Insu Kwon

Neuroprotective effects of endurance exercise against neuroinflammation in MPTP-induced Parkinson's disease mice

Parkinsons 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.

Effects of long-term resistance exercise training on autophagy in rat skeletal muscle of chloroquine-induced sporadic inclusion body myositis

Purpose We examined whether resistance exercise training restores impaired autophagy functions caused by Chloroquine (CQ)-induced Sporadic Inclusion Body Myositis (sIBM) in rat skeletal muscle. Methods Male wistar rats were randomly assigned into three groups: Sham (n = 6), CQ (n = 6), and CQ + Exercise (CE, n = 6). To create a rat model of sIBM, rats in the CQ and CE group were intraperitoneally injected with CQ 5 days a week for 16 weeks. Rats in the CE group performed resistance exercise training 3 times a week for 8 weeks in conjunction with CQ starting from week 9 to week 16. During the training period, maximal carrying load, body weight, muscle weight, and relative muscle weight were measured. Autophagy responses were examined by measuring specific markers. Results While maximal carrying capacity for resistance exercise training was dramatically increased in the CE group, no significant changes occurred in the skeletal muscle weight as well as in the relative muscle weight of CE compared to the other groups. CQ treatment caused significant increases in the levels of Beclin-1 and p62, and decreases in the levels of LAMP-2 proteins. Interestingly, no significant differences in the LC3-II/I ratio or the LC3-II protein levels were observed. Although CQ-treatment groups suppressed the levels of the potent autophagy inducer, BNIP3, p62 levels were decreased in only the CE group. Conclusion Our findings demonstrate that sIBM induced by CQ treatment results in muscle degeneration via impaired autophagy and that resistance exercise training improves movable loading activity. Finally, regular exercise training may provide protection against sIBM by enhancing the autophagy flux through p62 protein.

Correction to: Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection

The article Potential signaling pathways of acute endurance exercise-induced cardiac autophagy and mitophagy and its possible role in cardioprotection, written by Youngil Lee.

Endurance exercise mediates neuroprotection against MPTP-mediated Parkinson’s disease via enhanced neurogenesis, antioxidant capacity, and autophagy

Parkinsons disease (PD) is a neurodegenerative disorder caused by loss of dopaminergic neurons in the substantia nigra, leading to motor dysfunction. Growing evidence has demonstrated that endurance exercise (EE) confers neuroprotection against PD. However, the exact molecular mechanisms responsible for exercise-induced protection of dopaminergic neurons in PD remain unclear. Since oxidative stress plays a key role in the degenerative process of PD. We investigated whether EE-induced neuroprotection is associated with enhanced antioxidative capacity and autophagy, using a mouse model of PD induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration. C57BL/6 male mice were randomly assigned to four groups: control (CON, n = 12), exercise (EXE, n = 12), MPTP (MPTP, n = 12) and MPTP + exercise (MPTP + EXE, n = 12). Our data demonstrated that while MPTP treatment impaired motor function, EE restored MPTP-induced motor deficits. Our biochemical data showed that EE-induced neuroprotection occurs in combination with multiple synergic neuroprotective pathways: (1) increased neurogenesis shown by an increase in BrdU-positive neurons; (2) diminished loss of dopaminergic neurons evidenced by upregulated tyrosine hydroxylase (TH) and dopamine transporter (DAT) levels; (3) increased antioxidant capacity (e.g., CuZnSOD, CATALASE, GPX1/2, HO-1, DJ1 and PRXIII); and (4) enhanced autophagy (LC3 II, p62, BECLIN1, BNIP3, LAMP2, CATHEPSIN L and TFEB). Our study suggests that EE-induced multiple synergic protective pathways including enhanced neurogenesis, antioxidative capacity, and concordant autophagy promotion contribute to restoration of impaired dopaminergic neuronal function caused by PD. Thus, PD patients should be encouraged to actively participate in regular EE as a potent nonpharmacological therapeutic strategy against PD.

