Entity

Time filter

Source Type


Kim H.K.,Tokyo Metropolitan University | Suzuki T.,National Institute for Longevity science | Saito K.,Tokyo Metropolitan University | Yoshida H.,Tokyo Metropolitan University | And 3 more authors.
Journal of the American Geriatrics Society | Year: 2012

Objectives To evaluate the effectiveness of exercise and amino acid supplementation in enhancing muscle mass and strength in community-dwelling elderly sarcopenic women. Design Randomized controlled trial. Setting Urban community in Tokyo, Japan. Participants One hundred fifty-five women aged 75 and older were defined as sarcopenic and randomly assigned to one of four groups: exercise and amino acid supplementation (exercise + AAS; n = 38), exercise (n = 39), amino acid supplementation (AAS; n = 39), or health education (HE; n = 39). Intervention The exercise group attended a 60-minute comprehensive training program twice a week, and the AAS group ingested 3 g of a leucine-rich essential amino acid mixture twice a day for 3 months. Measurements Body composition was determined using bioelectrical impedance analysis. Data from interviews and functional fitness parameters such as muscle strength and walking ability were collected at baseline and after the 3-month intervention. Results A significant group × time interaction was seen in leg muscle mass (P =.007), usual walking speed (P =.007), and knee extension strength (P =.017). The within-group analysis showed that walking speed significantly increased in all three intervention groups, leg muscle mass in the exercise + AAS and exercise groups, and knee extension strength only in the exercise + AAS group (9.3% increase, P =.01). The odds ratio for leg muscle mass and knee extension strength improvement was more than four times as great in the exercise + AAS group (odds ratio = 4.89, 95% confidence interval = 1.89-11.27) as in the HE group. Conclusion The data suggest that exercise and AAS together may be effective in enhancing not only muscle strength, but also combined variables of muscle mass and walking speed and of muscle mass and strength in sarcopenic women. © 2011, The American Geriatrics Society. Source


Matsuzaki K.,Kyoto University | Kato K.,Nagoya City University | Kato K.,Japan Institute for Molecular Science | Yanagisawa K.,National Institute for Longevity science
Biochimica et Biophysica Acta - Molecular and Cell Biology of Lipids | Year: 2010

Clarification of the molecular and cellular mechanisms underlying the assembly of amyloid β-protein (Aβ) into insoluble fibrils in the brain has been one of the biggest challenges in the research on Alzheimer disease (AD). We previously identified a novel Aβ species, which was characterized by its tight binding to GM1 ganglioside (GM1), in the brain showing early pathological changes of AD. The ganglioside-bound Aβ (GAβ) possessed unique characteristics, including its altered immunoreactivity, which suggests its distinct conformation from native Aβ, and its strong potency to accelerate Aβ assembly into fibrils. On the basis of these characteristics, it was hypothesized that Aβ adopts an altered conformation following interaction with GM1, leading to the generation of GAβ, and then GAβ acts as an endogenous seed for Alzheimer amyloid in the brain. To date, various in vitro and in vivo studies on GAβ have revealed how Aβ binds to gangliosides, i.e., what are the favorable physicochemical and neurobiological conditions for generating GAβ, and what is the pathological significance of ganglioside-induced Aβ assembly in the development of AD. Interestingly, GAβ is favorably generated in the unique ganglioside-enriched (clustered), raft-like microdomains; moreover, amyloid fibrils formed in the presence of gangliosides are neurotoxic. Furthermore, the conformational change of Aβ in the presence of ganglioside has been characterized by an NMR study. In this review, we focus on the recent progress of GAβ studies and highlight the possibility that ganglioside binding is the initial and common step in the development of a part of human misfolding-type amyloidoses, including AD. © 2010 Elsevier B.V. All rights reserved. Source


Into T.,Asahi University | Inomata M.,Asahi University | Niida S.,National Institute for Longevity science | Murakami Y.,Asahi University | Shibata K.-I.,Hokkaido University
Journal of Biological Chemistry | Year: 2010

