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 1 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b
Fish and lower vertebrates: Development and regeneration
Ttk protein kinase (mps1)Upregulated mps1: a target of miR-133Downregulation of miR-133 by FgfRegeneration of Zebrafish caudal fin (appendage)[68]
RhoADownregulation of RhoA mRNAUpregulation of miR-133b expressionRegenerating adult zebrafish spinal cord, axon outgrowth[69]
RhoADownregulation of RhoA proteinUpregulation of miR-1 and miR-133 expressionZebrafish muscle gene expression and regulation of sarcomeric actin organization[166]
Cell cycle factors mps1, cdc37 and PA2G4, and cell junction components cx43 and cldn5Upregulated mps1, cdc37, PA2G4, cx43, cldn5Downregulated miR-133(a1) stimulates cardiac cell regenerationRegenerating zebrafish cardiac muscle[167]
miR-133bMiR-133b found in developing somites, little in CNS tissuesWhole zebrafish embryos - normal development[168]
SRF activates muscle specific genes and miRs;MiR-1 targets HDAC4, promoting myogenesisIn contrast, miR-133a represses SRF, enhancing myoblast proliferationX. laevis embryos: skeletal muscle proliferation and differentiation in cultured myoblasts in vitro and in embryos in vivo[7]
HDAC4 represses muscle gene expression
nAChR subunits UNC-29, UCR-63; MEF2Subunits UNC-29, UCR-63, and MEF2 downregulatedmiR-1 upregulatedC. elegans muscle at the neuromuscular junction[34]
Mammalian pluripotent cells
Muscle-specific microRNAs: miR-1 and miR-133aMiR-1 and miR-133a have opposing functions during differentiation of progenitor cardiac musclesMuscle-specificPromotion of mesoderm formation from mouse ES cells[13]
microRNAs, miR-1 and miR-133(a) upregulated
Notch signalling, promotes neural differentiation and inhibits muscle differentiation; opposes miR-1 effectsDll-1 translationally repressedmiR-1 upregulation, promotes cardiomycete differentiationMouse and human ES cell differentiation into muscle[13]
SRF-/- EBs reflecting the loss of hematopoietic lineages in the absence of SRFEarly endoderm markers, Afp and Hnf4α: strongly down regulatedIncreased miR-1 and miR-133a relieve the block on mesodermal differentiationMouse endoderm[13]
Blood cell -specific genes, such as Cd53, CxCl4, and Thbs1, dramatically down regulatedCd53, CxCl4, and Thbs1 expression was reinitiated by reintroduction of miR-1 or miR-133
mES(miR-1)- and mES(miR-133a)- EBs compared to in control EBsNodal stimulated expression of endoderm markers Afp and Hnf4α in control EBs. Dramatically lower levels in mES(miR-1)- and mES(miR-133a)- EBsmiR-1 or miR-133 can each function as potent repressors of endoderm gene expressionmES cells, that lack either miR-1 or miR-133(a) during differentiation into EBs[13]
IGF-1IGF-1 signalling and miR-133 co-regulate myoblast differentiation via a feedback loopIGF-1 upregulates miR-133;Myogenic differentiation of C2C12 myoblasts; Mouse during development from embryonic to mature skeletal muscle[24]
IGF-1RmiR-133 downregulates IGF-1R
IGF-1IGF-1 signalling and miR-1 coregulate differentiation of myoblasts via a feedback loopIGF-1 signalling downregulates miR-1 by repression of FoxO3a;Differentiating C2C12 myoblasts[25]
miR-1 down-regulates IGF-1
Reversine [2-(4-morpholinoanilino)-N6-cyclohexyladenine]Decrease in active histone modifications; including trimethylation of histone H3K4/ H3K36, phosphorylation of H3S10;miR-133a expression strongly inhibited by reversine; reduced acetylation of H3K14 at miR-133a promoterReversine dedifferentiates murine C2C12 myoblasts back into multipotent progenitor cells, via extensive epigenetic modification of histones resulting in chromatin remodelling, and altered gene expression[20-23]
