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

Abstract

Purpose

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

Data Sharing Statement

All the data used to support the findings of this study are available from the corresponding author Zhihao Wang on reasonable request.

Ethical Approval

The animal protocol was approved by the Animal Ethics Committee of Qilu Hospital, Shandong University (Approval No. KYLL-2021(KS)-198). All the animals used in this study were handled according to the Guide for the Care and Use of Laboratory Animals published by the National Institutes of Health (NIH Publications No. 8023, revised 1978).

Disclosure

The authors report no conflicts of interest in this work.

Additional information

Funding

This work was supported by the research grants from the Taishan Scholars (No. tsqn202103146), Clinical Research Center of Shandong University (No. 2020SDUCRCC027), the National Natural Science Foundation of China (82070392, 81702194, 81801953, 31502051) and Key Research and Development Program of Shandong Province (2019GSF108041).