Abstract
Skeletal muscle has a remarkable regenerative capacity, which is orchestrated by multiple processes, including the proliferation, fusion, and differentiation of the resident stem cells in muscle. MicroRNAs (miRNAs) are small noncoding RNAs that mediate the translational repression or degradation of mRNA to regulate diverse biological functions. Previous studies have suggested that several miRNAs play important roles in myoblast proliferation and differentiation in vitro. However, their potential roles in skeletal muscle regeneration in vivo have not been fully established. In this study, we generated a mouse in which the Dicer gene, which encodes an enzyme essential in miRNA processing, was knocked out in a tamoxifen-inducible way (iDicer KO mouse) and determined its regenerative potential after cardiotoxin-induced acute muscle injury. Dicer mRNA expression was significantly reduced in the tibialis anterior muscle of the iDicer KO mice, whereas the expression of muscle-enriched miRNAs was only slightly reduced in the Dicer-deficient muscles. After cardiotoxin injection, the iDicer KO mice showed impaired muscle regeneration. We also demonstrated that the number of PAX7+ cells, cell proliferation, and the myogenic differentiation capacity of the primary myoblasts did not differ between the wild-type and the iDicer KO mice. Taken together, these data demonstrate that Dicer is a critical factor for muscle regeneration in vivo.
Highlights
Adult skeletal muscle has a remarkable regenerative capacity
Because the regenerative capacity of adult skeletal muscle largely depends on the functions of the resident muscle stem cells, such as muscle satellite cells (SCs), we investigated their numbers and the myogenic differentiation potential of primary myoblasts isolated from iDicer KO mice
The tamoxifen-inducible knockout of Dicer in adult mice impaired the skeletal muscle regeneration that oTcchuerrteadminoxreifsepno-ninsdeutociCblTeXkinnjoucrkyo(uFtiguorfe D2)i.cHerowinevaedr,uwlte fmouicned inmopraediruecdtiothnse insktheleePtaAl Xm7+ucsecllle regeneration that occurred in response to CTX injury (Figure 2)
Summary
Adult skeletal muscle has a remarkable regenerative capacity. After muscle injury, the resident muscle stem cells leave their quiescent state and begin to proliferate. The adult Pax7-mutant mice showed impaired injury-induced muscle regeneration [3]. These findings indicate that the proliferation and myogenic differentiation of resident muscle stem cells are necessary for muscle regeneration. The transcripts are cleaved by a nuclear ribonuclease III, Drosha, and exported to the cytoplasm and further cleaved by a cytoplasmic ribonuclease III, Dicer, into double-stranded RNA TThheessee tthhrreeee mmiiRRNNAAss aarree ttrraannssccrriippttiioonnaallllyy rreegguullaatteedd bbyy mmyyooggeenniicc rreegguullaattoorryy ffaaccttoorrss,, wwhhiicchh aarree mmaasstteerr ttrraannssccrriippttiioonnaall ffaaccttoorrss ffoorr sskkeelleettaall mmuussccllee cceellll--ffaattee ddeetteerrmmiinnaattiioonn aannddddeevveeloloppmmeennt,t,anadndaraeruepurpegreuglautleadteddudriunrginmgumsculesdclieffedriefnfetriaetniotinat[i1o4n–1[174].–I1t7h].asItbheaens bseheonwsnhtohwant mthiaRt-1mainRd-1maniRd-2m0i6R, -w20h6ic, hwhhaicvhe hidaevnetiicdaelnsteiceadl sseeqeduesnecqeuse, npcreosm, porteommoytoegmenyeosgiseninesvisitrino, vwithreor,ewashemreiRas-1m33iRp-r1o3m3 optreosmmoyteosbmlaystobplraosltifperraotliiofenra[t7i,o8n]. IInn tthhiiss ssttuuddyy,, wwee ggeenneerraatteedd aa ttaammooxxiiffeenn--iinndduucciibbllee ccoonnddiittiioonnaall DDiicceerr--KKOO ((iiDDiicceerr KKOO)) mmoouussee ttoo ddeepplleettee aallllmmaatutureremmiRiNRNAsAasndanadnaalynzaelydzietds reitgsenreegraetnivereactaivpeaccitaypdacuirtiyngdcuarridnigotcoaxridni-ointodxuicne-dinmduucseclde mreugsecnleerarteigoenn. Wild-type (WT) and iDicer KO mice were injected intramuscularly with cardiotoxin
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