Copyright ©The Author(s) 2015.
World J Biol Chem. Aug 26, 2015; 6(3): 162-208
Published online Aug 26, 2015. doi: 10.4331/wjbc.v6.i3.162
Table 2 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b in other precursor cells and tissues
Nerve tissues
Pitx3Pitx3 downregulatedmiR-133bMammalian midbrain DNs[73]
Exosome-mediated transfer of miR-133b from MSC to brain astrocytesmiR-133b transfer from multipotent mesenchymal stromal cells to neural cellsmiR-133b upregulatedMouse MSCs to neural cells[47]
Ctgf and RhoACtgf and RhoA downregulatedmiR-133b upregulatedMultipotent MSCs/Rat brain parenchymal cells[72]
miR-133b null mice: Striatum dopamine levels unchanged, Pitx3 expression unaffected; motor coordination unalteredmiR-133b has no significant role on mDA neuron development and maintenance in vivoNormal numbers of mDA neurons during development and aging of miR-133b null miceMouse mDA neuron development in -/-miR-133b mutant mice[45]
Acute or chronic morphine administration, or morphine withdrawalmiR-133b levels not affectedRat VTA/ nucleus accumbens shell[219]
GPM6A, a neuronal glycoproteinmicroRNA-133b upregulationReduction in gmp6a at mRNA and protein level. Cell filopodium density was reducedHippocampus and prefrontal cortex of neonatal male rats stressed when in utero[220]
Tac1 gene (neurotransmitter substance P)Tac1 downregulatedmiR-206 upregulatedMSCs-derived neural cells[221]
Ketamine (antidepressive) administrationBDNF, a direct target gene of miR-206, was upregulatedmiR-206 was downregulated by ketamineRat hippocampus tissue[222]
Adipogenic tissues
IGF-1 and IGF-1RIGF-1 signalling and miR-133b co-regulate ADSC differentiation via a feedback loopmiR-133b downregulation of Pitx3;Adipose tissue-derived stem cell differentiation into neuron-like cells[71]
IGF-1 upregulates miR-133b;
miR-133b downregulates IGF-1R
Pdrm16miR-133a directly targets Prdm16.Downregulation of miR-133 resultsin differentiation of pre-adipocyte precursors into BATMouse adipocyte differentiation to BAT[74]
Pdrm16miR-133 directly targets Prdm16Downregulation of miR-133 resulted in differentiation of pre-adipocyte precursors into BATMouse primary brown adipocyte (and myogenic) progenitor cells - differentiate into BAT or SAT[75]
Pdrm16miR-133 targets Prdm16 controlling brown adipose determination in skeletal muscle satellite cellsmiR-133 downregulates Prdm16Adult mouse skeletal muscle stem cells (satellite cells) differentiate into BAT[76]
HDAC4 downregulation directs SCs towards adipocyte differentiationBrown adipose master regulator Prdm16 is upregulated, while its inhibitor miR-133 is also downregulatedHDAC4 downregulated in SCs differentiating into adipocyte progenitor cellsMyogenenic satellite SCs[175]
GLUT4 expressionBoth basal and insulin-stimulated glucose uptake are increasedKLF15Mouse 3T3-L1 preadipocytes differentiating into adipocytes[182]
Intrinsic insulin resistanceElevated miR-133bUndefined roleAdipose tissue of women with PCOS[223]
Upregulation of LIM homeobox 8 and Zic family member 1 and downregulation of Homeobox C8 and Homeobox C9Undefined relation of upregulated miR-206, miR-133bUndefined relation with parallel upregulation of brite/beige markers, TBX1 and TMEM26Human BAT from the supraclavicular region[224]
Obesity developmentDownregulation of miR-133b, miR-1Undefined roleAdipose tissue from obese male C57BLJ6 mice[225]
LXRα regulation of lipogenic genesmiR-1/miR-206 represses LXRα expression at both mRNA and protein levelsmiR-1/miR-206-induces a decrease in lipogenic gene levels and lipid droplet accumulationMouse hepatocytes[226]
Osteogenic tissues
Development of bone on organic or inorganic substratesmiR-133 differentially expressed in osteoblasts grown on different substratesOsteoblast[227]
Runx2miR-133 directly down-regulates Runx2miR-133 up-regulatedOsteogenic differentiation from C2C12 mesenchymal cells[228]