MyD88 is an essential adaptor molecule for Toll-like receptors (TLRs) and interleukin (IL)-1 receptor. MyD88 is thought to be present as condensed forms or aggregated structures in the cytoplasm, although the reason has not yet been clear. Here, we show that endogenous MyD88 is present as small speckle-like condensed structures, formation of which depends on MyD88 dimerization. In addition, formation of large aggregated structures is related to cytoplasmic accumulation of sequestosome 1 (SQSTM1; also known as p62) and histone deacetylase 6 (HDAC6), which are involved in accumulation of polyubiquitinated proteins. A gene knockdown study revealed that SQSTM1 and HDAC6 were required for MyD88 aggregation and exhibited a suppressive effect on TLR ligand-induced expression of IL-6 and NOS2 in RAW264.7 cells. SQSTM1 and HDAC6 were partially involved in suppression of several TLR4-mediated signaling events, including activation of p38 and JNK, but they hardly affected degradation of IκBα (inhibitor of nuclear factor κB). Biochemical induction of MyD88 oligomerization induced recruitment of SQSTM1 and HDAC6 to the MyD88-TRAF6 signaling complex. Repression of SQSTM1 and HDAC6 enhanced formation of the MyD88-TRAF6 complex and conversely decreased interaction of the ubiquitin-specific negative regulator CYLD with the complex. Furthermore, ubiquitin-binding regions on SQSTM1 and HDAC6 were essential for MyD88 aggregation but were not required for interaction with the MyD88 complex. Thus, our study reveals not only that SQSTM1 and HDAC6 are important determinants of aggregated localization of MyD88 but also that MyD88 activates a machinery of polyubiquitinated protein accumulation that has a modulatory effect on MyD88-dependent signal transduction. © 2010 by The American Society for Biochemistry and Molecular Biology, Inc. Source


Inomata M.,Asahi University | Niida S.,National Institute for Longevity science | Shibata K.-I.,Hokkaido University | Into T.,Asahi University
Cellular and Molecular Life Sciences | Year: 2012

Toll-like receptor (TLR) signaling is linked to autophagy that facilitates elimination of intracellular pathogens. However, it is largely unknown whether autophagy controls TLR signaling. Here, we report that poly (I: C) stimulation induces selective autophagic degradation of the TLR adaptor molecule TRIF and the signaling molecule TRAF6, which is revealed by gene silencing of the ubiquitin- editing enzyme A20. This type of autophagy induced formation of autophagosomes and could be suppressed by an autophagy inhibitor and lysosomal inhibitors. However, this autophagy was not associated with canonical autophagic processes, including involvement of Beclin-1 and conversion of LC3-I to LC3-II. Through screening of TRIF-interacting 'autophagy receptors' in human cells, we identified that NDP52 mediated the selective autophagic degradation of TRIF and TRAF6 but not TRAF3. NDP52 was polyubiquitinated by TRAF6 and was involved in aggregation of TRAF6, which may result in the selective degradation. Intriguingly, only under the condition of A20 silencing, NDP52 could effectively suppress poly (I: C) - induced proinflammatory gene expression. Thus, this study clarifies a selective autophagic mechanism mediated by NDP52 that works downstream of TRIF-TRAF6. Furthermore, although A20 is known as a signaling fine-tuner to prevent excess TLR signaling, it paradoxically downregulates the fine-tuning effect of NDP52 on TLR signaling. © 2011 Springer Basel AG. Source


Uezumi A.,Health Science University | Ikemoto-Uezumi M.,National Institute for Longevity science | Tsuchida K.,Health Science University
Frontiers in Physiology | Year: 2014

Adult skeletal muscle possesses a remarkable regenerative ability that is dependent on satellite cells. However, skeletal muscle is replaced by fatty and fibrous connective tissue in several pathological conditions. Fatty and fibrous connective tissue becomes a major cause of muscle weakness and leads to further impairment of muscle function. Because the occurrence of fatty and fibrous connective tissue is usually associated with severe destruction of muscle, the idea that dysregulation of the fate switch in satellite cells may underlie this pathological change has emerged. However, recent studies identified nonmyogenic mesenchymal progenitors in skeletal muscle and revealed that fatty and fibrous connective tissue originates from these progenitors. Later, these progenitors were also demonstrated to be the major contributor to heterotopic ossification in skeletal muscle. Because nonmyogenic mesenchymal progenitors represent a distinct cell population from satellite cells, targeting these progenitors could be an ideal therapeutic strategy that specifically prevents pathological changes of skeletal muscle, while preserving satellite cell-dependent regeneration. In addition to their roles in pathogenesis of skeletal muscle, nonmyogenic mesenchymal progenitors may play a vital role in muscle regeneration by regulating satellite cell behavior. Conversely, muscle cells appear to regulate behavior of nonmyogenic mesenchymal progenitors. Thus, these cells regulate each other reciprocally and a proper balance between them is a key determinant of muscle integrity. Furthermore, nonmyogenic mesenchymal progenitors have been shown to maintain muscle mass in a steady homeostatic condition. Understanding the nature of nonmyogenic mesenchymal progenitors will provide valuable insight into the pathophysiology of skeletal muscle. In this review, we focus on nonmyogenic mesenchymal progenitors and discuss their roles in muscle pathogenesis, regeneration, and homeostasis. © 2014 Uezumi, Ikemoto-Uezumi and Tsuchida. Source

Discover hidden collaborations