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Full Length Article | Open Access

Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway

Yongshun Wanga,bJie Yuana,bHuadong Liua,bJie Chena,bJieru Zoua,bXiaoyi Zenga,bLei Dua,bXin Suna,bZhengyuan Xiac,dQingshan Genga,b( )Yin Caie( )Jingjin Liua,b( )
Department of Cardiology, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University; The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong 518020, China
Shenzhen Clinical Research Center for Geriatrics, Shenzhen People’s Hospital, Shenzhen, Guangdong 518020, China
Department of Anesthesiology, Affiliated Hospital of Guangdong Medical University, Zhanjiang, Guangdong 524001, China
Faculty of Chinese Medicine, State Key Laboratory of Quality Research in Chinese Medicine, Macau University of Science and Technology, Taipa, Macao 999078, China
Department of Health Technology and Informatics, The Hong Kong Polytechnic University, Kowloon, Hong Kong 999077, China

Peer review under responsibility of Chongqing Medical University.

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Abstract

High-intensity interval training (HIIT) has been found to be more effective in relieving heart failure (HF) symptoms, than moderate-intensity continuous aerobic training (MICT). Additionally, higher meteorin-like protein (Metrnl) levels are seen after HIIT versus MICT. We investigated whether Metrnl contributed to post-HF cardiac functional improvements, and the signaling pathways involved. 50 HF patients underwent MICT, and another 50, HIIT, which was followed by cardiac function and serum Metrnl measurements. Metrnl was also measured in both blood and skeletal muscle samples of mice with transverse aortic constriction-induced HF after undergoing HIIT. Afterward, shRNA-containing adenovectors were injected into mice, yielding five groups: control, HF, HF + HIIT + scrambled shRNA, HF + HIIT + shMetrnl, and HF + Metrnl (HF + exogenous Metrnl). Mass spectrometry identified specific signaling pathways associated with increased Metrnl, which was confirmed with biochemical analyses. Glucose metabolism and mitochondrial functioning were evaluated in cardiomyocytes from the five groups. Both HF patients and mice had higher circulating Metrnl levels post-HIIT. Metrnl activated AMPK in cardiomyocytes, subsequently increasing histone deacetylase 4 (HDAC4) phosphorylation, leading to its cytosolic sequestration and inactivation via binding with chaperone protein 14-3-3. HDAC4 inactivation removed its repression on glucose transporter type 4, which, along with increased mitochondrial complex Ⅰ-Ⅴ expression, yielded improved aerobic glucose respiration and alleviation of mitochondrial dysfunction. All these changes ultimately result in improved post-HF cardiac functioning. HIIT increased skeletal muscle Metrnl production, which then operated on HF hearts to alleviate their functional defects, via increasing aerobic glucose metabolism through AMPK-HDAC4 signaling.

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Genes & Diseases
Article number: 101100
Cite this article:
Wang Y, Yuan J, Liu H, et al. Elevated meteorin-like protein from high-intensity interval training improves heart function via AMPK/HDAC4 pathway. Genes & Diseases, 2024, 11(6): 101100. https://doi.org/10.1016/j.gendis.2023.101100

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Received: 30 March 2023
Revised: 29 June 2023
Accepted: 24 July 2023
Published: 14 September 2023
© 2023 The Authors.

This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

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