HDAC4HDAC4 downregulates Runx2miR-1 targets HDAC4, increasing Runx2 activityChondrocyte proliferation in cartilage growth plate[77]
AggrecanmiR-1 promotes late-stage differentiation of growing cartilage cellsmiR-1 targets Aggrecan gene expressionChicken chondrocytes and human HCS-2/8 cells[78]
Alveolar cells
VAMP2/ lung surfactant secretionmiR-206 targets VAMP-2miR-206 overexpression decreased lung surfactant secretionLung alveolar type II cells[229]
Hormonal regulation
L-thyroxinemiR-206/miR-133b downregulatedL-thyroxine treatmentL-thyroxine treated hypothroidic skeletal muscle from thyroidectomized patients[230]
miR-206/miR-133b upregulated-Hypothroidic human skeletal muscle
Thyroid hormone/TEAD1Thyroid hormone inhibits the slow muscle phenotype by upregulation of miR-133a1 which downregulates TEAD1miR-133a1 is enriched in fast-twitch muscle and regulates slow-to-fast muscle fiber type conversionMouse muscle[231]
Thyroid hormone/miR-133a1 TEAD1myosin heavy chain I expression downregulatedTH indirectly downregulates myosin heavy chain I via miR-133a/TEAD1Mouse muscle[232]
L-thyroxinepre-miR-206 and pre-mir-133b downregulatedL-thyroxineL-thyroxine treated hypothyroidic mouse liver;[232]
50-500x increase expression of miR-1/-133a and miR-206/-133b-Hypothyroidic mouse liver
Reduced insulin-mediated glucose uptake in cardiomycetesDownregulation KLF15, which downregulates GLUT4Forced overexpression of miR-133a and miR-133bRat cardiac myocytes[181]
Cardiac myocyte glucose metabolismUpregulation KLF15, which upregulates GLUT4Silencing endogenous miR-133Rat cardiac myocytes[181]
Metabolic control of glucose uptake by GLUT4 transporterDownregulates KLF15, which results in downregulation of GLUT4 levelsChronic heart failure has depressed miR-133a and -133b levelsRat cardiac myocytes during chronic heart failure and cardiac hyperthrophy[181]
Atrial natriuretic factor expression upregulationEnhanced at LVH and dramatically increased at CHF stageBoth miR-133a and miR-133b downregulated at CHF stageLVH and CHF in salt-sensitive Dahl rats[181]
EstrogenEstrogen replacement strongly decreased IGF-1 protein level in muscles at 1 wkOvariectomized rat skeletal muscle[233]
Multiple targetsmiR-133a upregulated in BTBR micePancreatic islets, adipose tissue, and liver from diabetes-resistant (B6) and diabetes-susceptible (BTBR) mice[234]
Augmentation of adipocyte differentiation by norepinephrine does not alter myomiR levelsmiRNAs miR-1, miR-133a and miR-206 specifically expressed both in brown pre- and mature adipocytesmiRNAs miR-1, miR-133a and miR-206 were absent from white adipocytesMouse brown adipocytes[235]
Foxl2miR-133b targets Foxl2;Foxl2 regulates StAR and CYP19A1 transcriptionallyEstradiol production in ovarian granulosa cells[236]
miR-133b inhibits Foxl2 binding to StAR and CYP19A1 promoter sequences
Exosome release and cell to cell transfer
Exosome-mediated transfer of miR-133b from MSCs to brain astrocytesmiR-133b transfer from multipotent mesenchymal stromal cells to neural cellsmiR-133b upregulatedMouse multipotent MSCs to neural cells[47]
Cell to cell transfer of exosome-enriched extracellular particlesmir-133b promotes neural plasticity and recovery of function after stroke induced damagemiR-133b upregulatedRat multipotent MSCs via transfer of exosome-enriched extracellular particles[72]
Transplanted stem cells
MSCs expressing miR-1Upregulated miR-1Increased rate of recovery, enhanced survival of transplanted MSCs and cardiomyogenic differentiationExperimental ligation of the mouse left coronary artery to model myocardial infarction[237]
Knockdown of Hes-1, member of Notch pathwayUpregulated miR-1 promotes the differentiation of MSCs into cardiac lineageRole in survival of transplanted MSCs and cardiomyogenic differentiationMouse MSCs[238]
Notch signalling and cardiomyocyte markers, Nkx2.5, GATA-4, cTnT, and Cx43MSCs expressing exogenous miR-1Mouse MSCs[238]
