論文 - 池田　真一

PARK2/Parkin-mediated mitochondrial clearance contributes to proteasome activation during slow-twitch muscle atrophy via NFE2L1 nuclear translocation

Norihiko Furuya, Shin-Ichi Ikeda, Shigeto Sato, Sanae Soma, Junji Ezaki, Juan Alejandro Oliva Trejo, Mitsue Takeda-Ezaki, Tsutomu Fujimura, Eri Arikawa-Hirasawa, Norihiro Tada, Masaaki Komatsu, Keiji Tanaka, Eiki Kominami, Nobutaka Hattori, Takashi Ueno

AUTOPHAGY （LANDES BIOSCIENCE）  10 （ 4 ） 631 - 641 2014年04月

査読有り,  ISSN  1554-8627

　概要を見る

Skeletal muscle atrophy is thought to result from hyperactivation of intracellular protein degradation pathways, including autophagy and the ubiquitin-proteasome system. However, the precise contributions of these pathways to muscle atrophy are unclear. Here, we show that an autophagy deficiency in denervated slow-twitch soleus muscles delayed skeletal muscle atrophy, reduced mitochondrial activity, and induced oxidative stress and accumulation of PARK2/Parkin, which participates in mitochondrial quality control (PARK2-mediated mitophagy), in mitochondria. Soleus muscles from denervated Park2 knockout mice also showed resistance to denervation, reduced mitochondrial activities, and increased oxidative stress. In both autophagy-deficient and Park2-deficient soleus muscles, denervation caused the accumulation of polyubiquitinated proteins. Denervation induced proteasomal activation via NFE2L1 nuclear translocation in control mice, whereas it had little effect in autophagy-deficient and Park2-deficient mice. These results suggest that PARK2-mediated mitophagy plays an essential role in the activation of proteasomes during denervation atrophy in slow-twitch muscles.

• Access to Document (DOI)

Exercise-induced enhancement of insulin sensitivity is associated with accumulation of M2-polarized macrophages in mouse skeletal muscle

Shin-ichi Ikeda, Yoshifumi Tamura, Saori Kakehi, Kageumi Takeno, Minako Kawaguchi, Takahiro Watanabe, Fumihiko Sato, Takeshi Ogihara, Akiko Kanazawa, Yoshio Fujitani, Ryuzo Kawamori, Hirotaka Watada

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  441 （ 1 ） 36 - 41 2013年11月

査読有り,  ISSN  0006-291X

　概要を見る

Exercise enhances insulin sensitivity in skeletal muscle, but the underlying mechanism remains obscure. Recent data suggest that alternatively activated M2 macrophages enhance insulin sensitivity in insulin target organs such as adipose tissue and liver. Therefore, the aim of this study was to determine the role of anti-inflammatory M2 macrophages in exercise-induced enhancement of insulin sensitivity in skeletal muscle. C57BL6J mice underwent a single bout of treadmill running (20 m/min, 90 min). Twenty-four hours later, ex vivo insulin-stimulated 2-deoxy glucose uptake was found to be increased in plantaris muscle. This change was associated with increased number of CD163-expressing macrophages (i.e. M2-polarized macrophages) in skeletal muscle. Systemic depletion of macrophages by pretreatment of mice with clodronate-containing liposome abrogated both CD163-positive macrophage accumulation in skeletal muscle as well as the enhancement of insulin sensitivity after exercise, without affecting insulin-induced phosphorylation of Akt and AS160 or exercise-induced GLUT4 expression. These results suggest that accumulation of M2-polarized macrophages is involved in exercise-induced enhancement of insulin sensitivity in mouse skeletal muscle, independently of the phosphorylation of Akt and AS160 and expression of GLUT4. (C) 2013 Elsevier Inc. All rights reserved.

• Access to Document (DOI)

Determinants of intramyocellular lipid accumulation after dietary fat loading in non-obese men

Yuko Sakurai, Yoshifumi Tamura, Kageumi Takeno, Naoki Kumashiro, Fumihiko Sato, Saori Kakehi, Shin-ichi Ikeda, Yuji Ogura, Norio Saga, Hisashi Naito, Shizuo Katamoto, Yoshio Fujitani, Takahisa Hirose, Ryuzo Kawamori, Hiritaka Watada

Journal of Diabetes Investigation （Journal of Diabetes Investigation）  2 （ 4 ） 310 - 317 2011年08月

査読有り

　概要を見る

UNLABELLED: Aims/Introduction:  Accumulation of intramyocellular lipid (IMCL) is associated with insulin resistance. However, the factors affecting the change in IMCL remain to be elucidated. The aim of the present study was to determine the factors that influence the change in IMCL level after high-fat loading. MATERIALS AND METHODS:   The study subjects were 37 non-obese men. Each subject consumed a high-fat diet for 3 days after a normal-fat diet for 3 days. After each diet program, IMCL levels in the tibialis anterior (TA-IMCL) and soleus (SOL-IMCL) were measured by proton magnetic resonance spectroscopy. Glucose infusion rate (GIR) was evaluated by euglycemic hyperinsulinemic clamp as an index of peripheral insulin sensitivity. RESULTS:   The high-fat diet significantly increased TA-IMCL and SOL-IMCL by ∼30 and ∼20%, respectively (P < 0.05), whereas it did not significantly alter GIR. The increase in SOL-IMCL, but not in TA-IMCL, negatively correlated with serum high molecular weight (HMW)-adiponectin (r = -0.36, P < 0.05) and HMW-/total-adiponectin ratio (r = -0.46, P < 0.05). Although high-fat diet-related changes in SOL-IMCL showed high inter-individual variations, in subjects doing exercise, changes in SOL-IMCL (r = 0.55, P < 0.05) and TA-IMCL (r = 0.61, P < 0.05) positively correlated with daily physical activity level. In contrast, in sedentary subjects, changes in SOL-IMCL (r = -0.50, P < 0.01) and TA-IMCL (r = -0.48, P < 0.05) negatively correlated with daily physical activity. CONCLUSIONS:   HMW-adiponectin and daily physical activity are determinants of IMCL accumulation by a high-fat diet. Intriguingly, the effect of daily physical activity on the change in IMCL depends on the level of regular exercise. (J Diabetes Invest,doi: 10.1111/j.2040-1124.2010.00091.x, 2011).

