Muscle-Derived miR-200a-3p Through Light-Intensity Exercise May Contribute to Improve Memory Dysfunction in Type 2 Diabetic Mice

Abstract

Memory dysfunction associated with type 2 diabetes mellitus (T2DM) poses a threat to well-being. Engaging in light-intensity exercise has favorable effects on hippocampal function and molecular profiles, including Mct2 mRNA and miR-200a-3p. Here, we investigated the involvement of exosomal miR-200a-3p secretion from gastrocnemius muscles in T2DM mice undergoing light-intensity exercise intervention, focusing on its potential to ameliorate memory dysfunction. We initially assessed the effects of light-intensity exercise over a 4-week period on memory function, the secretion of gastrocnemius muscle-derived exosomal miR-200a-3p, and hippocampal mRNA. Subsequently, the impact of a daily intraperitoneal injection of the mmu-miR-200a-3p mimic over a 4-week duration on hippocampal dysregulation in ob/ob mice was investigated. The light-intensity exercise intervention improved gastrocnemius muscle-derived and plasma exosomal miR-200a-3p levels in ob/ob mice, concomitant with improved memory dysfunction. Intriguingly, the daily intraperitoneal injection of the mmu-miR-200a-3p mimic also improved memory function in ob/ob mice. Notably, both the exercise intervention and miR-200a-3p mimic treatment induced downregulation in hippocampal Keap1 and upregulation in Hsp90aa1 and Mct2 mRNA in ob/ob mice. These results imply that the augmentation of peripherally derived miR-200a-3p contributes to ameliorating memory dysfunction in T2DM mice undergoing light-intensity exercise, with a possible contribution from gastrocnemius muscle-derived exosomal miR-200a-3p to these exercise effects.