Stimulates expression of polycomb genes Phc1 and Ezh2Reduced expression of myogenin, MyoD, Myf5 and Aurora A and B kinases
FZD7 and FRS2miR-1 promotes cardiac differentiation; miR-1 targets FZD7 and FRS2Activitation of WNT and signalling cause MCPs differentiation into cardiomyocytesMouse and human ES cells[169]
miR-206/133b clusterPAX7 gene expression unchanged;miR-206/133b cistron knock-out mice cellsMuscle satellite cell differentiation in vitro[170]
miR-206/133b cluster is not required for development, and survival of skeletal muscle cells
Differentiating skeletal muscle
DNA polymerase alphaRepression of Idl-3 protein expressionmiR-206 up-regulatedMouse skeletal muscle differentiation[42]
Repression of p180 subunit of DNA polymerase alpha
MEF2 transcription factorMEF2 activates of miR-1-2 and 133a-1 transcription; binds muscle-specific enhancerBicistronic primary transcript of miR-1-2 and 133a-1Development of mammalian skeletal muscle[9]
MRFs, Myf5, MyoD, Myogenin and MRF4Myf5 essential for miR-1 and miR-206 expression during skeletal muscle myogenesisForced expression of MRFs in neural tube induces miR-1 and miR-206 expressionChicken and mouse embryonic muscle[171]
PTB and neuronal homolog nPTB, exon splicing factorsDownregulation of PTB protein by miR-133 (and miR-206)Concurrent upregulation of miR-133 and induction of splicing of several PTB-repressed exonsDuring myoblast differentiation, microRNAs control a developmental exon splicing program[172]
BDNFBDNF downregulatedmiR-206 upregulatedDifferentiation of C2C12 myoblasts into myotubes[48]
Fstl1 and UtrnFstl1 and Utrn downregulatedmiR-206 upregulatedSkeletal muscle differentiation[40]
Utrophin A (muscle)Utrophin A down-regulated by both miRsUpregulated miR-133b, miR-206C2C12 mouse myoblasts, mouse soleus muscle[173]
CNN3 geneNegative correlation between miR-1 expression and CNN3 mRNA expressionNormal skeletal muscleTongcheng (Chinese) and Landrace (Danish) pigs[174]
FGFR1 and PP2AC, members of ERK1/2 signalling pathwaymiR-133 (a and b) activities increase during myogenesismiR-133 directly downregulates expression of FGFR1 and PP2ACMouse C2C12 myoblast cells[31]
ERK1/2 signalling pathway activityERK1/2 signalling activity suppresses miR-133 expressionDownregulation of expression of miR-133A reciprocal mechanism for regulating myogenesis
BAF chromatin remodelling complex (BAF60a, BAF60b and BAF60c)Positive inclusion of BAF60c in the BAF chromatin remodeling complexExpression of miR-133 and miR-1/206Progression of developing somites in chick embryos[63]
BAF chromatin remodelling complexNegative regulation of BAF60a and BAF60b; exclusion from BAF chromatin remodelling complexExpression of miR-133Progression of developing somites in chick embryos[63]
BAF chromatin remodelling complexExogenous upregulation of BAF60a and BAF60bDelay in developing somites in chick embryos[63]
Mitochondrial UCP2 and UCP3MyoD activates miR-133a expression which in turn directly downregulates UCP2 mRNAFeedback network involving MyoD-miR-133a-UCP2Mouse skeletal and cardiac muscles; UCP2 imposes developmental repression[56]
Mitochondrial UCP2 and UCP3Exogenous overexpression of myogenin and MyoD transcription factorsStrong increase in UCP3 promoter, expression, weak effect at the UCP2 promoterMouse C2C12 myoblasts[57]
Proliferating myogenic skeletal muscle cells
MiR-206/133b clusterMiR-206/133b cluster is not required for survival and regeneration of skeletal muscleMuscle regeneration proceeds in Mdx mice in vivomiR-206/133b cistron knock-out mice[170]
