Faculty Profiles - HIGASHIDA Kazuhiko

Papers - HIGASHIDA Kazuhiko

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PPARβ Is Essential for Maintaining Normal Levels of PGC-1α and Mitochondria and for the Increase in Muscle Mitochondria Induced by Exercise. Reviewed International journal

Jin-Ho Koh, Chad R Hancock, Shin Terada, Kazuhiko Higashida, John O Holloszy, Dong-Ho Han

Cell metabolism 25 ( 5 ) 1176 - 1185 2017.5

Language：English Publishing type：Research paper (scientific journal) Publisher：CELL PRESS

The objective of this study was to evaluate the specific mechanism(s) by which PPARβ regulates mitochondrial content in skeletal muscle. We discovered that PPARβ increases PGC-1α by protecting it from degradation by binding to PGC-1α and limiting ubiquitination. PPARβ also induces an increase in nuclear respiratory factor 1 (NRF-1) expression, resulting in increases in mitochondrial respiratory chain proteins and MEF2A, for which NRF-1 is a transcription factor. There was also an increase in AMP kinase phosphorylation mediated by an NRF-1-induced increase in CAM kinase kinase-β (CaMKKβ). Knockdown of PPARβ resulted in large decreases in the levels of PGC-1α and mitochondrial proteins and a marked attenuation of the exercise-induced increase in mitochondrial biogenesis. In conclusion, PPARβ induces an increase in PGC-1α protein, and PPARβ is a transcription factor for NRF-1. Thus, PPARβ plays essential roles in the maintenance and adaptive increase in mitochondrial enzymes in skeletal muscle by exercise.

DOI： 10.1016/j.cmet.2017.04.029

Web of Science

PubMed

Effects of rapid or slow body weight reduction on intramuscular protein degradation pathways during equivalent weight loss on rats Reviewed

Nonaka Y., Urashima S., Inai M., Nishimura S., Higashida K., Terada S.

Physiological Research 66 ( 5 ) 823 - 831 2017.1

A Mechanism Underlying Preventive Effect of High-Intensity Training on Colon Cancer

Matsuo K, Sato K, Suemoto K, Miyamoto-Mikami E, Fuku N, Higashida K, Tsuji K, Xu Y, Liu X, Iemitsu M, Hamaoka T, Tabata I

Med Sci Sports Exerc 2017

Alternate-Day High-Fat Diet Induces an Increase in Mitochondrial Enzyme Activities and Protein Content in Rat Skeletal Muscle. International journal

Xi Li, Kazuhiko Higashida, Takuji Kawamura, Mitsuru Higuchi

Nutrients 8 ( 4 ) 203 - 203 2016.4

Language：English Publishing type：Research paper (scientific journal)

Long-term high-fat diet increases muscle mitochondrial enzyme activity and endurance performance. However, excessive calorie intake causes intra-abdominal fat accumulation and metabolic syndrome. The purpose of this study was to investigate the effect of an alternating day high-fat diet on muscle mitochondrial enzyme activities, protein content, and intra-abdominal fat mass in rats. Male Wistar rats were given a standard chow diet (CON), high-fat diet (HFD), or alternate-day high-fat diet (ALT) for 4 weeks. Rats in the ALT group were fed a high-fat diet and standard chow every other day for 4 weeks. After the dietary intervention, mitochondrial enzyme activities and protein content in skeletal muscle were measured. Although body weight did not differ among groups, the epididymal fat mass in the HFD group was higher than those of the CON and ALT groups. Citrate synthase and beta-hydroxyacyl CoA dehydrogenase activities in the plantaris muscle of rats in HFD and ALT were significantly higher than that in CON rats, whereas there was no difference between HFD and ALT groups. No significant difference was observed in muscle glycogen concentration or glucose transporter-4 protein content among the three groups. These results suggest that an alternate-day high-fat diet induces increases in mitochondrial enzyme activities and protein content in rat skeletal muscle without intra-abdominal fat accumulation.

