Roles of the canonical myomiRs miR-1, -133 and -206 in cell development and disease

Table 1 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b

Factor(s)	Regulation	Regulator	Tissue/cell	Ref.
Fish and lower vertebrates: Development and regeneration
Ttk protein kinase (mps1)	Upregulated mps1: a target of miR-133	Downregulation of miR-133 by Fgf	Regeneration of Zebrafish caudal fin (appendage)	[68]
RhoA	Downregulation of RhoA mRNA	Upregulation of miR-133b expression	Regenerating adult zebrafish spinal cord, axon outgrowth	[69]
RhoA	Downregulation of RhoA protein	Upregulation of miR-1 and miR-133 expression	Zebrafish muscle gene expression and regulation of sarcomeric actin organization	[166]
Cell cycle factors mps1, cdc37 and PA2G4, and cell junction components cx43 and cldn5	Upregulated mps1, cdc37, PA2G4, cx43, cldn5	Downregulated miR-133(a1) stimulates cardiac cell regeneration	Regenerating zebrafish cardiac muscle	[167]
miR-133b	MiR-133b found in developing somites, little in CNS tissues		Whole zebrafish embryos - normal development	[168]
SRF activates muscle specific genes and miRs;	MiR-1 targets HDAC4, promoting myogenesis	In contrast, miR-133a represses SRF, enhancing myoblast proliferation	X. 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; MEF2	Subunits UNC-29, UCR-63, and MEF2 downregulated	miR-1 upregulated	C. elegans muscle at the neuromuscular junction	[34]
Mammalian pluripotent cells
Muscle-specific microRNAs: miR-1 and miR-133a	MiR-1 and miR-133a have opposing functions during differentiation of progenitor cardiac muscles	Muscle-specific	Promotion 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 effects	Dll-1 translationally repressed	miR-1 upregulation, promotes cardiomycete differentiation	Mouse and human ES cell differentiation into muscle	[13]
SRF-/- EBs reflecting the loss of hematopoietic lineages in the absence of SRF	Early endoderm markers, Afp and Hnf4α: strongly down regulated	Increased miR-1 and miR-133a relieve the block on mesodermal differentiation	Mouse endoderm	[13]
Blood cell -specific genes, such as Cd53, CxCl4, and Thbs1, dramatically down regulated	Cd53, 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 EBs	Nodal stimulated expression of endoderm markers Afp and Hnf4α in control EBs. Dramatically lower levels in mES(miR-1)- and mES(miR-133a)- EBs	miR-1 or miR-133 can each function as potent repressors of endoderm gene expression	mES cells, that lack either miR-1 or miR-133(a) during differentiation into EBs	[13]
IGF-1	IGF-1 signalling and miR-133 co-regulate myoblast differentiation via a feedback loop	IGF-1 upregulates miR-133;	Myogenic differentiation of C2C12 myoblasts; Mouse during development from embryonic to mature skeletal muscle	[24]
IGF-1R		miR-133 downregulates IGF-1R
IGF-1	IGF-1 signalling and miR-1 coregulate differentiation of myoblasts via a feedback loop	IGF-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 promoter	Reversine 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 Ezh2	Reduced expression of myogenin, MyoD, Myf5 and Aurora A and B kinases
FZD7 and FRS2	miR-1 promotes cardiac differentiation; miR-1 targets FZD7 and FRS2	Activitation of WNT and signalling cause MCPs differentiation into cardiomyocytes	Mouse and human ES cells	[169]
miR-206/133b cluster	PAX7 gene expression unchanged;	miR-206/133b cistron knock-out mice cells	Muscle 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 alpha	Repression of Idl-3 protein expression	miR-206 up-regulated	Mouse skeletal muscle differentiation	[42]
	Repression of p180 subunit of DNA polymerase alpha
MEF2 transcription factor	MEF2 activates of miR-1-2 and 133a-1 transcription; binds muscle-specific enhancer	Bicistronic primary transcript of miR-1-2 and 133a-1	Development of mammalian skeletal muscle	[9]
MRFs, Myf5, MyoD, Myogenin and MRF4	Myf5 essential for miR-1 and miR-206 expression during skeletal muscle myogenesis	Forced expression of MRFs in neural tube induces miR-1 and miR-206 expression	Chicken and mouse embryonic muscle	[171]
PTB and neuronal homolog nPTB, exon splicing factors	Downregulation of PTB protein by miR-133 (and miR-206)	Concurrent upregulation of miR-133 and induction of splicing of several PTB-repressed exons	During myoblast differentiation, microRNAs control a developmental exon splicing program	[172]
BDNF	BDNF downregulated	miR-206 upregulated	Differentiation of C2C12 myoblasts into myotubes	[48]
Fstl1 and Utrn	Fstl1 and Utrn downregulated	miR-206 upregulated	Skeletal muscle differentiation	[40]
Utrophin A (muscle)	Utrophin A down-regulated by both miRs	Upregulated miR-133b, miR-206	C2C12 mouse myoblasts, mouse soleus muscle	[173]
CNN3 gene	Negative correlation between miR-1 expression and CNN3 mRNA expression	Normal skeletal muscle	Tongcheng (Chinese) and Landrace (Danish) pigs	[174]
FGFR1 and PP2AC, members of ERK1/2 signalling pathway	miR-133 (a and b) activities increase during myogenesis	miR-133 directly downregulates expression of FGFR1 and PP2AC	Mouse C2C12 myoblast cells	[31]
