Accumulation of amyloid-β (Aβ) correlates significantly with progressive cognitive deficits, a main symptom of Alzheimer's disease (AD). Although treadmill exercise reduces Aβ levels, the molecular ...mechanisms underlying the effects are not fully understood. We hypothesize that treadmill exercise decreases Aβ production and alleviates cognitive deficits by activating the non-amyloidogenic pathway via SIRT-1 signaling. Treadmill exercise improved cognitive deficits and alleviated neurotoxicity. Most importantly, treadmill exercise increased SIRT-1 level, which subsequently resulted in increased ADAM-10 level by down-regulation of ROCK-1 and upregulation of RARβ, ultimately facilitating the non-amyloidogenic pathway. Treadmill exercise-induced activation in SIRT-1 level also elevated PGC-1α level and reduced BACE-1 and C-99 level, resulting in inhibition of the amyloidogenic pathway. Treadmill exercise may thus inhibit Aβ production via upregulation of SIRT-1, which biases amyloid precursor protein processing toward the non-amyloidogenic pathway. This study provides novel and valuable insight into the molecular mechanisms possibly by which treadmill exercise reduces Aβ production.
•Treadmill exercise increased SIRT-1 levels, resulting in increased ADAM-10 by downregulating ROCK-1 and upregulating RARβ.•Treadmill exercise increased PGC-1α levels, which reduced BACE-1 and C-99 expression.•Treadmill exercise inhibits Aβ production possibly by activating non-amyloidogenic pathway via SIRT-1/PGC-1α signaling.
▶ Treadmill exercise ameliorates cognitive deficits in Tg mice. ▶ Treadmill exercise reduces Aβ-42 and tau deposition in Tg mice. ▶ Treadmill exercise reduces the number of TUNEL-positive cells in Tg ...mice. ▶ Treadmill exercise reduces TC, insulin, glucose, and corticosterone levels in Tg mice. ▶ Treadmill exercise may be beneficial in prevention or treatment in AD.
The present study was undertaken to further investigate the protective effect of treadmill exercise on the hippocampal proteins associated with neuronal cell death in an aged transgenic (Tg) mice with Alzheimer's disease (AD). To address this, Tg mouse model of AD, Tg-NSE/PS2m, which expresses human mutant PS2 in the brain, was chosen. Animals were subjected to treadmill exercise for 12 weeks from 24 months of age. The exercised mice were treadmill run at speed of 12
m/min, 60
min/day, 5 days/week on a 0% gradient for 3 months. Treadmill exercised mice improved cognitive function in water maze test. Treadmill exercised mice significantly reduced the expression of Aβ-42, Cox-2, and caspase-3 in the hippocampus. In parallel, treadmill exercised Tg mice decreased the phosphorylation levels of JNK, p38MAPK and tau (Ser404, Ser202, Thr231), and increased the phosphorylation levels of ERK, PI3K, Akt and GSK-3α/β. In addition, treadmill exercised Tg mice up-regulated the expressions of NGF, BDNF and phospho-CREB, and the expressions of SOD-1, SOD-2 and HSP-70. Treadmill exercised Tg mice up-regulated the expression of Bcl-2, and down-regulated the expressions of cytochrome c and Bax in the hippocampus. The number of TUNEL-positive cells in the hippocampus in mice was significantly decreased after treadmill exercise. Finally, serum TC, insulin, glucose, and corticosterone levels were significantly decreased in the Tg mice after treadmill exercise. As a consequence of such change, Aβ-dependent neuronal cell death in the hippocampus of Tg mice was markedly suppressed following treadmill exercise. These results strongly suggest that treadmill exercise provides a therapeutic potential to inhibit both Aβ-42 and neuronal death pathways. Therefore, treadmill exercise may be beneficial in prevention or treatment of AD.
•Obesity induces oxidative stress causing various pathological phenomena.•Obesity-induced pathological phenomena are modelled in rats fed a high fat diet.•Treadmill exercise rescued obesity-induced ...pathological phenomena in rats.
Obesity induces oxidative stress by causing hyperglycemia and insulin resistance, while contributing to cognitive and memory decline by inducing insulin resistance in the brain and hyperphosphorylation of Tau proteins. We aimed to investigate the effects of treadmill exercise in improving these obesity-induced pathological phenomena. Sprague-Dawley rats aged 20 weeks were fed a high-fat diet (HFD) for 20 weeks to induce obesity. The rats were subsequently subjected to treadmill exercise (progressively increasing load intensity) for 8 weeks. The rats were divided into three groups: normal diet-control (n = 15), HFD-control (n = 15), and HFD-treadmill exercise (n = 15). We performed water maze and passive avoidance tests and assessed weight, area under the curve, homeostatic model assessment of insulin resistance, and abdominal visceral fat/body weight. Western blot was used to examine protein expression related to brain insulin signaling, tau hyperphosphorylation, and NADPH oxidase, and immunohistochemistry was performed to examine the immunoreactivity of p-Tau (Ser 202/Thr 205) and p22-phox. Treadmill exercise effectively rescued brain insulin signaling, hyperphosphorylation and aggregation of Tau protein, and NADPH oxidase activation in the high fat diet group. Furthermore, it improved insulin resistance inhibitors, decreased abdominal fat mass, inhibited weight gain, and rescued learning and memory. Obesity-induced insulin resistance contributes to cognitive decline, such as reduced learning and memory, but physical activity, such as treadmill exercise, was found to have a positive effect on brain function by improving thesepathological phenomena. Therefore, we suggest that treadmill exercise must be considered in the prevention and treatment of metabolic and neurodegenerative diseases.