• Access to Document (DOI)

Acute exercise induces biphasic increase in respiratory mRNA in skeletal muscle

Shin-ichi Ikeda, Takako Kizaki, Shuko Haga, Hideki Ohno, Tohru Takemasa

Biochemical and Biophysical Research Communications （Biochemical and Biophysical Research Communications）  368 （ 2 ） 323 - 328 2008年04月

査読有り,  ISSN  0006-291X

　概要を見る

Peroxisome proliferator-activated receptor 7 coactivator-lot (PGC-1 alpha) promotes the expression of oxidative enzymes in skeletal muscle. We hypothesized that activation of the p38 MAPK (mitogen-activated protein kinase) in response to exercise was associated with exercise-induced PGC-1 alpha and respiratory enzymes expression and aimed to demonstrate this under the physiological level. We subjected mice to a single bout of treadmill running and found that the exercise induced a biphasic increase in the expression of respiratory enzymes mRNA. The second phase of the increase was accompanied by an increase in PGC-1 alpha protein, but the other was not. Administration of SB203580 (SB), an inhibitor of p38 MAPK, suppressed the increase in PGC-1 alpha expression and respiratory enzymes mRNA in both phases. These data suggest that p38 MAPK is associated with the exercise-induced expression of PGC-1 alpha and biphasic increase in respiratory enzyme mRNAs in mouse skeletal muscle under physiological conditions. (C) 2008 Elsevier Inc. All rights reserved.

• Access to Document (DOI)

Muscle type-specific response of PGC-1 alpha and oxidative enzymes during voluntary wheel running in mouse skeletal muscle

Shin-ichi Ikeda, H. Kawamoto, K. Kasaoka, Y. Hitomi, Takako Kizaki, Y. Sankai, Hideki Ohno, Shuko Haga, Tohru Takemasa

Acta Physiologica （Acta Physiologica）  188 （ 3-4 ） 217 - 223 2006年11月

査読有り,  ISSN  1748-1708

　概要を見る

Aim: It is generally accepted that endurance exercise increases the expression of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1 alpha), which governs the expression of oxidative metabolic enzymes. A previous report demonstrated that the regulation of mitochondrial protein expression in skeletal muscles in response to cold exposure depends on muscle fibre type. Cold exposure and endurance exercise are both metabolic challenges that require adjustments in mitochondrial energy metabolism, we hypothesized that the exercise-induced increase in oxidative enzymes and PGC-1 alpha expression is higher in fast-type than in slow-type muscle.
Methods: Female ICR mice were individually housed in cages equipped with running wheel for 1, 2, 4, 6 or 8 weeks. The soleus, plantaris (PLA) and tibialis anterior (TA) muscles were then prepared from each mouse. The expression levels of PGC-1 alpha, mitochondrial proteins and GLUT4 were evaluated by Western blotting.
Results: The expression level of PGC-1 alpha was increased only in the PLA muscle. Furthermore, the expression levels of all mitochondrial proteins and GLUT4 in the PLA muscle were increased. In the TA muscle, although there was no increase in PGC-1 alpha expression, the expression levels of mitochondrial proteins and GLUT4 were increased.
Conclusion: These results suggest that muscle type-specific responses occur during endurance exercise, and that the increase in PGC-1 alpha expression is not the only factor that promotes oxidative capacity as a result of endurance exercise.

• Access to Document (DOI)

Simple method for the identification of oxidative fibers in skeletal muscle

Tohru Takemasa, K. Sugimoto, Mitsunori Miyazaki, Masanao Machida, Shin-ichi Ikeda, Y. Hitomi, Takako Kizaki, Hideki Ohno, K. Yamashita, Shuko Haga

European Journal of Applied Physiology （ European Journal of Applied Physiology）  91 （ 2-3 ） 357 - 359 2004年03月

査読有り,  ISSN  1439-6319

　概要を見る

Skeletal muscle is composed of several different types of myofiber: slow oxidative (SO), fast glycolytic oxidative and fast glycolytic. However, the classification is usually determined by myosin heavy chain typing rather than by metabolic index. In this study, the oxidative metabolic index was investigated as a possible method of myofiber typing. Myoglobin, which is involved in oxygen transport and storage in myofibers, and mitochondria, which are the central organelles for oxidative metabolism, were studied. High levels of myoglobin and mitochondria are believed to exist in SO fibers, but the current study showed that they are considerably richer in some fast type fibers. As myofiber typing using the oxidative metabolic index is important physiologically, an attempt was made to find a simple method for this purpose. Some mitochondrial proteins have been observed to auto-fluoresce but until now this effect was too faint to detect easily. Owing to the recent advances in cooling charge-coupled device technology, such auto-fluorescence can now be used for myofiber typing, and the simple and rapid method for doing so is reported here.

• Access to Document (DOI)