DOI： 10.3390/nu8040203

PubMed

酪酸摂取がラット骨格筋における糖輸送体GLUT-4タンパク質の発現量に及ぼす影響

野中雄大, 東田一彦, 木村典代, 寺田新

体力科学 65 ( 1 ) 169 - 176 2016.2

Language：Japanese Publishing type：Research paper (scientific journal) Publisher：(一社)日本体力医学会

酪酸摂取がラット骨格筋における糖輸送体GLUT-4タンパク質の発現量に及ぼす影響について検討した。Sprague-Dawley系雄ラットを使用し、予備飼育期間と同じ粉末飼料を摂取させる対照群(C群)、もしくは酪酸を配合した粉末飼料を摂取させる群(SB群)に分けた。飼育期間中の総摂取量、飼料効率は両群間で有意差は認めなかった。クエン酸合成酵素タンパク質発現量は、滑車上筋およびヒラメ筋いずれの筋においても2群間に有意差は認めなかった。ヒラメ筋のアミノレブリン酸合成酵素タンパク質発現量は、C群と比較してSB群で有意に高値を示した。GLUT-4タンパク質発現量は、滑車上筋ではC群と比較してSB群で有意に低値、ヒラメ筋ではC群と比較してSB群で有意に低値を示した。SB群の滑車上筋およびヒラメ筋におけるMCT1タンパク質発現量は、C群に比べて有意に高値を示した。インスリン投与前、即ち空腹時の血糖値には両群間に有意差は認めなかった。食餌条件と時間における交互作用は認めなかったが、食餌条件による主効果を認め、C群と比較してSB群の血糖値は有意に高値を示した。

DOI： 10.7600/jspfsm.65.169

【未来の扉をひらく運動の研究】運動による抗糖尿病効果とエピジェネティクス

寺田新, 野中雄大, 東田一彦

体育の科学 66 ( 1 ) 36 - 43 2016.1

Dehydroepiandrosterone activates AMP kinase and regulates GLUT4 and PGC-1α expression in C2C12 myotubes. Reviewed

Yokokawa T, Sato K, Iwanaka N, Honda H, Higashida K, Iemitsu M, Hayashi T, Hashimoto T

Biochemical and biophysical research communications 463 ( 1-2 ) 42 - 47 2015.7

Publishing type：Research paper (scientific journal)

Exercise and caloric restriction (CR) have been reported to have anti-ageing, anti-obesity, and health-promoting effects. Both interventions increase the level of dehydroepiandrosterone (DHEA) in muscle and blood, suggesting that DHEA might partially mediate these effects. In addition, it is thought that either 5'-adenosine monophosphate-activated protein kinase (AMPK) or peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) mediates the beneficial effects of exercise and CR. However, the effects of DHEA on AMPK activity and PGC-1α expression remain unclear. Therefore, we explored whether DHEA in myotubes acts as an activator of AMPK and increases PGC-1α. DHEA exposure increased glucose uptake but not the phosphorylation levels of Akt and PKCζ/λ in C2C12 myotubes. In contrast, the phosphorylation levels of AMPK were elevated by DHEA exposure. Finally, we found that DHEA induced the expression of the genes PGC-1α and GLUT4. Our current results might reveal a previously unrecognized physiological role of DHEA; the activation of AMPK and the induction of PGC-1α by DHEA might mediate its anti-obesity and health-promoting effects in living organisms.

