The Role of Non-Coding RNAs in Regulating Cachexia Muscle Atrophy

Abstract

Cachexia is a late consequence of various diseases that is characterized by systemic muscle loss, with or without fat loss, leading to significant mortality. Multiple signaling pathways and molecules that increase catabolism, decrease anabolism, and interfere with muscle regeneration are activated. Non-coding RNAs (ncRNAs), such as microRNAs (miRNAs), long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs), play vital roles in cachexia muscle atrophy. This review mainly provides the mechanisms of specific ncRNAs to regulate muscle loss during cachexia and discusses the role of ncRNAs in cachectic biomarkers and novel therapeutic strategies that could offer new insights for clinical practice.

Keywords: cachexia; circRNAs; lncRNAs; microRNAs; muscle atrophy; non-coding RNAs.

Figure 1

Overexpressed miR1, miR18, miR29, miR33a, miR199, miR204, miR483 can inhibit IGF-1—PI3K—AKT—mTOR pathway by targeting IGF-1. lncIRS1 rescues muscle atrophy by upregulating the expression of its target gene, IRS1, with the sponge of the miR15 family. miR18 can also inhibit IRS-1 to regulate the IGF-1 pathway. DRAIC can regulate the translation of proteins during tumorigenesis by influencing the AMPK-mTOR-S6K signaling pathway. Overexpression of miR-322/miR-503 targets translation initiation factors specifically to decrease protein translation, leading to muscle atrophy.

Figure 2

miR-18a targets IGF-1 3′ UTR to repress IGF-1 expression and, through PI3K-AKT-FOXO signaling, reduce muscle atrophy. miR-1, miR-206, miR-133a/b, lnc Atrolnc, miR-532-5p, and miR-let-7g-5p through the NF-Kβ pathway cause muscle atrophy. miR-330 causes muscle atrophy by affecting myostatin and STAT3 pathways. miR-27a and miR-23a directly affect MuRF-1 and restrain myostatin to cause muscle atrophy. The overexpression of miR-185-5p promotes muscle atrophy via the SMAD pathway.

Figure 3

MiR-542-5p inhibits SMAD7/SMURF1, lncSMUL inhibits SMURF2, and miR-22/miR-200a-3p can inhibit TGF-β signaling to improve muscle atrophy. Gtl2-Dio3miRNAs suppress the WNT signaling via regulating sFRPs, and lncMAR1 acts as the sponge of miR-487b to promote muscular reconstruction. LncMGPF (the sponge of miR-135a-5p), lncMUMA (the sponge of miR-762), and miR-378 improve the MyoD. MiR-21 targets TLR7 to trigger muscle apoptosis. MiR-125b targets IGF-II, and miR-431 and miR-1/206 target Pax7 to control myoblast differentiation negatively. MiR-127 regulates S1PR3 to affect muscle differentiation.