Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure
2018; Lippincott Williams & Wilkins; Volume: 138; Issue: 18 Linguagem: Inglês
10.1161/circulationaha.118.035212
ISSN1524-4539
AutoresJunichi Matsumoto, Shingo Takada, Shintaro Kinugawa, Takaaki Furihata, Hideo Nambu, Naoya Kakutani, Masaya Tsuda, Arata Fukushima, Takashi Yokota, Shinya Tanaka, Hidehisa Takahashi, Masashi Watanabe, Shigetsugu Hatakeyama, Masaki Matsumoto, Keiichi I. Nakayama, Yutaro Otsuka, Hisataka Sabe, Hiroyuki Tsutsui, Toshihisa Anzai,
Tópico(s)Neuroscience and Neural Engineering
ResumoHomeCirculationVol. 138, No. 18Brain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure Free AccessLetterPDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessLetterPDF/EPUBBrain-Derived Neurotrophic Factor Improves Limited Exercise Capacity in Mice With Heart Failure Junichi Matsumoto, MD, PhD, Shingo Takada, PhD, Shintaro Kinugawa, MD, PhD, Takaaki Furihata, MD, PhD, Hideo Nambu, MD, Naoya Kakutani, BS, Masaya Tsuda, MD, PhD, Arata Fukushima, MD, PhD, Takashi Yokota, MD, PhD, Shinya Tanaka, MD, PhD, Hidehisa Takahashi, MD, PhD, Masashi Watanabe, MD, PhD, Shigetsugu Hatakeyama, MD, PhD, Masaki Matsumoto, PhD, Keiichi I. Nakayama, MD, PhD, Yutaro Otsuka, MD, PhD, Hisataka Sabe, PhD, Hiroyuki Tsutsui, MD, PhD and Toshihisa Anzai, MD, PhD Junichi MatsumotoJunichi Matsumoto Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Shingo TakadaShingo Takada Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Cancer Pathology (S. Tanaka), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Shintaro KinugawaShintaro Kinugawa Shintaro Kinugawa, MD, PhD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. Email E-mail Address: [email protected] Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Takaaki FurihataTakaaki Furihata Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Hideo NambuHideo Nambu Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Naoya KakutaniNaoya Kakutani Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Masaya TsudaMasaya Tsuda Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Arata FukushimaArata Fukushima Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Takashi YokotaTakashi Yokota Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Shinya TanakaShinya Tanaka , Hidehisa TakahashiHidehisa Takahashi , Masashi WatanabeMasashi Watanabe Biochemistry (M.W., S.H.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Shigetsugu HatakeyamaShigetsugu Hatakeyama Biochemistry (M.W., S.H.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Masaki MatsumotoMasaki Matsumoto Department of Molecular and Cellular Biology, Medical Institute of Bioregulation (M.M., K.I.N.), Kyushu University, Fukuoka, Japan. , Keiichi I. NakayamaKeiichi I. Nakayama Department of Molecular and Cellular Biology, Medical Institute of Bioregulation (M.M., K.I.N.), Kyushu University, Fukuoka, Japan. , Yutaro OtsukaYutaro Otsuka Molecular Biology (Y.O., H.S.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Hisataka SabeHisataka Sabe Molecular Biology (Y.O., H.S.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. , Hiroyuki TsutsuiHiroyuki Tsutsui Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Japan (H. Takahashi). Department of Cardiovascular Medicine, Faculty of Medical Sciences (H. Tsutsui), Kyushu University, Fukuoka, Japan. and Toshihisa AnzaiToshihisa Anzai Departments of Cardiovascular Medicine (J.M., S. Takada, S.K., T.F., H.N., N.K., M.T., A.F., T.Y., T.A.), Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Sapporo, Japan. Originally published29 Oct 2018https://doi.org/10.1161/CIRCULATIONAHA.118.035212Circulation. 