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Abstract 17034: Deletion of NAD(P)H Oxidase 2 Attenuates Angiotensin II-induced Skeletal Muscle Atrophy

Kadoguchi, Tomoyasu ; Kinugawa, Shintaro ; Takada, Shingo ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2015

In: Circulation Vol. 132, No. suppl_3 ( 2015-11-10)

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In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)

Abstract: Introduction: Skeletal muscle atrophy is observed in aging and a variety of diseases including chronic obstructive pulmonary disease, chronic renal failure, and heart failure. It has been considered that it is associated with chronic inflammation in the skeletal muscle. We have previously reported that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities including atrophy in mice. Hypothesis: Here, we hypothesized that the activation of NAD(P)H oxidase by Ang II induced the skeletal muscle atrophy. Methods: Either saline (vehicle) or Ang II (1000 ng/kg/min) was infused into male wild-type (WT) and Nox2 knock out (KO) mice via subcutaneously implanted osmotic minipumps for 4 weeks. Experiments were performed in following 4 groups; WT+vehicle (n=8), KO+vehicle (n=6), WT+Ang II (n=8), and KO+Ang II (n=6). Lower skeletal muscle limbs were removed and used for the analysis. Exercise capacity was measured by using treadmill test. Results: Increased activation of NAD(P)H oxidase and production of superoxide in the skeletal muscle by Ang II were completely inhibited in KO mice. Body and skeletal muscle weight, and myocyte cross sectional area were significantly decreased in WT+Ang II compared to WT+vehicle (24±1 vs. 28±1 g, 356±3 vs. 390±4 mg, and 2351±84 vs. 3221±118 μm2, respectively). These changes were significantly attenuated in KO+Ang II (27±1 g, 392±9 mg, 3012±150 μm2, respectively) Phospho-Akt and phospho-p70S6K, key molecule of protein synthesis, were decreased in WT+Ang II compared to WT+vehicle, which was attenuated in KO+Ang II. On the other hand, protein expressions of Muscle RING Finger-1 and MAFbx/Atrogin-1, key molecule of protein degradation, were significantly increased in WT+Ang II compare to WT+vehicle, which was not affected in KO+Ang II. Mitochondrial electron transfer complex and citrate synthase activities were also impaired in WT+Ang II and were not improved in KO+Ang II. In agreements with these results, exercise, Ang II-induced reduction in exercise capacity was not improved in KO mice. Conclusions: The deletion of Nox2 attenuated the skeletal muscle atrophy and decreased protein synthase induced by Ang II, suggesting that Nox2 plays an essential role in the development of skeletal muscle atrophy.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/circ.132.suppl_3.17034

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2015

detail.hit.zdb_id: 1466401-X

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Abstract 17415: Recombinant Human BDNF Can Mimic Effects of Exercise Training in Mice

Takada, Shingo ; Kinugawa, Shintaro ; Matsushima, Shouji ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2015

In: Circulation Vol. 132, No. suppl_3 ( 2015-11-10)

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In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 132, No. suppl_3 ( 2015-11-10)

Abstract: Background: Brain-derived neurotrophic factor (BDNF), a member of the neurotrophic factor family, has been known to be increased by exercise training (ET) and associated with exercise capacity, which are dependent on mitochondrial function in the skeletal muscle (SKM). We thus hypothesized that an increase in BDNF and an activation of its binding receptor, tropomyosin-related kinase B (TrkB), could increase the exercise capacity by enhancing mitochondrial function in SKM in mice. Therefore, we investigated whether an administration of recombinant human (rh)BDNF into sedentary (SED) mice could mimic the effect of ET on exercise capacity and SKM. Methods and Results: C57BL/6J mice randomly assigned either SED (n=20) or ET (n=10), SED mice was divided into 2 groups of the treatment with vehicle (phosphate-buffered saline; n=10) or rhBDNF (10 mg/kg body weight/day, s.c.; n=10), for 5 weeks. ET was performed by swimming for 90 min/day and 5 times/week. SKM weight did not differ among groups. The work (distance x body weight) and peak oxygen uptake (VO2) evaluated by treadmill test were significantly increased in ET+vehicle compared to SED+vehicle (work 24±1 vs 32±1 J and peak VO2 150±2 vs 166±2 mL/kg/min, p 〈 0.05) and also in SED+rhBDNF to the same extent (work 29±1 and peak VO2 170±2). Serum BDNF levels was significantly increased in SED+rhBDNF compared to SED+vehicle, whereas it did not change in ET+vehicle. BDNF mRNA and protein expressions, and TrkB mRNA were increased in SKM from ET+vehicle compared with SED+vehicle (respectively, p 〈 0.05), whereas they did not change in SED+rhBDNF. Phosphorylation of TrkB, AMP-activated protein kinase (AMPK) and Sirt-1, and PGC-1α protein levels were increased in SED+rhBDNF and ET+vehicle compared with SED+vehicle (respectively, p 〈 0.05). Mitochondrial complex activities and citrate synthase activity were in parallel with these results. In C2C12 myotubes, rhBDNF significantly increased mRNA levels related to mitochondrial function and these effects were completely inhibited by anti-TrkB antibody or AMPK inhibitor, compound C. Conclusions: rhBDNF can mimic the effects of ET on exercise capacity. BDNF-TrkB pathway may play an important role in the beneficial effects of ET on the exercise capacity and SKM function.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/circ.132.suppl_3.17415

