Shima Takeru, Onishi Hayate, Terashima Chiho
Department of Health and Physical Education, Cooperative Faculty of Education, Gunma University, Maebashi, Gunma, Japan.
Graduate School of Medicine, Gunma University, Maebashi, Gunma, Japan.
FASEB J. 2025 Apr 15;39(7):e70531. doi: 10.1096/fj.202500336R.
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.
2型糖尿病（T2DM）相关的记忆功能障碍对健康构成威胁。进行低强度运动对海马功能和分子特征有积极影响，包括Mct2 mRNA和miR-200a-3p。在此，我们研究了低强度运动干预的T2DM小鼠腓肠肌中外泌体miR-200a-3p的分泌情况，重点关注其改善记忆功能障碍的潜力。我们首先评估了为期4周的低强度运动对记忆功能、腓肠肌来源的外泌体miR-200a-3p分泌以及海马mRNA的影响。随后，研究了在为期4周的时间里每天腹腔注射mmu-miR-200a-3p模拟物对ob/ob小鼠海马失调的影响。低强度运动干预提高了ob/ob小鼠腓肠肌来源和血浆外泌体miR-200a-3p水平，同时改善了记忆功能障碍。有趣的是，每天腹腔注射mmu-miR-200a-3p模拟物也改善了ob/ob小鼠的记忆功能。值得注意的是，运动干预和miR-200a-3p模拟物治疗均诱导ob/ob小鼠海马中Keap1的下调以及Hsp90aa1和Mct2 mRNA的上调。这些结果表明，外周来源的miR-200a-3p的增加有助于改善进行低强度运动的T2DM小鼠的记忆功能障碍，腓肠肌来源的外泌体miR-200a-3p可能对这些运动效果有贡献。