Enhanced translation of specific mitochondrial genome-encoded transcriptsmiR-1 enters muscle mitochondria and binds mtRNA targets along with Ago factorIncreased expression of mtRNA targetsProliferating myogenic skeletal muscle cells after muscle injury[53]
mTOR (serine/threonine kinase)MyoD stability regulated by mTORRegulates miR-1 expression via MyoD availabilityRegenerating mouse skeletal muscle and differentiating myoblast cells[32]
AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathwaysmTORC regulates timing of satellite cell proliferation during myogenesisKnockdown of mTORC reduces miR-1 expressionMyogenenic satellite SCs proliferating and differentiating into myogenic precursors following rat skeletal muscle injury[58]
HDAC4 regulates Pax7-dependent muscle regenerationPax7 stimulates SCs differentiation toward the muscle lineage, and limits adipogenic differentiationHDAC4 upregulated in SCs differentiating into muscle cellsMyogenenic satellite SCs[175]
pcRNA encoded by the H strand of the rat mitochondrial genomeIntroduction of mt pcRNAs into injured muscle restoring mitochondrial mRNA levels; Intramuscular ATP levels were elevated after pcRNA treatment of injured muscleEnhanced organellar translation and respiration; similarly reactive oxygen species were reduced; Resulted in accelerated rate of wound resolutionInjured rat skeletal muscle is associated with general downregulation of mitochondrial function; reduced ATP, and increased ROS[176]
Cardiac muscle precursor cells
GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133Reprogrammed human fibroblasts show sarcomere-like structures and calcium transients; Some cells have spontaneous contractilityForced over-expression of GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133Human embryonic and adult fibroblasts activated to express cardiac markers[15]
SRF, MyoD and Mef2 transcription factorsmiR-1-1 and miR-1-2miR-1 genes upregulated;Cardiac muscle precursor cells[30]
During cardiogenesis miR-1 genes titrate critical cardiac regulatory proteins, control ratio of differentiation to proliferationElevated miR-1 targets downregulation of Hand2
Histone deacetylase inhibitor, trichostatin A forces differentiation, yet reduced miR-1 and miR-133amiR-1 and miR-133a reduce cardiac specific Nkx2.5 protein and Cdk9miR-1 and miR-133a increase during spontaneous differentiation of cardiac myoblastsMouse cardiac stem cells (ES cells)[10]
Specific inhibition of HDAC4 modulates CSCs to facilitate myocardial repairPositively proliferative myocytes increased in MI hearts receiving HDAC4 downregulated CSCsCSCs with downregulated HDAC4 expression improved ventricular function, attenuated ventricular remodeling, promoted regeneration and neovascularization in MI heartsMouse CSCs transplanted into MI mouse hearts[177]
Snai1Overexpression of miR-133a (miR-133), Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and MyocD improved cardiac cell reprogramming from mouse or human fibroblastsmiR-133a directly represses Snai1 expression, which silences fibroblast signatures; a key molecular process during cardiac reprogrammingMouse/human fibroblasts more efficiently reprogrammed into cardiomycete-like cells[16]
β1AR signal transduction cascadeAdenylate cyclase VI and the catalytic subunit of the cAMP-dependent PKA are components of β1AR transduction cascademiR-133 directly targets β1AR, Adenylate cyclase VI and PKATetON-miR-133 inducible transgenic mice, subjected to transaortic constriction, maintained cardiac performance with attenuated apoptosis and reduced fibrosis via elevated miR-133 expression[17]
ROS, MDA, SOD and GPxmiR-133 produced a reduction of ROS and MDA levels, and an increase in SOD activity and GPx levelsOverexpression of miR-133, a recognized anti-apoptotic miRNAIn vitro rat cardiomyocytes[18]