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2015

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3

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Metabolomic Analysis Reveals New Insights Towards Understanding Skeletal Muscle Mass and Exercise Capacity in Patients with Heart Failure

Tsuda, Masaya ; Kinugawa, Shintaro ; Fukushima, Arata ; [et al.]

Elsevier BV ; 2015

In: Journal of Cardiac Failure Vol. 21, No. 10 ( 2015-10), p. S195-

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In: Journal of Cardiac Failure, Elsevier BV, Vol. 21, No. 10 ( 2015-10), p. S195-

Type of Medium: Online Resource

ISSN: 1071-9164

URL: Article

DOI: 10.1016/j.cardfail.2015.08.285

Language: English

Publisher: Elsevier BV

Publication Date: 2015

detail.hit.zdb_id: 2048826-9

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Abstract 16555: Angiotensin II Directly Induces Mitochondrial Dysfunction and Atrophy in the Skeletal Muscle

Kadoguchi, Tomoyasu ; Kinugawa, Shintaro ; Fukushima, Arata ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2014

In: Circulation Vol. 130, No. suppl_2 ( 2014-11-25)

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In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)

Abstract: Background: Skeletal muscle abnormalities such as mitochondrial dysfunction, fiber type transition, and atrophy are the main cause of reduced exercise capacity observed in various diseases such as diabetes mellitus and heart failure. Renin-angiotensin system (RAS) was activated in the skeletal muscle in these conditions. We thus hypothesized that angiotensin II (Ang II) could directly induce skeletal muscle abnormalities. Methods and Results: Ang II (1000ng/kg/min, n=8) or vehicle (saline, n=8) was administrated into male C57BL/6J mice (10-12 week of age) via subcutaneously implanted osmotic minipumps for 4 weeks. Ang II significantly decreased body weight (26.6±0.3 vs. 27.6±0.3 g, p 〈 0.05) and hind limb skeletal muscle weight compared with vehicle at 4 weeks (159±2 vs. 166±2 mg, p 〈 0.05). It also decreased myocyte cross-sectional area in the skeletal muscle at 4 weeks (1869±29 vs. 2233±46 μm2, p 〈 0.05). Muscle RING finger-1 and atrogin-1, the markers of protein degradation, were significantly increased in the skeletal muscle tissue from Ang II at 4 weeks by 133% and 102%, respectively (p 〈 0.05). In addition, cleaved caspase-3 and TUNEL positive cells were significantly increased in Ang II at 4 weeks by 2.5 and 1.4-folds, respectively (p 〈 0.05). Citrate synthase (1 week, 121±4 vs. 162±9; 4 weeks, 117±7 vs. 152±4 nmol/min/mg protein), complex I (1 week, 264±27 vs. 396±30; 4 weeks, 281±21 vs. 400±30 nmol/min/mg protein) and complex III (1 week, 321±33 vs. 508±49; 4 weeks, 347±30 vs. 503±43 nmol/min/mg protein) activities were significantly decreased in mitochondria isolated from skeletal muscle from Ang II at 1 and 4 weeks (all p 〈 0.05). NADH staining revealed that type I fiber decreased by 31% and type IIb fiber increased by 38% in Ang II at 1 week. The work (16±1 vs. 27±3 J, p 〈 0.05) and run distance (359±18 vs. 589±59 m, p 〈 0.05) evaluated by treadmill test significantly decreased in Ang II at 4 weeks. An administration of Ang II for 1 week also induced mitochondrial dysfunction, fiber type shift, and protein degradation, but did not skeletal muscle atrophy. Conclusion: Ang II could directly induce the reduction of exercise tolerance in association with the abnormalities in skeletal muscle function and structure.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/circ.130.suppl_2.16555

