TTR调控骨骼肌干细胞增殖和骨骼肌再生  

Transthyretin Regulates Skeletal Muscle Stem Cell Proliferation and Skeletal Muscle Regeneration

作　　者：杨茜妮 韩婉虹 张潜英 韩春苗 高庆 李虎 张勇[1,2] 朱大海 YANG Qianni;HAN Wanhong;ZHANG Qianying;HAN Chunmiao;GAO Qing;LI Hu;ZHANG Yong;ZHU Dahai(Institute of Basic Medical Sciences,Chinese Academy of Medical Sciences,School of Basic Medicine,Peking Union Medical College,Beijing 100005,China;Bioland Laboratory(Guangzhou Regenerative Medicine and Health Guangdong Laboratory),Guangzhou 510005,China)

机构地区：[1]中国医学科学院基础医学研究所,北京协和医学院基础学院,北京100005 [2]生物岛实验室,广州再生医学与健康广东省实验室,广州510005

出　　处：《中国细胞生物学学报》2024年第10期1764-1771,共8页Chinese Journal of Cell Biology

摘　　要：甲状腺素运载蛋白(transthyretin,TTR)主要功能是运送甲状腺素和维生素A。TTR主要在肝脏中合成,在脉络丛和骨骼肌组织中也有表达。已有的研究主要聚焦TTR对脑和心肌功能的调控,TTR在骨骼肌中的功能并不十分清楚。为了探讨TTR对骨骼肌生长发育和再生的影响,该研究制备了ttr基因敲除小鼠。与野生型小鼠相比,ttr基因敲除小鼠的体质量和骨骼肌质量无显著性差异。但是,ttr基因敲除小鼠的跑步距离和前肢抓力显著小于野生型小鼠,说明TTR对于骨骼肌力量和运动等生理功能至关重要。进一步采用心肌毒素诱导的骨骼肌损伤再生模型,发现ttr基因敲除小鼠中损伤再生肌纤维面积显著减小,提示ttr对骨骼肌损伤再生具有重要的调控作用。损伤再生的骨骼肌制备冰冻切片,Pax7免疫荧光染色统计骨骼肌干细胞数量,发现ttr敲除小鼠骨骼肌中Pax7阳性细胞数量显著减少,提示TTR可能通过调控骨骼肌干细胞增殖影响骨骼肌再生。将ttr基因敲除小鼠与Pax7-nGFP小鼠杂交,采用流式细胞仪分选GFP阳性的骨骼肌干细胞,利用EdU掺入的方法检测细胞增殖,发现ttr基因敲除显著抑制骨骼肌干细胞增殖。总之,该研究利用ttr基因敲除小鼠模型,揭示了TTR不仅调控骨骼肌力量和运动等生理功能,而且通过影响骨骼肌干细胞增殖调控骨骼肌再生。Primary function of TTR(transthyretin)is to transport thyroxine and vitamin A.The ttr gene is predominantly expressed in the liver and is also expressed in choroid plexus and skeletal muscle.Previous studies have mainly focused on TTR functions in the brain and heart.The role of TTR in skeletal muscle is not well understood.To investigate TTR function in regulating skeletal muscle development and regeneration,ttr KO(knockout)mice were generated in this study.There was no overt difference in body weight and skeletal muscle mass between ttr KO and WT(wild type)littermates.However,the ttr KO mice had poor skeletal muscle performance,as evidenced by smaller running exhaustion distance and weaker forelimb grip strength than that of WT littermates,suggesting that TTR played important roles for physiological function of skeletal muscle.To explore the role of TTR in regulating skeletal muscle regeneration,the TA(tibialis anterior)muscle of ttr KO and WT mice were injured by CTX(cardiotoxin)and the regeneration was evaluated by quantifying size of regenerating myofibers.The data showed that the size of regenerating myofibers was significantly smaller in ttr KO mice than that of WT littermates,indicating that TTR played a role in regulating skeletal muscle regeneration.The number of Pax7-positive cells in the cryosection of the regenerated TA muscle from ttr KO mice was significantly reduced compared to that of WT mice,suggesting that TTR might implicate skeletal muscle regeneration by regulating muscle stem cell proliferation.Furthermore,EdU incorporation assay demonstrated that the proliferation of muscle stem cells FACS-sorted from ttr KO mice(Pax7-nGFP;ttr^(-/-))was slower than that of WT mice(Pax7-nGFP;ttr^(+/+)).Collectively,this study reveals that TTR regulates skeletal muscle strength,exercise performance,muscle stem cell proliferation and skeletal muscle regeneration.

关 键 词：甲状腺素运载蛋白 骨骼肌干细胞 骨骼肌再生 

分 类 号：R329.2[医药卫生—人体解剖和组织胚胎学]