DOI： 10.1016/j.bbrc.2015.05.013

Scopus

PubMed

Mixed lactate and caffeine compound increases satellite cell activity and anabolic signals for muscle hypertrophy. Reviewed International journal

Yoshimi Oishi, Hayato Tsukamoto, Takumi Yokokawa, Keisuke Hirotsu, Mariko Shimazu, Kenji Uchida, Hironori Tomi, Kazuhiko Higashida, Nobumasa Iwanaka, Takeshi Hashimoto

Journal of applied physiology (Bethesda, Md. : 1985) 118 ( 6 ) 742 - 9 2015.3

Language：English Publishing type：Research paper (scientific journal)

We examined whether a mixed lactate and caffeine compound (LC) could effectively elicit proliferation and differentiation of satellite cells or activate anabolic signals in skeletal muscles. We cultured C2C12 cells with either lactate or LC for 6 h. We found that lactate significantly increased myogenin and follistatin protein levels and phosphorylation of P70S6K while decreasing the levels of myostatin relative to the control. LC significantly increased protein levels of Pax7, MyoD, and Ki67 in addition to myogenin, relative to control. LC also significantly increased follistatin expression relative to control and stimulated phosphorylation of mTOR and P70S6K. In an in vivo study, male F344/DuCrlCrlj rats were assigned to control (Sed, n = 10), exercise (Ex, n = 12), and LC supplementation (LCEx, n = 13) groups. LC was orally administered daily. The LCEx and Ex groups were exercised on a treadmill, running for 30 min at low intensity every other day for 4 wk. The LCEx group experienced a significant increase in the mass of the gastrocnemius (GA) and tibialis anterior (TA) relative to both the Sed and Ex groups. Furthermore, the LCEx group showed a significant increase in the total DNA content of TA compared with the Sed group. The LCEx group experienced a significant increase in myogenin and follistatin expression of GA relative to the Ex group. These results suggest that administration of LC can effectively increase muscle mass concomitant with elevated numbers of myonuclei, even with low-intensity exercise training, via activated satellite cells and anabolic signals.

DOI： 10.1152/japplphysiol.00054.2014

PubMed

PGC-1α mediates a rapid, exercise-induced downregulation of glycogenolysis in rat skeletal muscle. International journal

Sang Hyun Kim, Jin Ho Koh, Kazuhiko Higashida, Su Ryun Jung, John O Holloszy, Dong-Ho Han

The Journal of physiology 593 ( 3 ) 635 - 43 2015.2

Language：English Publishing type：Research paper (scientific journal)

KEY POINTS: Long-term endurance exercise training results in a reduction in the rates of muscle glycogen depletion and lactic acid accumulation during submaximal exercise; this adaptation is mediated by an increase in muscle mitochondria. There is evidence suggesting that short-term training induces adaptations that downregulate glycogenolysis before there is an increase in functional mitochondria. We discovered that a single long bout of exercise induces decreases in expression of glycogenolytic and glycolytic enzymes in rat skeletal muscle; this adaptation results in slower rates of glycogenolysis and lactic acid accumulation in muscle during contractile activity. Two additional days of training amplified the adaptive response, which appears to be mediated by PGC-1α; this adaptation is biologically significant, because glycogen depletion and lactic acid accumulation are major causes of muscle fatigue. ABSTRACT: Endurance exercise training can increase the ability to perform prolonged strenuous exercise. The major adaptation responsible for this increase in endurance is an increase in muscle mitochondria. This adaptation occurs too slowly to provide a survival advantage when there is a sudden change in environment that necessitates prolonged exercise. In the present study, we discovered another, more rapid adaptation, a downregulation of expression of the glycogenolytic and glycolytic enzymes in muscle that mediates a slowing of muscle glycogen depletion and lactic acid accumulation. This adaptation, which appears to be mediated by PGC-1α, occurs in response to a single exercise bout and is further enhanced by two additional daily exercise bouts. It is biologically significant, because glycogen depletion and lactic acid accumulation are two of the major causes of muscle fatigue and exhaustion.