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2014

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5

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Abstract 12306: Changes of Metabolomic Profiling Are Associated With Reduced Exercise Capacity in Patients With Heart Failure

Tsuda, Masaya ; Kinugawa, Shintaro ; Fukushima, Arata ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2014

In: Circulation Vol. 130, No. suppl_2 ( 2014-11-25)

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In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 130, No. suppl_2 ( 2014-11-25)

Abstract: Background: Exercise intolerance is a major clinical manifestation, and closely related to poor prognosis in heart failure (HF) patients. Metabolic derangements have been shown to play an important role in this phenomenon. Recent metabolomic investigations have highlighted several novel biochemical pathways in HF, however, metabolic profiling associated with exercise capacity has not been elucidated. We thus investigated the metabolites associated with exercise capacity by using global metabolomic analysis of plasma samples in HF patients. Methods: Ten consecutive HF patients with reduced ejection fraction (57 ± 12 years old, New York Heart Association class II - III) and 5 age-matched healthy subjects as controls (56 ± 3 years old) were studied. Charged metabolites in plasma samples were measured by capillary electrophoresis mass spectrometry. Peak oxygen uptake (peak VO 2 ) and VE/VCO 2 slope were measured by cardiopulmonary exercise test. Results: A total of 233 charged metabolites were identified and quantified absolutely using standard chemicals for each metabolite. Significant increases in arginine methylation, phospholipid metabolites, and urea cycle metabolites were observed in HF patients compared to controls (Figure). Peak VO 2 was negatively correlated with methylarginine including asymmetric dimethylarginine (ADMA) (r=-0.77, P 〈 0.001) and symmetric dimethylarginine (SDMA) (r=-0.65, P=0.040) levels, and phospholipid metabolites including choline (r=-0.63, P=0.049) and N,N -dimethylglycine (r=-0.75, P=0.011) levels in HF patients. VE/VCO 2 slope was positively correlated with N,N -dimethylglycine (r=0.72, P=0.026) and Urea (r=0.82, P=0.006) levels. Conclusions: Increases in metabolites of arginine methylation, phospholipid metabolism, and urea cycle were associated with exercise intolerance in HF. These results provide mechanistic insights into exercise intolerance associated with HF.

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/circ.130.suppl_2.12306

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2014

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6

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Direct renin inhibitor ameliorates insulin resistance by improving insulin signaling and oxidative stress in the skeletal muscle from post-infarct heart failure in mice

Fukushima, Arata ; Kinugawa, Shintaro ; Takada, Shingo ; [et al.]

Elsevier BV ; 2016

In: European Journal of Pharmacology Vol. 779 ( 2016-05), p. 147-156

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In: European Journal of Pharmacology, Elsevier BV, Vol. 779 ( 2016-05), p. 147-156

Type of Medium: Online Resource

ISSN: 0014-2999

URL: Article

DOI: 10.1016/j.ejphar.2016.03.022

Language: English

Publisher: Elsevier BV

Publication Date: 2016

detail.hit.zdb_id: 1483526-5

SSG: 15,3

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Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure

Matsumoto, Junichi ; Takada, Shingo ; Kinugawa, Shintaro ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2018

In: Circulation Vol. 138, No. 18 ( 2018-10-30), p. 2064-2066

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In: Circulation, Ovid Technologies (Wolters Kluwer Health), Vol. 138, No. 18 ( 2018-10-30), p. 2064-2066

Type of Medium: Online Resource

ISSN: 0009-7322 , 1524-4539

URL: Article

DOI: 10.1161/CIRCULATIONAHA.118.035212

Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2018

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8

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Abstract 105: The Novel Heart-specific Ring-finger Protein 207 Regulates Energy Metabolism in Cardiomyocytes

Mizushima, Wataru ; Takahashi, Hidehisa ; Watanabe, Masashi ; [et al.]

