Sarcopenic obesity is attenuated by E-syt1 inhibition via improving skeletal muscle mitochondrial function
Chao Song,
Wu Zheng,
Guoming Liu,
Yiyang Xu,
Zhibo Deng,
Yu Xiu,
Rongsheng Zhang,
Linhai Yang,
Yifei Zhang,
Guoyu Yu,
Yibin Su,
Jun Luo,
Bingwei He,
Jie Xu,
Hanhao Dai
Affiliations
Chao Song
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China; School of Mechanical Engineering and Automation, Fuzhou University, Fuzhou, 350001, China
Wu Zheng
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Guoming Liu
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Yiyang Xu
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Zhibo Deng
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Yu Xiu
Department of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
Rongsheng Zhang
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Linhai Yang
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Yifei Zhang
Department of Pediatrics, First Affiliated Hospital of Fujian Medical University, Fuzhou, 350005, China
Guoyu Yu
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Yibin Su
Department of Traditional Chinese Medicine, Fujian University of Traditional Chinese Medicine, Fuzhou, 350122, China
Jun Luo
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China
Bingwei He
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China; School of Mechanical Engineering and Automation, Fuzhou University, Fuzhou, 350001, China; Corresponding author. School of Mechanical Engineering and Automation, Fuzhou University, China.
Jie Xu
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China; Corresponding author. Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China.
Hanhao Dai
Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China; Corresponding author. Department of Orthopedics, Shengli Clinical Medical College of Fujian Medical University, Fujian Provincial Hospital, Fuzhou University Affiliated Provincial Hospital, School of Medicine, Fuzhou University, Fuzhou, 350001, China.
In aging and metabolic disease, sarcopenic obesity (SO) correlates with intramuscular adipose tissue (IMAT). Using bioinformatics analysis, we found a potential target protein Extended Synaptotagmin 1 (E-syt1) in SO. To investigate the regulatory role of E-syt1 in muscle metabolism, we performed in vivo and in vitro experiments through E-syt1 loss- and gain-of-function on muscle physiology. When E-syt1 is overexpressed in vitro, myoblast proliferation, differentiation, mitochondrial respiration, biogenesis, and mitochondrial dynamics are impaired, which were alleviated by the silence of E-syt1. Furthermore, overexpression of E-syt1 inhibited mitophagic flux. Mechanistically, E-syt1 overexpression leads to mitochondrial calcium overload and mitochondrial ROS burst, inhibits the fusion of mitophagosomes with lysosomes, and impedes the acidification of lysosomes. Animal experiments demonstrated the inhibition of E-syt1 increased the capacity of endurance exercise, muscle mass, mitochondrial function, and oxidative capacity of the muscle fibers in OVX mice. These findings establish E-syt1 as a novel contributor to the pathogenesis of skeletal muscle metabolic disorders in SO. Consequently, targeting E-syt1-induced dysfunction may serve as a viable strategy for attenuating SO.