Abstract Parkinson's disease (PD) is one of the main degenerative neurological disorders accompanying death of dopaminergic neurons prevalent in aged population. Endurance exercise (EE) has been ...suggested to confer neurogenesis and mitigate the degree of seriousness of PD. However, underlying molecular mechanisms responsible for exercise-mediated neuroprotection against PD remain largely unknown. Given the relevant interplay between elevated α-synuclein and neuroinflammation in a poor prognosis and vicious progression of PD and anti-inflammatory effects of EE, we hypothesized that EE would reverse motor dysfunction and cell death caused by PD. To this end, we chose a pharmacological model of PD (e.g., chronic injection of neurotoxin MPTP). Young adult male mice (7 weeks old) were randomly divided into three groups: sedentary control (C, n=10), MPTP (M, n=10), and MPTP + endurance exercise (ME, n= 10). Our data showed that EE restored motor function impaired by MPTP in parallel with reduced cell death. Strikingly, EE exhibited a significant reduction in α-synuclein protein along with diminished pro-inflammatory cytokines (i.e., TNF-α and IL-1β). Supporting this, EE prevented activation of Toll like receptor 2 (TLR2) downstream signaling cascades such as MyD88, TRAF6 and TAK-1 incurred by in MPTP administration in the striatum. Moreover, EE reestablished tyrosine hydroxylase at levels similar to C group. Taken together, our data suggest that an EE-mediated neuroprotective mechanism against PD underlies anti-neuroinflammation conferred by reduced levels of α-synuclein. Our data provides an important insight into developing a non-pharmacological countermeasure against neuronal degeneration caused by PD.
The diagnosis of myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is problematic due to the lack of established objective measurements. Postexertional malaise (PEM) is a hallmark of ...ME/CFS, and the two-day cardiopulmonary exercise test (CPET) has been tested as a tool to assess functional impairment in ME/CFS patients. This study aimed to estimate the potential of the CPET.
We reviewed studies of the two-day CPET and meta-analyzed the differences between ME/CFS patients and controls regarding four parameters: volume of oxygen consumption and level of workload at peak (VO
, Workload
) and at ventilatory threshold (VO
@VT, Workload@VT).
The overall mean values of all parameters were lower on the 2nd day of the CPET than the 1st in ME/CFS patients, while it increased in the controls. From the meta-analysis, the difference between patients and controls was highly significant at Workload@VT (overall mean: -10.8 at Test 1 vs. -33.0 at Test 2,
< 0.05), which may reflect present the functional impairment associated with PEM.
Our results show the potential of the two-day CPET to serve as an objective assessment of PEM in ME/CFS patients. Further clinical trials are required to validate this tool compared to other fatigue-inducing disorders, including depression, using well-designed large-scale studies.
Mitochondrial dysfunction is implicated in the pathogenesis of multiple muscular diseases, including sporadic inclusion body myositis (s-IBM), the most common aging-related muscle disease. However, ...the factors causing mitochondrial dysfunction in s-IBM are unknown.
We hypothesized that resistance exercise (RE) may alleviate muscle impairment by improving mitochondrial function via reducing amyloid-beta (Aβ) accumulation.
Twenty-four male Wistar rats were randomized to a saline-injection control group (sham, n = 8), a chloroquine (CQ) control group (CQ-CON, n = 8), and a CQ plus RE group (CQ-RE, n = 8) in which rats climbed a ladder with weight attached to their tails 9 weeks after starting CQ treatment.
RE markedly inhibited soleus muscle atrophy and muscle damage. RE reduced CQ-induced Aβ accumulation, which resulted in decreased formation of rimmed vacuoles and mitochondrial-mediated apoptosis. Most importantly, the decreased Aβ accumulation improved both mitochondrial quality control (MQC) through increased mitochondrial biogenesis and mitophagy, and mitochondrial dynamics. Furthermore, RE-mediated reduction of Aβ accumulation elevated mitochondrial oxidative capacity by upregulating superoxide dismutase-2, catalase, and citrate synthase via activating sirtuin 3 signaling.
RE enhances mitochondrial function by improving MQC and mitochondrial oxidative capacity via reducing Aβ accumulation, thereby inhibiting CQ-induced muscle impairment, in a rat model of s-IBM.