Ovid Technologies (Wolters Kluwer Health) ; 2016

In: Circulation Research Vol. 119, No. suppl_1 ( 2016-07-22)

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In: Circulation Research, Ovid Technologies (Wolters Kluwer Health), Vol. 119, No. suppl_1 ( 2016-07-22)

Abstract: Background: Ring-finger proteins constitute a large protein family in the human genome and play essential roles in various biological processes. However, little is known about heart-specific Ring-finger proteins and those relations with cardiac functions. We performed the comprehensive analysis of the expression profiles of various kinds of Ring-finger proteins and found that Ring-finger protein 207 (RNF207) was largely expressed in the heart. The purpose of our study was to elucidate a role of RNF207 in the heart. Methods and Results: First, we confirmed that RNF207 was predominantly expressed in the heart at the mRNA and protein level. Next, we examined whether the expression of RNF207 changed in transverse aortic constriction (TAC) model mice and coronary ischemic heart failure model mice . 4 weeks after TAC, mRNA level of RNF207 was significantly decreased to approximately 40% of that in sham mice. Moreover, we found that the protein level of RNF207 in the mice with heart failure was significantly reduced to around 70% of that in sham mice. Considering the well-known facts that the heart is a high-energy demanding organ and that the levels of ATP in cardiomyocytes are reduced in those model mice, we hypothesized that RNF207 got involved in cardiac energy metabolism. To investigate the hypothesis, we depleted RNF207 in rat neonatal cardiomyocytes (RNC) and performed metabolomic analysis. Metabolomic analysis revealed that ATP concentration and NADH/NAD + ratio were significantly lower and mitochondrial function was significantly reduced in RNF207 depleted RNC, compared to control NRC. Next, to elucidate the molecular mechanism by which RNF207 had effect on cardiac energy metabolism, we explored RNF207-associated proteins by mass spectrometric analysis. We identified voltage-dependent anion channel 1 (VDAC1) as a RNF207-associated protein. It has been shown that mitochondrial protein VDAC1 plays a crucial role in mitochondrial functions, such as energy metabolism. We confirmed that RNF207 directly interacted with VDAC1 by in vitro binding assay. Our results strongly indicate that RNF207 functions as a regulator of cardiac energy metabolism. Conclusion: RNF207 is a novel heart-specific protein and regulates energy metabolism in cardiomyocytes.

Type of Medium: Online Resource

ISSN: 0009-7330 , 1524-4571

URL: Article

DOI: 10.1161/res.119.suppl_1.105

RVK:

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Language: English

Publisher: Ovid Technologies (Wolters Kluwer Health)

Publication Date: 2016

detail.hit.zdb_id: 1467838-X

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9

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Serum Brain-derived Neurotrophic Factor Level Predicts Adverse Clinical Outcomes in Patients with Heart Failure

Kudo, Masato ; Kinugawa, Shintaro ; Fukushima, Arata ; [et al.]

Elsevier BV ; 2014

In: Journal of Cardiac Failure Vol. 20, No. 10 ( 2014-10), p. S207-

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In: Journal of Cardiac Failure, Elsevier BV, Vol. 20, No. 10 ( 2014-10), p. S207-

Type of Medium: Online Resource

ISSN: 1071-9164

URL: Article

DOI: 10.1016/j.cardfail.2014.07.414

Language: English

Publisher: Elsevier BV

Publication Date: 2014

detail.hit.zdb_id: 2048826-9

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10

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Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure

Furihata, Takaaki ; Takada, Shingo ; Kakutani, Naoya ; [et al.]

Springer Science and Business Media LLC ; 2021

In: Communications Biology Vol. 4, No. 1 ( 2021-01-29)

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In: Communications Biology, Springer Science and Business Media LLC, Vol. 4, No. 1 ( 2021-01-29)

Abstract: Heart failure (HF) occurs frequently among older individuals, and dysfunction of cardiac mitochondria is often observed. We here show the cardiac-specific downregulation of a certain mitochondrial component during the chronological aging of mice, which is detrimental to the heart. MitoNEET is a mitochondrial outer membrane protein, encoded by CDGSH iron sulfur domain 1 (CISD1). Expression of mitoNEET was specifically downregulated in the heart and kidney of chronologically aged mice. Mice with a constitutive cardiac-specific deletion of CISD1 on the C57BL/6J background showed cardiac dysfunction only after 12 months of age and developed HF after 16 months; whereas irregular morphology and higher levels of reactive oxygen species in their cardiac mitochondria were observed at earlier time points. Our results suggest a possible mechanism by which cardiac mitochondria may gradually lose their integrity during natural aging, and shed light on an uncharted molecular basis closely related to age-associated HF.

Type of Medium: Online Resource

ISSN: 2399-3642

URL: Article

DOI: 10.1038/s42003-021-01675-4

Language: English

Publisher: Springer Science and Business Media LLC

Publication Date: 2021

detail.hit.zdb_id: 2919698-X

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