Sodium Butyrate Ameliorates Type 2 Diabetes-Related Sarcopenia Through IL-33-Independent ILC2s/IL-13/STAT3 Signaling Pathway

Abstract

Yuan Cao,1– 3 Yulin Li,1– 3 Wenqiang Han,1– 3 Xu Jia,1– 3 Ping Zhu,1– 3 Bin Wei,4 Xiaoyan Cong,5,6 Zhihao Wang7,8 1Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese National Health Commission and Chinese Academy of Medical Sciences, Jinan, People’s Republic of China; 2State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Jinan, People’s Republic of China; 3Department of Cardiology, Qilu Hospital, Shandong University, Jinan, People’s Republic of China; 4Shandong Asia-Pacific Highvarve Organisms Science and Technology Co, Ltd, Jinan, People’s Republic of China; 5Institute of Animal Science and Veterinary Medicine, Shandong Key Laboratory of Animal Disease Control and Breeding, Shandong Academy of Agricultural Sciences, Jinan, People’s Republic of China; 6Jinan Kuoda Biotechnology Co, Ltd, Jinan, People’s Republic of China; 7Department of Geriatric Medicine, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of China; 8Key Laboratory of Cardiovascular Proteomics of Shandong Province, Qilu Hospital, Cheeloo College of Medicine, Shandong University, Jinan, People’s Republic of ChinaCorrespondence: Xiaoyan Cong; Zhihao Wang, Email [email protected]; [email protected]: Sarcopenia has been described as a new complication of type 2 diabetes mellitus (T2DM). T2DM and sarcopenia impact each other, resulting in a variety of adverse outcomes such as frailty, disability, poor quality of life and increased mortality. Sodium butyrate (NaB) is reported to play a protective role against T2DM. The present study aimed to investigate whether NaB could ameliorate T2DM-related sarcopenia and the underlying mechanisms.Materials and Methods: The male db/db mice at 7-weeks were used as T2DM-related sarcopenia animal model with C57BL/6J mice as control. Mice were grouped according to whether they received NaB orally as follows: C57BL/6J+water group, C57BL/6J+NaB group, db/db+water group, and db/db+NaB group. Then, db/db mice receiving NaB orally were administered with inhibitors of group 2 innate lymphocytes (ILC2s), anti-CD90.2 by intraperitoneal injection divided into db/db+NaB+PBS group and db/db+NaB+anti-CD90.2 group. NaB dissolved in water at 150 mM. The skeletal muscle mass was measured by dural X-ray (DXA) test. ILC2s in spleen and skeletal muscle were evaluated by flow cytometry. The expressions of IL-33, IL-13, STAT3, P-STAT3, GATA-3 and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α) were assessed by ELISA or WB. The morphology of skeletal muscle fibers was assessed by immunofluorescence staining.Results: The proportion of ILC2s and the expressions of ILC2s markers IL-13 and GATA-3 were all significantly decreased in db/db mice, and these changes were improved by NaB. NaB increased the proportion of slow-twitch fibers in gastrocnemius, thus partially reversing the reduced exercise capacity of db/db mice. The expression of slow-twitch fibers marker PGC-1α induced by NaB was increased via activation of ILC2s/IL-13/STAT3 pathway. On the other way, IL-33 was not necessary for the activation of ILC2s/IL-13/STAT3 pathway. After depletion of ILC2s by anti-CD90.2, the ameliorating effect of NaB on T2DM-related sarcopenia was partially antagonized.Conclusion: These results indicated that NaB could ameliorate type 2 diabetes-related sarcopenia by activating IL-33-independent ILC2s/IL-13/STAT3 signaling pathway.Keywords: diabetes mellitus, sarcopenia, ILC2s, sodium butyrate, IL-13

Keywords

• diabetes mellitus
• sarcopenia
• ilc2s
• sodium butyrate
• il-13