trained for 8 weeks and detrained for 4 weeks; and (3) (S) age-matched sedentary. Training consisted of treadmill running sessions (1 h/day, 5 days/week, 50-60% maximal race capacity). KEY FINDINGS: Physical detraining increased glucose oxidation, lipogenesis, and adipocyte size in the SC and RP depots. The number of apoptotic SC adipocytes was reduced by 53% in the T (p < 0.0001) and by 43% in the D (p < 0.001) as compared with S. RP adipocyte apoptosis in the T and D was 9.48% and 10.9% greater compared to the S, respectively (p < 0.05). In the SC stromal vascular fraction (SVF) of D rats, adiponectin, sterol regulatory element binding protein (SREBP)-1c, Peroxisome proliferator-activated receptor gamma (PPARγ), and Perilipin A mRNA expressions were more pronounced than S group, suggesting a more intense adipogenesis. This putative adipogenic effect was not observed in the RP depot. The physical detraining promoted rapid increase in the SC and RP depots however not through the same mechanisms. SIGNIFICANCE: Physical detraining induced fat cell hypertrophy (increase of lipogenesis) in both SC and RP whereas hyperplasia (increase of adipogenesis and reduction of apoptosis) was found in SC only. These results indicate the mechanism associated with obesogenic effects of detraining varies with the fat depot.

Impact of moderate- and high-intensity exercise on the endothelial ultrastructure and function in mesenteric arteries from hypertensive rats.

Oxidative stress (OS) influences vascular function and structure in spontaneously hypertensive rats (SHRs). It is also responsible for the decreased nitric oxide (NO) bioavailability that influences endothelial vasodilation. The effects of high-intensity exercise on endothelial function and ultrastructure in hypertension remain unknown. Thus, this study investigated the effects of moderate- and high-intensity exercise on hypertension-associated endothelial dysfunction and ultrastructural remodeling. Moderate-intensity (SHR-M) and high-intensity (SHRH) aerobic exercise training groups were compared in age-matched sedentary SHRs (SHRC) and normotensive Wistar-Kyoto rats (WKY-C). The results showed that the endothelial ultrastructure was impaired in the SHR-H and SHR-C groups. Glutathione peroxidase levels were significantly increased in the SHR-M group compared to the SHR-C group. MDA content was higher in the SHR-H group than in the SHR-C group, but the levels of antioxidant enzymes did not increase accordingly. Apocynin scavenging reactive oxygen species (ROS) ameliorated endothelium-dependent vasodilator function in the SHR-H group. However, the SHR-M and WKY-C groups abolished the increased vasodilation induced by apocynin. L-NAME, a NO synthase inhibitor, was applied to isolated mesenteric arteries (MAs) to evaluate NO contribution. Moderate-intensity exercise reversed the decreased NO contribution to MAs in hypertension, and high-intensity exercise aggravated this change. These data suggest that moderate-intensity exercise ameliorated adverse remodeling of the endothelial ultrastructure and function in hypertension by decreasing oxidative stress and increasing NO contribution. However, high-intensity exercise exacerbated all of these changes by increasing OS and ROS contribution, and decreasing NO contribution.

Characterization of the dynamic changes in left ventricular morphology and function induced by exercise training and detraining.

BACKGROUND: Although exercise-induced cardiac hypertrophy has been intensively investigated, its development and regression dynamics have not been comprehensively described. In the current study, we aimed to characterize the effects of regular exercise training and detraining on left ventricular (LV) morphology and function. METHODS: Rats were divided into exercised (n = 12) and control (n = 12) groups. Exercised rats swam 200 min/day for 12 weeks. After completion of the training protocol, rats remained sedentary for 8 weeks (detraining period). Echocardiographic follow-up was performed regularly to obtain LV long- and short-axis recordings for speckle-tracking echocardiography analysis. Global longitudinal and circumferential strain and systolic strain rate were measured. LV pressure-volume analysis was performed using additional groups of rats to obtain haemodynamic data. RESULTS: Echocardiographic examinations showed the development of LV hypertrophy in the exercised group. These differences disappeared during the detraining period. Strain and strain rate values were all increased after the training period, whereas supernormal values rapidly reversed to the control level after training cessation. Load-independent haemodynamic indices, e.g., preload recruitable stroke work, confirmed the exercise-induced systolic improvement and complete regression after detraining. CONCLUSIONS AND TRANSLATIONAL ASPECT: Our results provide the first comprehensive data to describe the development and regression dynamics of morphological and functional aspects of physiological hypertrophy in detail. Speckle-tracking echocardiography has been proven to be feasible to follow-up changes induced by exercise training and detraining and might provide an early possibility to differentiate between physiological and pathological conditions.