Caspase-9miR-133 directly suppresses caspase-9 expression resulting in downregulation of downstream apoptotic pathwaysOverexpression of miR-133In vitro rat cardiomyocytes[18]
Spred1miR-1 directly targets Spred1miR-1 is upregulated in hCMPCs during angiogenic differentiationhCMPCs[178]
miRNA-1 and miRNA-133amiRNA-1 and miRNA-133a have antagonistic roles in the regulation of cardiac differentiationForced overexpression of miR-1 alone enhanced cardiac differentiation, in contrast overexpression of miR-133a reduced cardiac differentiation, compared to control cellsPluripotent P19.CL6 stem cells[179]
Overexpression of both miRNAs promoted mesodermal commitment and decreased expression of neural differentiation markers
Cardiac muscle
Induction of GATA6, Irx4/5, and Hand2Cardiac myocytes show defective heart development, altered cardiac morphogenesis, channel activity, and cell cyclingmiR-1-2-/- gene knockoutCardiac myocytes with knockout of both miR-1-2 genes[180]
mt-COX1 mRNA3’-UTR of mt-COX1 mRNA bound by miR-181c and Ago1 factorOverexpression of miR-181c significantly decreased mt-COX1 protein, but not mt-COX1 mRNA levelOverexpression of miR-181c increased mitochondrial respiration and reactive oxygen species in neonatal rat ventricular myocytes[54]
mt-COX1 mRNAIn vivo elevation of miR-181c in rat heart, reduces levels of mt-COX1 proteinResults in reduced capacity for strenuous exercise and evidence of heart failureRat cardiac muscle[55]
Carvedilol, a β-adrenergic blockerInduces upregulation of miR-133Cytoprotective effects against cardiomyocyte apoptosisRat cardiac tissue, in vivo[18]
GLUT4, and SRFBoth miRs downregulate SRF and KLF15Both miR-133a and miR-133b target KLF15Mouse cardiac myocytes[181]
GLUT4 expressionBoth basal and insulin-stimulated glucose uptake are increasedKLF15Mouse muscle cell lines[182]
MEF2 transcription factorMEF2 directly activates transcription of miR-1-2 and 133a-1 binding muscle-specific enhancer between the genesBicistronic primary transcript of miR-1-2 and 133a-1Development of mammalian cardiac muscle[9]
Myocardium tissueEnriched in miR-1, miR-133b, miR-133aHeart structures of rat, Beagle dog and cynomolgus monkey[183]
GelsolinOne common miR-133a isomiR targets gelsolin gene more efficiently than standard isomer; New second rat miR-1 geneMany isomiRs were detected by deep sequencing at higher frequency than the canonical sequence in miRBasemiRNA/isomiR expression profiles in the left ventricular wall of rat heart[184]
CTGFCTGF downregulated by both miRsExogenous upregulation of miR-133b (and miR-30c)Cultured cardiomyocytes and ventricular fibroblasts[185]
MT1-MMPmiR-133a upregulatedmiR-133a targets MT1-MMPHuman left ventricular fibroblasts[186]
Injured and regenerating cardiac muscle
SERCA2aAkt/FoxO3A-dependent pathwayDownregulation of miR-1 expression in failing heart muscleFailing mouse heart muscle[187]
Activated SERC2a reduces phosphorylation of FoxO3a, allowing entry to nucleus and activation of miR-1 expression
IGF-1IGF-1 signalling and miR-1 co-regulate differentiation of myoblasts via a feedback loopIGF-1 signalling down-regulates miR-1 by repression of FoxO3a;Mouse heart muscle during cardiac failure states[25]
miR-1 down-regulates IGF-1
Bim and BmfOnly miR-133a expression enhanced under in vitro oxidative stressmiR-133a targets proapoptotic genes Bim and BmfRat adult CPCs[188]
miR-1 favors differentiation of CPCs, whereas
