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

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-1 alpha) 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-1 alpha 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.