2018;138:2064–2066Individuals with heart failure (HF) have reduced exercise capacity that is closely related to the severity and prognosis of HF.1 This reduction in capacity is caused by peripheral skeletal muscle abnormalities, including mitochondrial dysfunction, as well as disturbed cardiac function and central hemodynamics.2 Exercise training can improve the exercise capacity and prognosis of patients with HF,3 but some patients with severe HF cannot engage in sufficient exercise training because of their severely impaired daily life. Effective pharmacological therapy is strongly desired as an alternative to exercise training for individuals with limited exercise capacity and skeletal muscle abnormalities.Exercise has been reported to increase brain-derived neurotrophic factor (BDNF) in skeletal muscle.4,5 We thus hypothesized that BDNF treatment could improve exercise capacity; we tested this hypothesis using a mouse model of HF. All experiments and animal care accorded with the Guide for the Care and Use of Laboratory Animals from the National Institutes of Health, were approved by our institutional animal research committee, and conformed to the Hokkaido University Graduate School of Medicine Animal Care Guidelines for the Care and Use of Laboratory Animals.We induced a myocardial infarction (MI) in 10- to 12-week-old male C57BL/6J mice by ligating the coronary artery. Sham operations were conducted in controls. At 2 weeks after surgery, the MI mice exhibited left ventricular dilation and depressed left ventricular function, and they developed HF (data not shown). We assessed the exercise capacity and mitochondrial respiration in skeletal muscle (Figure [A]). The work and peak oxygen uptake evaluated with a motorized treadmill with an expired gas analyzer (Oxymax 2, Columbus Instruments) were significantly lower in the MI mice compared with the sham mice (Figure [B]). The mitochondrial respiration in the gastrocnemius muscle was also significantly lower in MI mice compared with the sham mice as measured by high-resolution respirometry (Oxygraph-2k, Oroboros Instruments; Figure [C]).Download figureDownload PowerPointFigure. Brain-derived neurotrophic factor (BDNF) improves limited exercise capacity and mitochondrial respiration in skeletal muscle from heart failure mice.A, Study protocol 1 (at 2 weeks after surgery in sham and myocardial infarction [MI] mice). B, Total work and peak oxygen uptake to exhaustion (n=6 per group). C, Mitochondrial respiration in permeabilized gastrocnemius muscle fibers from sham and MI mice (n=6 per group). Values are relative to the O2 flux of complex I+II electron transfer system (ETS) in sham mice. D, Study protocol 2 (2 weeks after administration of vehicle or recombinant human [rh] brain-derived neurotrophic factor [BDNF]). E, Representative Western blots and summary data of BDNF protein expression in gastrocnemius muscle (n=7 per group). Values are normalized by GAPDH. F, Total work and peak oxygen uptake to exhaustion (n=7 per group). G, Mitochondrial respiration in permeabilized gastrocnemius muscle fibers. Values are relative to the O2 flux of complex I+II ETS in sham+vehicle mice (n=5–7 per group). Data are mean±SEM. Complex I leak indicates respiration on complex I substrates to compensate for proton leak; complex I oxidative phosphorylation (OXPHOS), complex I–dependent oxidative phosphorylation; complex I+II OXPHOS, complex I and II–dependent oxidative phosphorylation; complex I+II ETS, noncoupled respiration with complex I and II substrates; and complex II ETS, noncoupled complex II–dependent respiration. *P<0.05 vs sham by unpaired t test. †P<0.05 vs sham+vehicle. ‡P<0.05 vs MI+vehicle by 1-way ANOVA followed by the Tukey test.We designed a treatment for the impaired exercise capacity and skeletal muscle mitochondrial dysfunction in the MI mice. At 2 weeks after surgery, we randomly divided the MI mice into 2 groups: those treated with recombinant human BDNF (rhBDNF; 5 mg/kg body weight per day, 5 times/wk) and those treated with vehicle (PBS) by subcutaneous daily injection for an additional 2 weeks. Dainippon Sumitomo Pharma (Osaka, Japan) kindly provided the rhBDNF. Non-MI sham mice were treated with vehicle. At 4 weeks after surgery (2 weeks after treatment), all experiments were performed in the sham+vehicle, MI+vehicle, and MI+rhBDNF groups (Figure [D]).Echocardiography revealed that left ventricular morphology and function were not affected by the rhBDNF administration (data not shown). Western blot analyses revealed significantly lower protein expression of BDNF in the gastrocnemius muscle of the MI+vehicle group compared with that of the sham+vehicle mice. rhBDNF administration resulted in a significantly higher BDNF expression in the MI+rhBDNF mice compared with the MI+vehicle mice (Figure [E]). In our preliminary experiments in vitro using C2C12 myotubes, exogenously treated rhBDNF increased endogenous BDNF via cellular uptake rather than gene expression (data not shown). The exercise capacity was significantly improved in the MI+rhBDNF mice compared with the MI+vehicle mice (Figure [F]). Mitochondrial respiration was significantly lower in the skeletal muscle of MI+vehicle mice, and rhBDNF significantly improved mitochondrial respiration (Figure [G]). We also clarified that BDNF increased mitochondrial biogenesis and fatty acid oxidation via an upregulation of AMP-activated protein kinase α–peroxisome proliferator-activated receptor γ coactivator 1α signaling in skeletal muscle (data not shown).We thus provide the first report that the protein expression of BDNF was decreased in skeletal muscle from HF mice after MI and that the administration of rhBDNF to MI mice improved their exercise capacity and skeletal muscle mitochondrial dysfunction. This effective treatment with rhBDNF was accompanied by activation of AMP-activated protein kinase α–peroxisome proliferator-activated receptor γ coactivator 1α signaling, because links between AMP-activated protein kinase and BDNF were identified.5 Given that BDNF is involved in mitochondrial biogenesis and fatty acid metabolism, we speculate that the decrease in BDNF expression in skeletal muscle is one of the mechanisms underlying the reduction in exercise capacity and skeletal muscle abnormalities in HF. Various hormones are secreted by skeletal muscles, resulting in various physiological effects; BDNF may be one of these hormones. However, it is not yet known how BDNF is regulated and secreted from skeletal muscle.Our experiments demonstrated that the administration of rhBDNF improved the exercise capacity of HF mice via an improvement in the mitochondrial function of skeletal muscle. In the present HF pandemic era, the development of treatments that reverse the reduced exercise capacity and improve the quality of life in patients with HF is a very important task. Treatment with BDNF or a combination of BDNF plus exercise training may be such a treatment.Sources of FundingThis study was supported in part by the Center of Innovation Program from the Japan Science and Technology Agency and the Japan Society for the Promotion of Science (KAKENHI grants JP26750331 and JP17H04758 to Dr Takada and JP18H03187 to Dr Kinugawa).DisclosuresH. Tsutsui received lecture fees from Astellas Pharma, Otsuka Pharmaceutical, Takeda Pharmaceutical, Daiichi-Sankyo, Mitsubishi Tanabe Pharma, Nippon Boehringer Ingelheim, Novartis Pharma, Bayer Yakuhin, and Bristol-Myers Squibb, as well as research funding from Actelion Pharmaceuticals, Daiichi-Sankyo, and Astellas Pharma. The other authors report no conflicts.Footnotes*Drs J. Matsumoto and Takada contributed equally.https://www.ahajournals.org/journal/circData sharing: All data and materials supporting the findings of this study are available in the article or from the corresponding author on reasonable request.Shintaro Kinugawa, MD, PhD, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University, Kita-15, Nishi-7, Kita-ku, Sapporo 060-8638, Japan. Email [email protected]hokudai.ac.jpReferences1. Mancini DM, Eisen H, Kussmaul W, Mull R, Edmunds LH, Wilson JR. Value of peak exercise oxygen consumption for optimal timing of cardiac transplantation in ambulatory patients with heart failure.Circulation. 