Bim and BmfCPCs overexpressing miR-133a improved cardiac function by reducing Bim and BmfCPCs overexpressing miR-133a improved cardiac function, increasing vascularization and cardiomyocyte proliferation, reduced fibrosis and hypertrophyCPCs overexpressing miR-133a in rat myocardial infarction model[188]
MT1-MMP activity increased in both. Ischemia and reperfusion regionsInterstitial miR-133a decreased with ischemia in vitro and in vivo; reperfusion returned to steady-statePhosphorylated Smad2 increased within the ischemia-reperfusion regionIschemia-reperfusion Yorkshire pigs (90 min ischemia/120 min reperfusion)[186]
Cardiovascular disease
CNN2Strong upregulation of CNN2 expressionmiR-133b downregulated; miR-133b directly targets CNN2Pre-inflammatory events in diseased cardiac tissues[65]
Circulating platelet derived microparticlesElevated miR-133Patients with stable and unstable coronary artery disease[189]
Acute MI causes upregulation of circulating serum miRsmiR-1, -133a, -133b, and -499-5p were about 15- to 140-fold elevated over controlAcute STEMI patients and experimental mouse MI model[190]
Circulating miRNAs in serum of cardiovascular disease patientsReleased miR-1 and miR-133a are localized in exosomes, and are released by Ca(2+) stimulationLevels of miR-1, miR-133a, reduced in infarcted mouse myocardium model heartmiR release indicates myocardial damage[191]
LVM after valve replacement in aortic stenosismicroRNA-133a is a significant positive predictor of LVM normalisationmiR-133 is a key element of the reverse remodelling processPatients following valve replacement[192]
Circulating levels of miR-133aElevated miR-133a (11-fold)Troponin-positive acute coronary syndrome patients[193]
Circulating levels of miR-133aElevated miR-133aImproved potential regression of Left Ventricular Hypertrophy after valve replacementPatients with aortic stenosis surgery[194]
Apelin treatment reduces elevated circulating miRsElevated miR-133a, miR-208 and miR-1 reducedHigh-fat diet elevated miRs and increased left ventricular diastolic and systolic diameters, and wall thicknessObesity-associated cardiac dysfunction in mouse model[195]
NAC treatmentExpressed miR-1, miR-499, miR-133a, and miR-133b were strongly depressed in the diabetic cardiomyocytesNAC restored expression of miR-499, miR-1, miR-133a, and miR-133b significantly in the myocardiumDiabetic rat hearts[196]
Myocardial junctin elevatedmiR-1 targets junctinNAC reduces junction levelsDevelopment of diabetic cardiomyopathy in rat hearts[196]
CAD associated ischemic heart failuremiR-133 expression decreased with increased severity of heart failurePatients with CAD[197]
Runx2miR-133a targets Runx2Transition of VSMCs to osteoblast-like cells[198]
Increased alkaline phosphatase activity, osteocalcin secretion and Runx2 expressionmiR-133a was decreased during osteogenic differentiationTransition of VSMCs to osteoblast-like cells[198]
Circulating miR-133a and 208a levelsCardiac muscle-enriched microRNAs (miR-133a, miR-208a) elevatedPatients with coronary artery disease[199]
Hypertrophic cardiac muscle
Cx43 increasedmiR-1 targets Cx43Downregulation of miR-1 mediates induction of pathologic cardiac hypertrophyHypertrophic rat cardiomyocytes in vitro and in vivo[200]
Cx43 downregulatedmiR-1 targets Cx43Cx43 protein downregulated in miR-1 Tg mice compared to WT miceCardiac-specific miR-1 transgenic (Tg) mouse model[201]
Twf1 upregulatedmiR-1 targets Twf1Strong downregulation of miR-1 in pathologic hypertrophic cardiac cells compared to normal, induces Twf1 expressionIn vivo in hypertrophic mouse left ventricle; and in vitro in phenylephrine-induced hypertrophic cardiomyocytes[202]
RhoA, Cdc42, Nelf-A/WHSC2Increased levels of RhoA, Cdc42, Nelf-A/WHSC2Reduction miR-133aHypertrophic cardiac muscle[6]