Alzheimer’s disease (AD) is characterized by the deposition of aggregated amyloid-beta (Aβ), which triggers a cellular stress response called the unfolded protein response (UPR). The UPR signaling ...pathway is a cellular defense system for dealing with the accumulation of misfolded proteins but switches to apoptosis when endoplasmic reticulum (ER) stress is prolonged. ER stress is involved in neurodegenerative diseases including AD, but the molecular mechanisms of neuronal apoptosis and inflammation by Aβ-induced ER stress to exercise training are not fully understood. Here, we demonstrated that treadmill exercise (TE) prevented PS2 mutation-induced memory impairment and reduced Aβ-42 deposition through the inhibition of β-secretase (BACE-1) and its product, C-99 in cortex and/or hippocampus of aged PS2 mutant mice. We also found that TE down-regulated the expression of GRP78/Bip and PDI proteins and inhibited activation of PERK, eIF2α, ATF6α, sXBP1 and JNK-p38 MAPK as well as activation of CHOP, caspase-12 and caspase-3. Moreover, TE up-regulated the expression of Bcl-2 and down-regulated the expressions of Bax in the hippocampus of aged PS2 mutant mice. Finally, the generation of TNFα and IL-1α and the number of TUNEL-positive cells in the hippocampus of aged PS2 mutant mice was also prevented or decreased by TE. These results showed that TE suppressed the activation of UPR signaling pathways as well as inhibited the apoptotic pathways of the UPR and inflammatory response following Aβ-induced ER stress. Thus, therapeutic strategies that modulate Aβ-induced ER stress through TE could represent a promising approach for the prevention or treatment of AD.
Growing evidence has shown that endurance exercise is a strong inducer of autophagy in various tissues. Thus, we define here endurance exercise-induced autophagy as "kinetophagy" derived from the ...Greek terms "kineto" (movement), "auto" (self), and "phagy" (eating). Currently, the exact cellular mechanisms responsible for kinetophagy remain unclear; hence, we examined kinetophagy signaling transduction pathways occurring during acute endurance exercise (AEE).
C57BL/6 mice were randomly assigned to either AEE (n = 7) or control sedentary group (CON, n = 7). After 5 d of treadmill running acclimation, mice performed 60 min of a single bout of treadmill running at 12 m · min(-1) on a 0% grade. Hearts were excised immediately 1 h after exercise and homogenized for Western blot analyses.
Our data showed that AEE promoted kinetophagy flux (an increase in LC3-II to LC3-I ratio and LC3-II levels and a reduction in p62 levels) with Beclin-1 levels suppressed but Atg7 levels elevated compared with those in the sedentary group. We also observed that AEE increased lysosome-associated membrane protein and cathepsin L, linked to the termination process of autophagy, and that AEE augmented potent autophagy inducers (i.e., adenosine monophosphate kinase phosphorylation, BNIP3, and HSP70). Moreover, we found that exercise-mediated BNIP3 upregulation is associated with hypoxia-inducing factor 1α rather than FoxO3a. Intriguingly, we found for the first time that kinetophagy parallels with anabolic signaling activation (Akt and mammalian target of rapamycin).
Our findings provide evidence that AEE results in kinetophagy without a time-associated elevation in Beclin-1 but with the presence of Akt-mTOR activation and that AEE-induced activation of anabolic signaling is not associated with kinetophagy promotion.
Sporadic inclusion body myositis (sIBM), a muscular degenerative disease in the elderly, is an inflammatory myopathy characterized by muscle weakness in the wrist flexor, quadriceps, and tibialis ...anterior muscles. We aimed to identify the therapeutic effect of resistance exercise (RE) in improving sIBM symptoms in an sIBM animal model.
Six-week-old male Wistar rats were divided into a sham group (sham, n = 12), chloroquine-control group (CQ-con, n = 12), and chloroquine-RE group (CQ-RE, n = 12). The rats were subjected to 1 wk of exercise adaptation and 8 wk of exercise (three sessions per week). Protein expression was measured by Western blotting. Rimmed vacuoles (RV) were identified by hematoxylin and eosin staining and modified Gömöri trichrome staining, and amyloid deposition was examined by Congo red staining.
The effects of CQ and RE differed depending on myofiber characteristics. Soleus muscles showed abnormal autophagy in response to CQ, which increased RV generation and amyloid-β accumulation, resulting in atrophy. RE generated RV and decreased amyloid deposition in soleus muscles and also improved autophagy without generating hypertrophy. This reduced the atrophy signal transduction, resulting in decreased atrophy compared with the CQ-con group. Despite no direct effect of CQ, flexor hallucis longus muscles showed loss of mass because of reduced activity or increased inflammatory response; however, RE increased the hypertrophy signal, resulting in reduced autophagy and atrophy.
These results demonstrate that RE had a preventive effect on sIBM induced by CQ treatment in an animal model. However, because the results were from an animal experiment, a more detailed study should be conducted over a longer period, and the effectiveness of different RE programs should also be investigated.
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