Progression of thanatophagy in cadaver brain and heart tissues

Autophagy is an evolutionarily conserved catabolic process for maintaining cellular homeostasis during both normal and stress conditions. Metabolic reprogramming in tissues of dead bodies is inevitable due to chronic ischemia and nutrient deprivation, which are well-known features that stimulate autophagy. Currently, it is not fully elucidated whether postmortem autophagy, also known as thanatophagy, occurs in dead bodies is a function of the time of death. In this study, we tested the hypothesis that thanatophagy would increase in proportion to time elapsed since death for tissues collected from cadavers. Brain and heart tissue from corpses at different time intervals after death were analyzed by Western blot. Densitometry analysis demonstrated that thanatophagy occurred in a manner that was dependent on the time of death. The autophagy-associated proteins, LC3 II, p62, Beclin-1 and Atg7, increased in a time-dependent manner in heart tissues. A potent inducer of autophagy, BNIP3, decreased in the heart tissues as time of death increased, whereas the protein levels increased in brain tissues. However, there was no expression of BNIP3 at extended postmortem intervals in both brain and heart samples. Collectively, the present study demonstrates for the first time that thanatophagy occurs in brain and heart tissues of cadavers in a time-dependent manner. Further, our data suggest that cerebral thanatophagy may occur in a Beclin-1- independent manner. This unprecedented study provides potential insight into thanatophagy as a novel method for the estimation of the time of death in criminal investigationsAbstract: Autophagy is an evolutionarily conserved catabolic process for maintaining cellular homeostasis during both normal and stress conditions. Metabolic reprogramming in tissues of dead bodies is inevitable due to chronic ischemia and nutrient deprivation, which are well-known features that stimulate autophagy. Currently, it is not fully elucidated whether postmortem autophagy, also known as thanatophagy, occurs in dead bodies is a function of the time of death. In this study, we tested the hypothesis that thanatophagy would increase in proportion to time elapsed since death for tissues collected from cadavers. Brain and heart tissue from corpses at different time intervals after death were analyzed by Western blot. Densitometry analysis demonstrated that thanatophagy occurred in a manner that was dependent on the time of death. The autophagy-associated proteins, LC3 II, p62, Beclin-1 and Atg7, increased in a time-dependent manner in heart tissues. A potent inducer of autophagy, BNIP3, decreased in the heart tissues as time of death increased, whereas the protein levels increased in brain tissues. However, there was no expression of BNIP3 at extended postmortem intervals in both brain and heart samples. Collectively, the present study demonstrates for the first time that thanatophagy occurs in brain and heart tissues of cadavers in a time-dependent manner. Further, our data suggest that cerebral thanatophagy may occur in a Beclin-1- independent manner. This unprecedented study provides potential insight into thanatophagy as a novel method for the estimation of the time of death in criminal investigations

Modulation of mitochondrial phenotypes by endurance exercise contributes to neuroprotection against a MPTP-induced animal model of PD

Aim: Endurance exercise (EE) has been reported to confer neuroprotection against Parkinsons disease (PD); however, underlying molecular mechanisms of the protection remain still unclear. Since mitochondrial impairment is commonly observed in the brain of PD patients and animals, this study investigated whether EE‐induced neuroprotection is associated with mitochondrial phenotypes, using a mouse model of PD induced by intraperitoneal administration of 1‐methyl‐4‐phenyl‐1,2,3,6‐tetrahydropyridine (MPTP). Main methods: SH‐SY5Y cells were cultured with a neurotoxin MPP+ known to cause PD‐like symptoms to examine if modifications of mitochondrial morphology are linked to etiology of PD. For in vivo experiments, C57BL/6 male mice were randomly assigned to four groups: control (CON, n = 12), endurance exercise (EXE, n = 12), MPTP (MPTP, n = 12) and MPTP plus endurance exercise (MPTP + EXE, n = 12). Mice assigned to endurance exercise performed treadmill running at 12 m/min for 60 min/day, 5 days/week for 6 weeks. Key findings: SH‐SY5Y cells exposed to a neurotoxin MPP+ exhibited mitochondrial fragmentation and diminished mitochondrial proteins, and cell death. Similarly, animals administered with MPTP displayed comparable impairments in the substantia nigra pars compacta (SNpc). In contrast, EE intervention restored motor function to control levels and reduced apoptosis. These propitious effects of EE were associated with mitochondrial phenotypic changes such as upregulated anti‐apoptotic proteins (e.g., MCL‐1 and BLC‐2), reduced a pro‐apoptotic protein (e.g., AIF), and improved mitochondrial biogenesis and fusion. Significance: Our finding that EE‐induced mitochondrial phenotypic changes that resist mitochondrial impairment and cell death against PD introduce potential insight into mitochondria as a new therapeutic target for PD.

The Effects of Treadmill Exercise on Cognitive Performance, Brain Mitochondrial Aβ-42, Cytochrome c, SOD-1, 2 and Sirt-3 Protein Expression in Mutant (N141I) Presenilin-2 Transgenic Mice of Alzheimer`s Disease

본 연구의 목적은 PS-2 (N141I) 알츠하이머 형질전환 모델 생쥐를 대상으로 트레드밀 운동이 뇌의 세포질과 미토콘드리아의

Cardiac Kinetophagy Coincides with Activation of Anabolic Signaling.

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Long-term resistance exercise-induced muscular hypertrophy is associated with autophagy modulation in rats

-42, cytochrome c, SOD-1, 2 and Sirt-3 단백질 발현에 미치는 효과를 알아보는데 있다. 우선 알츠하이머 형질전환 생쥐를 Non-Tg-sedentary (n=5), Non-Tg-treadmill exercise (n=5) 집단과 Tg-sedentary (n=5), Tg-treadmill exercise (n=5) 집단으로 구분하고 트레드밀 운동을 통한 신경보호 효과를 검증하기 위해 Tg와 Non-Tg집단에 12주간 트레드밀 운동을 수행한 후 인지능력을 살펴보고 뇌의 세포질과 미토콘드리아의

Electrical Stimulation Mimics Endurance Exercise-induced Autophagy in Skeletal Muscle

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