Calcineurin, agonist of cardiac hypertrophyIncreased Calcineurin activity;Reduced miR-133a;Hypertrophic cardiac muscle;[203]
Cyclosporin A inhibits calcineurinPrevents miR-133 down-regulationCardiac hypertrophy reduced
NFATc4NFAFc4 targetted by miR-133amiR-133aCardiomyocyte hypertrophic repression[204]
Interdependent Calcineurin-NFAT and MEK1-ERK1/2 signalling pathways in cardiomyocytesMEK1-ERK1/2 signalling augments NFAT and NFAF gene expression; Activated calcineurin activates NFAT, inducing cardiac hypertrophyMEK1 is part of mitogen-activated protein kinase (MAPK) cascade; MEK1 activates ERK directlyHypertrophic growth response of mouse cardiomyocytes[205]
Innervating skeletal muscle
Innervated skeletal muscleMyoD, Myf5, Mrt4, nAChRαMyogenin expressionMouse skeletal muscle[50,51]
Each is strongly repressed
Denervated muscle (unstimulated)Myogenin expression up-regulated MyoD, Myf5, Mrt4, nAChRαMouse skeletal muscle[51]
All strongly stimulated
Electrically stimulated - Denervated muscleMyogenin, MyoD, Myf5, Mrt4, partly stimulated; nAChRα inhibitedMouse skeletal muscle[51]
HDAC4miR-1 promotes myogenesis by targetting HDAC4miR-133 enhances myoblast proliferation by targetting SRFSkeletal muscle proliferation and differentiation in myoblast cultures[7]
Neural activity effect on muscle (HDAC4 - MEF2 Axis)Loss of neural input leads to concomitant nuclear accumulation of HDAC4HDAC4 inhibits activation of muscle transcription factor MEF2; results in progressive muscle dysfunctionMEF-2 activity strongly inhibited in denervated mouse skeletal muscle and in ALS muscle[49]
Innervation and formation of airway smooth muscleSonic hedgehog (Shh) /miR-206/ BDNFShh signalling blocks miR-206 expression, which in turn increases BDNF proteinShh coordinates innervation and formation of airway smooth muscle[206]
nAChR subunits (UNC-29 and UNC-63); retrograde signallingSubunits UNC-29, UCR-63 and MEF2 downregulatedmiR-1 upregulatedC. elegans muscle at the neuromuscular junction[34]
MEF2Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulatedmiR-206 upregulatedRat skeletal muscle/re-innervating muscle[43]
HDAC4HDAC4 (miR-206 target, prospective miR-133b target) downregulatedmiR-206/-133b upregulated (and miR-1/-133a downregulated)Mouse fast twitch skeletal muscle/re-innervating muscle[12]
Regenerating injured muscle
Hnrpu and Npy downregulatedmiR-1 upregulatedmiR-1, -133a, downregulated 1 mo after denervation, then increased 2 × at 4 mo after re-innervationRat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation[43]
Ptprd downregulatedmiR-133a upregulated
Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated3 × increase in miR-206 1 mo later, after reinnervation; elevated at least 4 moPredominant type II fiber at 4 mo, after nerve re-innervationRat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation[43]
PP2A B56aPP2A B56a downregulated133a upregulatedCanine heart failure model: myocytes[207]
CaMKII-dependent hyperphosphorylation of RyR2VF myocytes had increased reactive oxygen species and increased RyR oxidationmiR-1 upregulatedCanine post-myocardial infarction model[208]
Collagen upregulatedTGF-b1 and TGFbRII: upregulatedmiR-133a or miR-590: downregulatedCanine model of acute nicotine exposure. Atrial fibrosis in vivo; cultured canine atrial fibroblasts in vitro[209]
miR-208 upregulatedmiR-1 and miR-133a downregulatedHuman MI compared to healthy adult hearts[210]
Myogenic proteins, MyoD1, myogenin and Pax7Induced expression of MyoD1, myogenin and Pax7 several days after miR injectionExogenous injection of miR-1, -133 and -206 promotes myotube differentiationRegenerating injured mouse skeletal muscle[211]