Tissue inflammation
Selective release of miRs during inflammation into serummiR-133 selectively releasedReview[239]
Inflammation and cancerMicroRNA, free radical, cytokine and p53 pathwaysReview[240]
Immunological switch which shapes tissue responsesTWEAK/Fn14 pathwayReview[241]
Tumor biologyHMOX1Review[242]
GM-CSFDirect supression of GM-CSF expression by miR-133Elevated expression of miR-133a/-133b during oxidative stressMouse alveolar epithelial cells during oxidative stress[82]
PI3K/Akt and IGF-1 pathwaysActivation of PI3K/Akt and IGF-1 pathway activitiesDownregulation of miR-133a (and other miRs) by AOM/DSS induced chronic inflammationMouse model: AOM/DSS-induced colitis-associated gastro-intestinal cancer[83]
CTGF, SMA, and COL1A1Increased expression of CTGF, SMA and COL1A1, which are miR-133b targetsStrong downregulation of miR-133b (and other miRs)TGF-β treated rabbit corneal fibroblasts; Recovering mouse cornea after laser ablation,[70]
IL-10 and TGF-βExogenous IL-10 and TGF-β induces miR-133b expressionUpregulation of miR-133bHuman tolerogenic dendritic cells during maturation[79]
IL-17-producing T-cellsUpregulation of Il17a/f gene expressionmiR-133b/-206 cistron transcription occurs along with nearby Il17a/f gene expressionImmunocompetent mouse Th17 cells[80]
NLRP3 inflammasome which processes IL-1β by caspase-1 cleavagemiR-133a-1 suppresses activation of inflammasomes via suppression of expression of mitochondrial UCP2miR-133a-1 overexpression in cells increases caspase-1 p10 and IL-1β p17 cleavage,Differentiated mouse THP1 cells[81]
Concanavalin A-induced fulminant hepatitismiR-133a is the most strongly differentially upregulated miRMouse liver following ConA injection[243]
Infection/immune response to influenza virus (H1N2)miR-206 expressionExperimental influenza infection in pig lung[244]
HIF-1α, and its regulator Four-and-a-half LIM (Lin-11, Isl-1 and Mec-3) domain 1 (Fhl-1)Downregulation of miR-206 and upregulated HIF-1α and Fhl-1 in hypoxic lung tissue and PASMCsmiR-206 targets HIF-1α directly. Hypoxia-induced down-regulation of miR-206 promotes PH in PASMCsHypoxia-induced PH in hypoxic rat model in cultured hypoxic PASMCs[245]
miR-206/NR4A2/NFKB1;NFKB1 stimulates inflammatory cytokines (IL6, IL1B, CCL5)Liposaccharides induce miR-206 expression which targets NR4A2 downregulation, which in turn allows upregulation of NFKB1 activityAstrocyte-associated inflammation during recovery from chronic central nervous system injury[246]
Indirectly: inflammatory cytokines (IL6, IL1B, CCL5)
Cellular factors influencing myomir expression/activity
Skeletal muscle
Positive regulatorNegative regulatorRegulated target miRTissue/cellRef.
Myogenin, MyoDUpregulates miR-1-1 and miR-133a-2Primary human myoblasts; C2C12 cells[11]
Upregulates miR-1-2 and miR-133a-1
SRF, MyoD and MEF2Upregulates miR-1-2Muscle somites[30]
MEF2Upregulates miR-1 and miR-133aSkeletal muscle[9]
KSRP (part of Drosha and Dicer complexes)miR-206 binds 3’-UTR of KSRP and inhibits its expressionKSRP upregulates miR-1 expressionSkeletal muscle[35,37]
RNA-binding protein LIN28LIN28 upregulates miR-1 expression; LIN28 promotes pre-miR-1 uridylation by ZCCHC11 (TUT4)Cardiac muscle of patients with muscular dystrophy[36]
MBNL1MBNL1 downregulates miR-1 expression; MBNL1 binds to UGC motif in the loop of pre-miR-1 and competes for the binding of LIN28; MBNL1 blocks DICER processing of pre-miR-1Cardiac muscle of patients with muscular dystrophy[36]
CX43 and CACNA1C calcium channelCX43 and CACNA1C both increased in both DM1-/DM2-affected hearts, contributing to the cardiac dysfunctionsCX43 and CACNA1C are direct targets of miR-1 repressionCardiac muscle of patients with muscular dystrophy;[36]
CACNA1C and CX43 encode the main calcium- and gap-junction channels in heart