Exercise Reverses Nociceptive Sensitization, Upregulated Neuropeptide Signaling, Inflammatory Changes, Anxiety, and Memory Impairment in a Mouse Tibia Fracture Model.

WHAT WE ALREADY KNOW ABOUT THIS TOPIC: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: This study tested the hypothesis that ad lib running wheel exercise in a tibia fracture model of complex regional pain syndrome can reverse hindlimb nociceptive sensitization and inflammation in mice. METHODS: Three weeks after tibia fracture, the cast was removed and hindlimb von Frey thresholds and unweighting were tested; the mice were then randomized to either ad lib access to a running wheel for 4 weeks or no wheel access. After 4 weeks the behavioral testing was repeated and then skin, sciatic nerve, and spinal cord tissues collected for polymerase chain reaction and enzyme immunoassay measurements of neuropeptide and inflammatory mediator levels. A similar protocol was used in fracture mice treated with exercise for 4 weeks, and then the running wheel was removed for 2 weeks. Memory and anxiety were measured in both groups with use of open-field, zero-maze, and novel-objects recognition assays. RESULTS: At 7 weeks postfracture the mice with no wheel access exhibited hindlimb allodynia and unweighting, anxiety, memory loss, upregulated spinal neuropeptide signaling, and increased hind paw and spinal inflammatory mediator expression, but the postfracture mice allowed to exercise for 4 weeks exhibited none of these changes (n = 12/cohort). When exercise was stopped for 2 weeks after 4 weeks of running, hindlimb allodynia and unweighting were rekindled, and this nociceptive sensitization was associated with increased sciatic nerve neuropeptide levels and hind paw skin interleukin 6 and nerve growth factor expression (n = 12/cohort). CONCLUSIONS: Daily exercise reversed nociceptive sensitization, inflammation, anxiety, and memory loss after tibia fracture.

Chronic exercise induces pathological left ventricular hypertrophy in adrenaline-deficient mice.

Adrenaline-deficient phenylethanolamine-N-methyltransferase-knockout mice (Pnmt-KO) have concentric heart remodeling and though their resting blood pressure is normal, it becomes higher during acute exercise. The aim of this study was to evaluate cardiac morphological, functional and molecular alterations after chronic exercise in adrenaline-deficient mice. Genotypes at the Pnmt locus were verified by polymerase chain reaction (PCR) of ear samples of Pnmt-KO and wild-type (WT) mice. These mice were submitted to chronic exercise training during 6weeks. Blood pressure was determined by a photoelectric pulse detector. Mice were anesthetized and cardiac morphology and function were evaluated by echocardiography and hemodynamics. IGF-1, IGF-1R, ANP and BNP mRNA were quantified by real-time PCR in left ventricle (LV) samples. Pnmt-KO mice showed increased systolic blood pressure compared with WT mice. A significant increase was found in LV mass, and LV posterior wall thickness in trained Pnmt-KO compared to trained WT mice, without significant differences in LV volumes. Acute ß1-adrenergic stimulation with dobutamine increased systolic function indexes in WT mice, but not in Pnmt-KO mice. LV expression of IGF-1 and ANP was increased in trained Pnmt-KO mice when compared to trained WT mice. In conclusion, in response to chronic exercise adrenaline-deficient Pnmt-KO mice show concentric LV hypertrophy and impaired response to dobutamine, suggesting an initial stage of pathological cardiac hypertrophic remodeling. These results support the need for an efficient partial conversion of noradrenaline into adrenaline for prevention of blood pressure overshoot and thus pathological cardiac hypertrophic remodeling in chronic exercise.

Long-term wheel-running can prevent deterioration of bone properties in diabetes mellitus model rats.

