LncRNA DLEU2 acts as a miR-181a sponge to regulate SEPP1 and inhibit skeletal muscle differentiation and regeneration.

Yao Wang,Zhe-Min Shen,Zhi-Jie Zhao,Tao Bian,Bao Sun,Yang Jiang,Yi-Sheng Chen,Xue-Ran Kang,Han-Bing Hu

doi:10.18632/aging.104095

Abstract

Sarcopenia is a serious public health problem associated with the loss of muscle mass and function. The purpose of this study was to identify molecular markers and construct a ceRNA pathway as a significant predictor of sarcopenia. We designed a prediction model to select important differentially expressed mRNAs (DEMs), and constructed a sarcopenia associated ceRNA network. After correlation analysis of each element in the ceRNA network based on clinical samples and GTEX database, C2C12 mouse myoblasts were used as a model to verify the identified ceRNA pathways. A new model for predicting sarcopenia based on four molecular markers SEPP1, SV2A, GOT1, and GFOD1 was developed. The model was used to construct a ceRNA network and showed high accuracy. Correlation analysis showed that the expression levels of lncDLEU2, SEPP1, and miR-181a were closely associated with a high risk of sarcopenia. lncDLEU2 inhibits muscle differentiation and regeneration by acting as a miR-181a sponge regulating SEPP1 expression. In this study, a highly accurate prediction tool was developed to improve the prediction outcomes of sarcopenia. These findings suggest that the lncDLEU2-miR-181a-SEPP1 pathway inhibits muscle differentiation and regeneration. This pathway may be a new therapeutic target for the treatment of sarcopenia.

Highlights

Sarcopenia has be closely associated with physical disabilities as well as the risk of diabetes and fractures characterized by a generalized and gradual loss of the function and strength of skeletal muscles. [1,2,3,4,5,6,7] With the increase of age, the incidence of sarcopenia has gradually increased and has become an important factor affecting the physical health of the elderly.[8,9,10] Skeletal muscle differentiation is affected by multiple signaling pathways
We found that long non-coding RNAs (lncRNAs) DLEU2 acts as a miR-181a sponge and inhibits skeletal muscle regeneration and differentiation
The lncDLEU2-miR-181a-SEPP1 pathway inhibits muscle differentiation and regeneration could be used as novel therapeutic targets for the treatment of sarcopenia caused by aging

Summary

Introduction

Sarcopenia has be closely associated with physical disabilities as well as the risk of diabetes and fractures characterized by a generalized and gradual loss of the function and strength of skeletal muscles. [1,2,3,4,5,6,7] With the increase of age, the incidence of sarcopenia has gradually increased and has become an important factor affecting the physical health of the elderly.[8,9,10] Skeletal muscle differentiation is affected by multiple signaling pathways. Myogenic regulation factor (MyoD, MyoG) is the core component of myogenic pathway.[11] With the development of sequencing, the role of lncRNA as a microRNA sponge to regulate miRNA's ceRNA network in biological processes is becoming more and more widely recognized.[12,13,14,15] Several studies have demonstrated that long non-coding RNAs (lncRNAs), including MAR1, [16] H19,[17,18] MUMA,[19] Yam-1,[20] IRS1,[21] Malat1,[22] lncR-125b (TCONS_00006810),[23] and lnc-mg,[24] are associated with muscle differentiation and regeneration These previous researches mainly study the pathological role of the ceRNA network in sarcopenia, no quantifying method has been brought up to forecast the risk of sarcopenia; it is necessary based on several simple molecular markers to develop an reliable predictive tool and early interventions to reduce the risk of sarcopenia. Interpretation: Our research developed a highly accurate prediction tool for the risk of sarcopenia These findings suggest that lncDLEU2-miR-181a-SEPP1 pathway inhibits muscle differentiation and regeneration. This pathway may uncover some new therapeutic targets for the treatment of sarcopenia caused by aging

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Conclusion