Utrophin AmiR-206 and KSRP are negative regulators of utrophin AOverexpression of miR-206 promotes the upregulation of utrophin A, via the downregulation of KSRPNormal and dystrophic muscle cells;[37]
miR-206 can switch between (1) direct repression of utrophin A expression, and (2) activation of its expression by decreasing KSRP, allowing close regulation
MyostatinDownregulates miR-1, miR-133a, miR-133b, miR-206Mouse (35 d) pectoralis skeletal muscle[29]
SRFDownregulates miRs-133aSkeletal muscle[1,3]
Prmt5 and Prmt4Upregulates myomiR expression during differentiationMouse skeletal muscle[247]
Smooth muscle
Sp-1 transcription factorpERK1/2Upregulates miR-133(a)VSMCs[248]
Brg1Upregulates miR-133 (ChIP complex with SRF)Smooth muscle[249]
Cardiac muscle
GATA4, Nkx2.5, Myocardin, SRFUpregulates miR-1 and miR-133aDifferentiating cardiac muscle[5]
SRF plus MyocardinUpregulates miR-1-1 and miR-1-2Cardiomycetes[30]
CalcineurinDownregulates miR-133aHypertrophic cardiac muscle[203]
miR-206/ miR-133b
Skeletal muscle
Mrf5Upregulates miR-1, miR-206Skeletal muscle[171]
Myogenin, MyoDUpregulates miR-206Primary human myoblasts; C2C12 cells[11]
MyoDUpregulates linc MD1 (encodes miR-133b)Differentiating myoblasts[11, 38]
Binds to (E-box) enhancer of miR-206, miR-133bskeletal muscle (mouse)[12,40]
Upregulates miR-206/miR-133bDifferentiated human foetal skeletal muscle cells[250]
FGF2 allows upregulation of Sp1/Cyclin D1Downregulates p38-mediated miR-1/133 expressionRegenerating rat skeletal muscle[212]
MyostatinDownregulates miR-133a, mir-133b, miR-1, and miR-206Mouse (35 d) pectoralis skeletal muscle[29]
TWEAK downregulates myoD and MEF2cDownregulates miR-1-1 and miR-133Degenerating/wasting skeletal muscle[59]
HMOX1 downregulates MyoD and myogeninDownregulates all myomiRsInflamed skeletal muscle[60]
L-Thyroxine treatmentDownregulation of pri-miR-206 and pri-miR-133bHuman skeletal muscle[230]
No effect on miR-1/miR-133a pairs
Smooth muscle
p-ERKActivated extracellular signal-regulated kinase p-ERK inversely correlated with VSMC growthDownregulates miR-133 expressionVSMCs[248]
Other tissues
MyogeninBinds miR-206 enhancer (ChIP)Fibroblast cell line:[40]
IGF-I signallingUpregulates miR-133bMouse Adipose derived stem cells[71]
L-Thyroxine deficiencyUpregulated Col5a3Strong upregulation of miR-133a and -133bHypothyroid mouse liver[232]
Downregulated Slc17a8, Gp2, Phlda1, Klk1d3, Klk1 and Dmbt1Strong upregulation of miRs -1, -206
Upregulated Vldlr and Akr1c19, and downregulated Upp2, Gdp2, Mup1, Nrp1, and Serpini2
L-Thyroxine treatmentPre-miR-206 and Pre-miR-133b down-regulatedUpregulation of Gdp2 andMup1Hypothyroid mouse liver in vivo, and in vitro mouse hepatocyte AML12 cells[232]
PA2G4, mps1, cdc37, cx43, cldn5; cx43 is a miR-133 targetUpregulation of cell cycle factors mps1, cdc37, and PA2G4, and cell junction components cx43 and cldn5Suppression of miR-133a1 stimulates cardiac cell proliferationRegeneration of damaged Zebrafish cardiac muscle, associated with reduced miR-133a1[167]
FgfUpregulated FgfDownregulates miR-133Zebrafish regenerating fin blastema[67]
SHP (nuclear receptor)Downregulation of miR-206 in nuclear receptor SHP(-/-) miceSHP(-/-) mice strain, mouse liver[251]
AP1 transcription factor complexAP1 induced miR-206 promoter transactivity and expression; this is repressed by YY1ChIP analysis shows physical association of AP1 (c-Jun) and YY1 with miR-206 promoterSHP(-/-) nuclear receptor mice strain, mouse liver[251]
NR3B3YY1 promoter transactivated by ERRgamma; this inhibited by SHP (NROB2)Nuclear receptor ERRgamma (NR3B3) binding site on the YY1 promoterMouse liver[251]
Novel cascade "dual inhibitory" mechanism governing miR-206 gene transcription by SHP(1) SHP inhibition of ERRgamma leads to decreased YY1 expression(2) Derepression of YY1 on AP1 activity, leads to activation of miR-206Mouse liver[251]
Il17a/f locusmiR-133b and miR-206 expressionCoregulated with IL-17 productionαβ and γδ T cells[80]