OBJECTIVES: The purpose of this study was to examine the effects of long-term wheel-running on tibia bone properties in T2DM Otsuka Long-Evans Tokushima Fatty (OLETF) rats. METHODS: Ten five-week-old male OLETF rats were used as experimental animals and 5 Long-Evans Tokushima Otsuka (LETO) rats as controls. Half of OLETF rats performed daily voluntary wheel-running for 17 months (OLETF-EXE), while neither the remainder of OLETF nor LETO rats had exercise. At the end of experiment, in addition to serum biochemical and bone formation/resorption marker analyses, bone mass, trabecular bone microarchitecture and cortical bone geometry were analyzed in left tibia, and bone mechanical strength of right tibia was measured. RESULTS: Tibia bone mass, trabecular bone microarchitecture, cortical bone geometry and bone mechanical strength deteriorated in diabetic OLETF rats. However, such deterioration was obviously attenuated in OLETF-EXE rats, which maintained normal levels of blood glucose, HbA1c and blood urea nitrogen. CONCLUSIONS: Daily wheel-running could prevent the deterioration of bone properties in OLETF rats. This would be induced mainly by suppressing the development of T2DM. Regular physical exercise may be a potent strategy for preventing not only the development of diabetes but also the deterioration of bone properties in patients with chronic T2DM.

Long-term exercise modulates hippocampal gene expression in senescent female mice.

The senescence-accelerated SAMP8 mouse is considered a useful non-transgenic model for studying aspects of progressive cognitive decline and Alzheimer's disease (AD). Using SAMR1 mice as controls, here we explored the effects of 6 months of voluntary wheel running in 10-month-old female SAMP8 mice. Exercise in SAMP8 mice improved phenotypic features associated with premature aging (i.e., skin color and body tremor) and enhanced vascularization and BDNF gene expression in the hippocampus compared with controls. With the aim of identifying genes involved in brain aging responsive to long-term exercise, we performed whole genome microarray studies in hippocampus from sedentary SAMP8 (P8sed), SAMR1 (R1sed), and exercised SAMP8 (P8run) mice. The genes differentially expressed in P8sed versus R1sed were considered as putative aging markers (i) and those differentially expressed in P8run versus P8sed were considered as genes modulated by exercise (ii). Genes differentially expressed in both comparisons (i and ii) were considered as putative aging genes responsive to physical exercise. We identified 34 genes which met both criteria. Gene ontology analysis revealed that they are mainly involved in functions related to extracellular matrix maintenance. Selected genes were validated by real-time quantitative PCR assays, i.e., collagen type 1 alpha 1 (col1a1), collagen type 1 alpha 2 (col1a2), fibromodulin (fmod), prostaglandin D(2) synthase (ptgds), and aldehyde dehydrogenase (Aldh1a2). As a whole, our study suggests that exercise training during adulthood may prevent or delay gene expression alterations and processes associated with hippocampal aging in at-risk subjects.

Combination therapy prevents amyloid-dependent and -independent structural changes.

Neuropathological features of Alzheimer's disease (AD) are recapitulated in transgenic mice expressing familial AD-causing mutations, but ectopic transgene overexpression makes it difficult to relate these abnormalities to disease pathogenesis. Alternatively, the APP/PS-1 double knock-in (DKI) mouse produces mutant amyloid precursor protein (APP) and presenilin-1 (PS-1) with normal levels and regulatory controls. Here, we investigated effects of amyloid on brain structure and neuroplasticity by vaccinating DKI mice with amyloid-ß starting at 8 months of age. At 14 months, vaccination blocked cerebral amyloid deposition and its attendant microglial activation. Neuropil abnormalities were pronounced only within plaques, and included circumscribed loss and dysmorphology of axons, dendrites, terminals and spines. Blockade of amyloid deposition restored neuropil integrity. Amyloid removal did not rescue reductions in the hippocampal neural progenitor and neuroblast populations, but adding 1 month of voluntary exercise to amyloid-ß vaccination markedly stimulated hippocampal neurogenesis. These results identify amyloid-dependent and -independent structural changes in the DKI mouse model of AD. Combining exercise with amyloid-directed immunotherapy produces greater restoration of brain structure and neuroplasticity than is achieved with either maneuver alone.