1991; 83:778–786.LinkGoogle Scholar2. Okita K, Kinugawa S, Tsutsui H. Exercise intolerance in chronic heart failure: skeletal muscle dysfunction and potential therapies.Circ J. 2013; 77:293–300.CrossrefMedlineGoogle Scholar3. Belardinelli R, Georgiou D, Cianci G, Purcaro A. Randomized, controlled trial of long-term moderate exercise training in chronic heart failure: effects on functional capacity, quality of life, and clinical outcome.Circulation. 1999; 99:1173–1182.LinkGoogle Scholar4. Yu T, Chang Y, Gao XL, Li H, Zhao P. Dynamic expression and the role of BDNF in exercise-induced skeletal muscle regeneration.Int J Sports Med. 2017; 38:959–966. doi: 10.1055/s-0043-118343CrossrefMedlineGoogle Scholar5. Matthews VB, Aström MB, Chan MH, Bruce CR, Krabbe KS, Prelovsek O, Akerström T, Yfanti C, Broholm C, Mortensen OH, Penkowa M, Hojman P, Zankari A, Watt MJ, Bruunsgaard H, Pedersen BK, Febbraio MA. Brain-derived neurotrophic factor is produced by skeletal muscle cells in response to contraction and enhances fat oxidation via activation of AMP-activated protein kinase.Diabetologia. 2009; 52:1409–1418. doi: 10.1007/s00125-009-1364-1CrossrefMedlineGoogle Scholar Previous Back to top Next FiguresReferencesRelatedDetailsCited By Fang F, Zhang X, Li B and Gan S (2022) miR-182-5p combined with brain-derived neurotrophic factor assists the diagnosis of chronic heart failure and predicts a poor prognosis, Journal of Cardiothoracic Surgery, 10.1186/s13019-022-01802-0, 17:1, Online publication date: 1-Dec-2022. 髙田 真 and 絹川 真 (2022) Symposium22-6骨格筋における線維化の意義, Japanese Journal of Physical Fitness and Sports Medicine, 10.7600/jspfsm.71.106, 71:1, (106-106), . Takada S, Sabe H and Kinugawa S (2022) Treatments for skeletal muscle abnormalities in heart failure: sodium-glucose transporter 2 and ketone bodies, American Journal of Physiology-Heart and Circulatory Physiology, 10.1152/ajpheart.00100.2021, 322:2, (H117-H128), Online publication date: 1-Feb-2022. QIAN M, FENG Z, ZHENG R, HU K, SUN J, SUN H and DAI L (2022) Qi-Tai-Suan, an oleanolic acid derivative, ameliorates ischemic heart failure via suppression of cardiac apoptosis, inflammation and fibrosis, Chinese Journal of Natural Medicines, 10.1016/S1875-5364(22)60156-0, 20:6, (432-442), Online publication date: 1-Jun-2022. Matsumoto J, Takada S, Furihata T, Nambu H, Kakutani N, Maekawa S, Mizushima W, Nakano I, Fukushima A, Yokota T, Tanaka S, Handa H, Sabe H and Kinugawa S (2020) Brain-Derived Neurotrophic Factor Improves Impaired Fatty Acid Oxidation Via the Activation of Adenosine Monophosphate-Activated Protein Kinase-ɑ – Proliferator-Activated Receptor-r Coactivator-1ɑ Signaling in Skeletal Muscle of Mice With Heart Failure, Circulation: Heart Failure, 14:1, Online publication date: 1-Jan-2021. (2021) Symposium19-2不全心筋における栄養療法, Japanese Journal of Physical Fitness and Sports Medicine, 10.7600/jspfsm.70.70, 70:1, (70-70), . Furihata T, Takada S, Kakutani N, Maekawa S, Tsuda M, Matsumoto J, Mizushima W, Fukushima A, Yokota T, Enzan N, Matsushima S, Handa H, Fumoto Y, Nio-Kobayashi J, Iwanaga T, Tanaka S, Tsutsui H, Sabe H and Kinugawa S (2021) Cardiac-specific loss of mitoNEET expression is linked with age-related heart failure, Communications Biology, 10.1038/s42003-021-01675-4, 4:1, Online publication date: 1-Dec-2021. Lin B, Zhao H, Li L, Zhang Z, Jiang N, Yang X, Zhang T, Lian B, Liu Y, Zhang C, Wang J, Wang F, Feng D and Xu J (2020) Sirt1 improves heart failure through modulating the NF-κB p65/microRNA-155/BNDF signaling cascade, Aging, 10.18632/aging.103640, 13:10, (14482-14498), Online publication date: 31-May-2021. Nambu H, Takada S, Maekawa S, Matsumoto J, Kakutani N, Furihata T, Shirakawa R, Katayama T, Nakajima T, Yamanashi K, Obata Y, Nakano I, Tsuda M, Saito A, Fukushima A, Yokota T, Nio-Kobayashi J, Yasui H, Higashikawa K, Kuge Y, Anzai T, Sabe H and Kinugawa S (2020) Inhibition of xanthine oxidase in the acute phase of myocardial infarction prevents skeletal muscle abnormalities and exercise intolerance, Cardiovascular Research, 10.1093/cvr/cvaa127, 117:3, (805-819), Online publication date: 22-Feb-2021. Berezin A, Berezin A, Lichtenauer M and Pichler R (2021) Myokines and Heart Failure: Challenging Role in Adverse Cardiac Remodeling, Myopathy, and Clinical Outcomes, Disease Markers, 10.1155/2021/6644631, 2021, (1-17), Online publication date: 13-Jan-2021. Nishikawa Y, Watanabe K, Kawade S, Maeda N and Maruyama H (2021) The Effect of a Portable Electrical Muscle Stimulation on Brain-Derived Neurotrophic Factor in Elderly People: Three Case Studies, Gerontology and Geriatric Medicine, 10.1177/23337214211040319, 7, (233372142110403), Online publication date: 1-Jan-2021. Furihata T, Maekawa S, Takada S, Kakutani N, Nambu H, Shirakawa R, Yokota T and Kinugawa S (2021) Premedication with pioglitazone prevents doxorubicin-induced left ventricular dysfunction in mice, BMC Pharmacology and Toxicology, 10.1186/s40360-021-00495-w, 22:1, Online publication date: 1-Dec-2021. Kakutani N, Takada S, Nambu H, Maekawa S, Hagiwara H, Yamanashi K, Obata Y, Nakano I, Fumoto Y, Hata S, Furihata T, Fukushima A, Yokota T and Kinugawa S (2021) Angiotensin‐converting enzyme inhibitor prevents skeletal muscle fibrosis in diabetic mice, Experimental Physiology, 10.1113/EP089375, 106:8, (1785-1793), Online publication date: 1-Aug-2021. (2020) Symposium2-5心不全の骨格筋異常における治療法の開発, Japanese Journal of Physical Fitness and Sports Medicine, 10.7600/jspfsm.69.22, 69:1, (22-22), . Yokota T (2020) BDNF as a novel therapeutic candidate for Kennedy's disease, The Journal of Physiology, 10.1113/JP279987, 598:13, (2543-2544), Online publication date: 1-Jul-2020. Nambu H, Takada S, Fukushima A, Matsumoto J, Kakutani N, Maekawa S, Shirakawa R, Nakano I, Furihata T, Katayama T, Yamanashi K, Obata Y, Saito A, Yokota T and Kinugawa S (2020) Empagliflozin restores lowered exercise endurance capacity via the activation of skeletal muscle fatty acid oxidation in a murine model of heart failure, European Journal of Pharmacology, 10.1016/j.ejphar.2019.172810, 866, (172810), Online publication date: 1-Jan-2020. Kakutani N, Takada S, Nambu H, Matsumoto J, Furihata T, Yokota T, Fukushima A and Kinugawa S (2020) Angiotensin-converting-enzyme inhibitor prevents skeletal muscle fibrosis in myocardial infarction mice, Skeletal Muscle, 10.1186/s13395-020-00230-9, 10:1, Online publication date: 1-Dec-2020. Nakano I, Kinugawa S, Hori H, Fukushima A, Yokota T, Takada S, Kakutani N, Obata Y, Yamanashi K and Anzai T (2020) Serum Brain-Derived Neurotrophic Factor Levels Are Associated with Skeletal Muscle Function but Not with Muscle Mass in Patients with Heart Failure, International Heart Journal, 10.1536/ihj.19-400, 61:1, (96-102), Online publication date: 31-Jan-2020. Katayama T, Kinugawa S, Takada S, Furihata T, Fukushima A, Yokota T, Anzai T, Hibino M, Harashima H and Yamada Y (2019) A mitochondrial delivery system using liposome-based nanocarriers that target myoblast cells, Mitochondrion, 10.1016/j.mito.2019.07.005, 49, (66-72), Online publication date: 1-Nov-2019. Takada S, Sabe H and Kinugawa S (2020) Abnormalities of Skeletal Muscle, Adipocyte Tissue, and Lipid Metabolism in Heart Failure: Practical Therapeutic Targets, Frontiers in Cardiovascular Medicine, 10.3389/fcvm.2020.00079, 7 Hang P, Zhu H, Li P, Liu J, Ge F, Zhao J and Du Z (2021) The Emerging Role of BDNF/TrkB Signaling in Cardiovascular Diseases, Life, 10.3390/life11010070, 11:1, (70) October 30, 2018Vol 138, Issue 18 Advertisement Article InformationMetrics © 2018 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.118.035212PMID: 30372141 Originally publishedOctober 29, 2018 Keywordsmiceexerciseheart failurebrain-derived neurotrophic factorPDF download Advertisement SubjectsBasic Science ResearchHeart FailureTreatment
Referência(s)