The muscle-enriched myokine Musclin impairs beige fat thermogenesis and systemic energy homeostasis via Tfr1/PKA signaling in male mice

Lu Jin, Shuang Han, Xue Lv, Xiaofei Li, Ziyin Zhang, Henry Kuang, Zhimin Chen, Cheng-an Lv, Wei Peng, Zhuoying Yang, Miqi Yang, Lin Mi, Tongyu Liu, Shengshan Ma, Xinyuan Qiu, Qintao Wang, Xiaowen Pan, Pengfei Shan, Yu Feng, Jin Li, Fudi Wang, Liwei Xie, Xuyun Zhao, Jun-Fen Fu (), Jiandie D. Lin and Zhuo-Xian Meng ()
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Lu Jin: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Shuang Han: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Xue Lv: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Xiaofei Li: The Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical University, Affiliated Hospital of Kangda College of Nanjing Medical University
Ziyin Zhang: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Henry Kuang: University of Michigan
Zhimin Chen: University of Michigan
Cheng-an Lv: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Wei Peng: Children’s Hospital, Zhejiang University School of Medicine
Zhuoying Yang: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Miqi Yang: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Lin Mi: University of Michigan
Tongyu Liu: University of Michigan
Shengshan Ma: The Lianyungang First People’s Hospital, Affiliated Hospital of Xuzhou Medical University, Affiliated Hospital of Kangda College of Nanjing Medical University
Xinyuan Qiu: National University of Defense Technology
Qintao Wang: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine
Xiaowen Pan: The Second Affiliated Hospital, Zhejiang University School of Medicine
Pengfei Shan: The Second Affiliated Hospital, Zhejiang University School of Medicine
Yu Feng: The Second Affiliated Hospital of Soochow University
Jin Li: The Second Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine
Fudi Wang: The Second Affiliated Hospital, School of Public Health, Zhejiang University School of Medicine
Liwei Xie: Institute of Microbiology, Guangdong Academy of Sciences
Xuyun Zhao: Shanghai Jiao Tong University School of Medicine
Jun-Fen Fu: Children’s Hospital, Zhejiang University School of Medicine
Jiandie D. Lin: University of Michigan
Zhuo-Xian Meng: Department of Pathology and Pathophysiology and Department of Cardiology of the Second Affiliated Hospital, Zhejiang University School of Medicine

Nature Communications, 2023, vol. 14, issue 1, 1-23

Abstract: Abstract Skeletal muscle and thermogenic adipose tissue are both critical for the maintenance of body temperature in mammals. However, whether these two tissues are interconnected to modulate thermogenesis and metabolic homeostasis in response to thermal stress remains inconclusive. Here, we report that human and mouse obesity is associated with elevated Musclin levels in both muscle and circulation. Intriguingly, muscle expression of Musclin is markedly increased or decreased when the male mice are housed in thermoneutral or chronic cool conditions, respectively. Beige fat is then identified as the primary site of Musclin action. Muscle-transgenic or AAV-mediated overexpression of Musclin attenuates beige fat thermogenesis, thereby exacerbating diet-induced obesity and metabolic disorders in male mice. Conversely, Musclin inactivation by muscle-specific ablation or neutralizing antibody treatment promotes beige fat thermogenesis and improves metabolic homeostasis in male mice. Mechanistically, Musclin binds to transferrin receptor 1 (Tfr1) and antagonizes Tfr1-mediated cAMP/PKA-dependent thermogenic induction in beige adipocytes. This work defines the temperature-sensitive myokine Musclin as a negative regulator of adipose thermogenesis that exacerbates the deterioration of metabolic health in obese male mice and thus provides a framework for the therapeutic targeting of this endocrine pathway.

Date: 2023
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DOI: 10.1038/s41467-023-39710-z

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