Jiaying Qiu1,2, Jianwei Zhu3, Ru Zhang4, Wenpeng Liang2, Wenjing Ma2, Qiuyu Zhang2, Ziwei Huang2, Fei Ding1,2, Hualin Sun2. 1. School of Biology and Basic Medical Sciences, Medical College of Soochow University, Suzhou 215123, China. 2. Key Laboratory of Neuroregeneration of Jiangsu and Ministry of Education, Jiangsu Clinical Medicine Center of Tissue Engineering and Nerve Injury Repair, Co-Innovation Center of Neuroregeneration, Nantong University, Nantong 226001, China. 3. Department of Orthopedics, Affiliated Hospital of Nantong University, Nantong 226001, China. 4. The Second Affiliated Hospital of Nantong University, Nantong University, Nantong 226001, China.
Abstract
BACKGROUND: Skeletal muscle atrophy, characterized by accelerated protein degradation, occurs in such conditions as unloading, immobilization, fasting, and denervation. Effective treatments for skeletal muscle atrophy are not yet available. Considering that microRNAs (miRs) may play an important role in the regulation of muscle atrophy, in the present study, we aimed to examine the effect of miR-125b-5p-based therapeutic strategies on skeletal muscle atrophy, and to explore the underlying mechanisms. METHODS: Fasting-induced atrophic mouse C2C12 myotubes and denervated rat tibialis anterior (TA) muscles were used as in vitro and in vivo models of skeletal muscle atrophy, respectively. The morphological parameters of skeletal muscle were measured by immunostaining-based quantification. The interaction between miR-125b-5p and TRAF6 3'-UTR was detected by luciferase reporter analysis. The mRNA and protein expressions were determined by real-time qPCR and Western blot analysis respectively. The miR mimics/agomir and miR inhibitor/antagomir were transfected into C2C12 myotubes and TA muscles respectively to alter the expression of miR-125b-5p. RESULTS: The expression of miR-125b-5p was down-regulated in both atrophic C2C12 myotubes and denervated TA muscles. The interaction between miR-125b-5p and TRAF6 3'-UTR was identified. Overexpression of miR-125b-5p protected skeletal muscle samples from atrophy in vitro and in vivo by targeting TRAF6 through inactivation of several ubiquitin-proteasome system (UPS)- and autophagy-lysosome system (ALS)-related proteins. CONCLUSIONS: Overexpression of miR-125b-5p may provide a promising therapeutic approach to treat muscle atrophy. 2019 Annals of Translational Medicine. All rights reserved.
BACKGROUND: Skeletal muscle atrophy, characterized by accelerated protein degradation, occurs in such conditions as unloading, immobilization, fasting, and denervation. Effective treatments for skeletal muscle atrophy are not yet available. Considering that microRNAs (miRs) may play an important role in the regulation of muscle atrophy, in the present study, we aimed to examine the effect of miR-125b-5p-based therapeutic strategies on skeletal muscle atrophy, and to explore the underlying mechanisms. METHODS: Fasting-induced atrophic mouse C2C12 myotubes and denervated rat tibialis anterior (TA) muscles were used as in vitro and in vivo models of skeletal muscle atrophy, respectively. The morphological parameters of skeletal muscle were measured by immunostaining-based quantification. The interaction between miR-125b-5p and TRAF6 3'-UTR was detected by luciferase reporter analysis. The mRNA and protein expressions were determined by real-time qPCR and Western blot analysis respectively. The miR mimics/agomir and miR inhibitor/antagomir were transfected into C2C12 myotubes and TA muscles respectively to alter the expression of miR-125b-5p. RESULTS: The expression of miR-125b-5p was down-regulated in both atrophic C2C12 myotubes and denervated TA muscles. The interaction between miR-125b-5p and TRAF6 3'-UTR was identified. Overexpression of miR-125b-5p protected skeletal muscle samples from atrophy in vitro and in vivo by targeting TRAF6 through inactivation of several ubiquitin-proteasome system (UPS)- and autophagy-lysosome system (ALS)-related proteins. CONCLUSIONS: Overexpression of miR-125b-5p may provide a promising therapeutic approach to treat muscle atrophy. 2019 Annals of Translational Medicine. All rights reserved.
Authors: Luis A Cea; Bruno A Cisterna; Carlos Puebla; Marina Frank; Xavier F Figueroa; Christopher Cardozo; Klaus Willecke; Ramón Latorre; Juan C Sáez Journal: Proc Natl Acad Sci U S A Date: 2013-09-16 Impact factor: 11.205