Cyclin D1/ Sp1Cyclin D1/ Sp1 downregulatedmiR-1/133 upregulatedRegenerating rat skeletal muscle[212]
PRP, source of pro-inflammatory cytokinesStong upregulation of the mRNA of pro-inflammatory cytokines IL-1β and TGF-β1; stimulation of both inflammatory and myogenic pathways; elevated heat shock proteins and increased phosphorylation of αB-cristallinStimulated tissue recovery via increased myogenic regulators MyoD1, Myf5, Pax7, and IGF-1Eb (muscle isoform) together with SRF; acts via increased expression of miR-133a with reduced levels of apoptotic factors (NF-κB-p65 and caspase 3)Regenerating flexor sublimis muscle of rats, 5 d after injury and treated with PRP[66]
Muscle degeneration
Pro-inflammatory cytokine TWEAKTWEAK upregulatedmiR-1-1, miR-1-2, miR-133a, miR-133b and miR-206 downregulatedDegenerating/wasting mouse skeletal muscle[59]
HMOX1 mediated by codependent inhibition of c/EBPδ binding to myoD promoterHMOX1 inhibits differentiation of myoblasts and modulates miRNA processingDownregulation of miR-1, miR-133a, miR-133b, and miR-206.Degenerating/wasting mouse skeletal muscle[60]
HMOX1 effects partially reversed by enforced expression of miR-133b and miR-206Downregulation of MyoD, myogenin and myosin, and disturbed formation of myotubes. Upregulation of SDF-1 and miR-146a
Dystrophic muscular disease
Circulating serum microRNAsmiR-1, miR-133a, and miR-206 highly abundant in Mdx serummiR-1, miR-133a, and miR-206 downregulated or modestly upregulated in muscleMuscle tissue from patients with Duchenne muscular dystrophy (Mdx)[213]
Laminin α2 chain deficiencymiR-1, miR-133a, and miR-206 are deregulated in laminin α2 chain-deficient muscleLaminin α2 chain-deficient mouseCongenital muscular dystrophy type 1A tissue[214]
Dystrophic process advances from prominent inflammation with necrosis and regeneration to prominent fibrosisDeficiency in calpain leads initially to accelerated myofiber formation followed by depletion of satellite cellsPax7-positive SCs highest in the fibrotic patient group; correlated with down-regulation of miR-1, miR-133a, and miR-206Muscle from Limb-girdle muscular dystrophy 2 type I patients[215]
Transgenic overexpression of miR-133a1 (in dystrophin point mutation Mdx mice)Extensive overexpression in skeletal muscle, lesser increase in heartNormal skeletal muscle and heart developmentMdx mice (model for human muscular dystrophy), extensor digitorum longus muscle[216]
miR-206 located in nuclear in both normal and DM1 tissues by in situ hybridizationOnly miR-206 showed an over-expression in majority of DM1 patientsNo change in expression of profiled miRs, miR-1, miR-133 (miR-133a/-133b), miR-181 (miR-181a/-181b/-181c)Skeletal muscle (vastus lateralis) of from patients with myotonic dystrophy type 1 (DM1)[217]
FAPs facilitate myofiber regenerationHDAC inhibitors can activate FAPs towards muscle regenerationInhibition of HDAC induces MyoD and BAF60C expression, which causes up-regulation of miR-1-2, miR-133, and miR-206 expressionEarly stage disease dystrophic mouse muscles, regeneration of myofibres[62]
TDP-43TDP-43 interacts with miR-1/-206 isomers, but not miR-133 isomersDepleted miR-1/-206 allow targets IGF-1 and HDAC4 to accumulate in ALS muscleMouse ALS model injured motor neurons and muscle[33]
Inflammation response in muscle
Inflammatory myopathiesIncreased expression of TNFαAssociated with decreased expression of miR-1, miR-133a, and miR-133bInflammatory myopathies including dermatomyositis, polymyositis, and inclusion body myositis[64]
hBSMCs sensitized with IL-13Increased muscle RhoAReduction of muscle miR-133aSensitized human bronchial smooth muscle cells (hBSMCs)[218]