DOI： 10.1113/jphysiol.2014.283820

PubMed

異なる脂質含量の食餌がラットの骨格筋ミトコンドリア酵素活性および持久性運動パフォーマンスに及ぼす影響

東田一彦, 園生智広, 藤本恵理, 樋口満

スポーツ科学研究 12 137 - 144 2015

Corticosterone accelerates atherosclerosis in the apolipoprotein E-deficient mouse. International journal

Mitsuharu Okutsu, Vitor A Lira, Kazuhiko Higashida, Jonathan Peake, Mitsuru Higuchi, Katsuhiko Suzuki

Atherosclerosis 232 ( 2 ) 414 - 9 2014.2

Language：English Publishing type：Research paper (scientific journal)

Chronic stress is an important risk factor for atherosclerosis, which is a chief process in the development of cardiovascular disease. Increased circulating levels of corticosterone have been documented in several animal models of chronic stress. However, it remains to be established whether corticosterone is sufficient to exacerbate atherosclerosis. To test this hypothesis, apolipoprotein E (ApoE)-deficient mice were fed a high-fat diet for 13 weeks with exposure to either corticosterone or vehicle in the drinking water (CORT and Con). Corticosterone treatment significantly increased atherosclerotic plaque area at the aortic root. Such exacerbation of atherosclerosis was accompanied by significantly lower levels of circulating white blood cells and serum interleukin-1β (IL-1β), and significantly elevated serum concentrations of total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and small dense low-density lipoprotein (sd-LDL) in CORT mice when compared to Con mice. These findings demonstrate that corticosterone is sufficient to exacerbate atherosclerosis in vivo despite its anti-inflammatory properties and that this marked pro-atherogenic phenotype is primarily associated with increased dyslipidaemia.

DOI： 10.1016/j.atherosclerosis.2013.11.076

PubMed

【運動刺激の正体を探る】運動刺激に伴う骨格筋代謝機能の適応

寺田新, 東田一彦

体育の科学 63 ( 8 ) 608 - 615 2013.8

β-Adrenergic Stimulation Does Not Activate p38 MAPKinase or Induce PGC-1α in Skeletal Muscle

Kim SH, Asaka M, Higashida K, Takahashi Y, Holloszy JO, Han DH

Am J Physiol Endocrinol Metab 304 ( 8 ) 844 - 852 2013

間欠的絶食による摂取エネルギー制限がラット骨格筋のPGC-1αおよびGLUT-4 蛋白発現量に及ぼす影響

東田　一彦、樋口　満、寺田　新

スポーツ科学研究 10 1 - 11 2013

Effects of alternate-day fasting on high-fat diet-induced insulin resistance in rat skeletal muscle

Higashida K, Fujimoto E, Higuchi M, Terada S

Life Sci 93 ( 5 ) 208 - 213 2013

Effects of Resveratrol and SIRT1 on PGC-1α Activity and Mitochondrial Biogenesis: A Reevaluation

Higashida　K, Kim　SH, Jung SR, Asaka M, Holloszy JO, Han DH

PLOS Biology 11 ( 7 ) e1001603 2013

Regulation of Skeletal muscle GLUT-4 expression by exercise and nutritional stimuli

Higashida K, Tabata I, Higuchi M, Terada S

J Phys Fitness Sports Med 2 ( 3 ) 355 - 360 2013

Ursolic acid stimulates mTORC1 signaling after resistance exercise in rat skeletal muscle

Ogasawara R, Sato K, Higashida K, Nakazato K, Fujita S

Am J Physiol Endocrinol Metab 305 ( 6 ) 760 - 765 2013

Modest hypoxia significantly reduces triglyceride content and lipid droplet size in 3T3-L1 adipocytes

Hashimoto T, Yokokawa T, Endo Y, Iwanaka N, Higashida K, Taguchi S

Biochem Biophys Res Commun 440 ( 1 ) 43 - 49 2013

The AMPK beta2 subunit is required for energy homeostasis during metabolic stress

Dasgupta B, Ju JS, Sasaki Y, Liu X, Jung SR, Higashida K, Lindquist D, Milbrandt J

Mol Cell Biol 32 ( 14 ) 2837 - 2848 2012

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Papers - HIGASHIDA Kazuhiko