ERK1/2 signalling pathway activity	ERK1/2 signalling activity suppresses miR-133 expression	Downregulation of expression of miR-133	A reciprocal mechanism for regulating myogenesis
BAF chromatin remodelling complex (BAF60a, BAF60b and BAF60c)	Positive inclusion of BAF60c in the BAF chromatin remodeling complex	Expression of miR-133 and miR-1/206	Progression of developing somites in chick embryos	[63]
BAF chromatin remodelling complex	Negative regulation of BAF60a and BAF60b; exclusion from BAF chromatin remodelling complex	Expression of miR-133	Progression of developing somites in chick embryos	[63]
BAF chromatin remodelling complex	Exogenous upregulation of BAF60a and BAF60b		Delay in developing somites in chick embryos	[63]
Mitochondrial UCP2 and UCP3	MyoD activates miR-133a expression which in turn directly downregulates UCP2 mRNA	Feedback network involving MyoD-miR-133a-UCP2	Mouse skeletal and cardiac muscles; UCP2 imposes developmental repression	[56]
Mitochondrial UCP2 and UCP3	Exogenous overexpression of myogenin and MyoD transcription factors	Strong increase in UCP3 promoter, expression, weak effect at the UCP2 promoter	Mouse C2C12 myoblasts	[57]
Proliferating myogenic skeletal muscle cells
MiR-206/133b cluster	MiR-206/133b cluster is not required for survival and regeneration of skeletal muscle	Muscle regeneration proceeds in Mdx mice in vivo	miR-206/133b cistron knock-out mice	[170]
Enhanced translation of specific mitochondrial genome-encoded transcripts	miR-1 enters muscle mitochondria and binds mtRNA targets along with Ago factor	Increased expression of mtRNA targets	Proliferating myogenic skeletal muscle cells after muscle injury	[53]
mTOR (serine/threonine kinase)	MyoD stability regulated by mTOR	Regulates miR-1 expression via MyoD availability	Regenerating mouse skeletal muscle and differentiating myoblast cells	[32]
AMPK-CRTC2-CREB and Raptor-mTORC-4EBP1 pathways	mTORC regulates timing of satellite cell proliferation during myogenesis	Knockdown of mTORC reduces miR-1 expression	Myogenenic satellite SCs proliferating and differentiating into myogenic precursors following rat skeletal muscle injury	[58]
HDAC4 regulates Pax7-dependent muscle regeneration	Pax7 stimulates SCs differentiation toward the muscle lineage, and limits adipogenic differentiation	HDAC4 upregulated in SCs differentiating into muscle cells	Myogenenic satellite SCs	[175]
pcRNA encoded by the H strand of the rat mitochondrial genome	Introduction of mt pcRNAs into injured muscle restoring mitochondrial mRNA levels; Intramuscular ATP levels were elevated after pcRNA treatment of injured muscle	Enhanced organellar translation and respiration; similarly reactive oxygen species were reduced; Resulted in accelerated rate of wound resolution	Injured 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-133	Reprogrammed human fibroblasts show sarcomere-like structures and calcium transients; Some cells have spontaneous contractility	Forced over-expression of GATA binding protein 4, Hand2, T-box5, myocardin, and microRNAs miR-1 and miR-133	Human embryonic and adult fibroblasts activated to express cardiac markers	[15]
SRF, MyoD and Mef2 transcription factors	miR-1-1 and miR-1-2	miR-1 genes upregulated;	Cardiac muscle precursor cells	[30]
	During cardiogenesis miR-1 genes titrate critical cardiac regulatory proteins, control ratio of differentiation to proliferation	Elevated miR-1 targets downregulation of Hand2
Histone deacetylase inhibitor, trichostatin A forces differentiation, yet reduced miR-1 and miR-133a	miR-1 and miR-133a reduce cardiac specific Nkx2.5 protein and Cdk9	miR-1 and miR-133a increase during spontaneous differentiation of cardiac myoblasts	Mouse cardiac stem cells (ES cells)	[10]
Specific inhibition of HDAC4 modulates CSCs to facilitate myocardial repair	Positively proliferative myocytes increased in MI hearts receiving HDAC4 downregulated CSCs	CSCs with downregulated HDAC4 expression improved ventricular function, attenuated ventricular remodeling, promoted regeneration and neovascularization in MI hearts	Mouse CSCs transplanted into MI mouse hearts	[177]
Snai1	Overexpression of miR-133a (miR-133), Gata4, Mef2c, and Tbx5 (GMT) or GMT plus Mesp1 and MyocD improved cardiac cell reprogramming from mouse or human fibroblasts	miR-133a directly represses Snai1 expression, which silences fibroblast signatures; a key molecular process during cardiac reprogramming	Mouse/human fibroblasts more efficiently reprogrammed into cardiomycete-like cells	[16]
β1AR signal transduction cascade	Adenylate cyclase VI and the catalytic subunit of the cAMP-dependent PKA are components of β1AR transduction cascade	miR-133 directly targets β1AR, Adenylate cyclase VI and PKA	TetON-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 GPx	miR-133 produced a reduction of ROS and MDA levels, and an increase in SOD activity and GPx levels	Overexpression of miR-133, a recognized anti-apoptotic miRNA	In vitro rat cardiomyocytes	[18]
Caspase-9	miR-133 directly suppresses caspase-9 expression resulting in downregulation of downstream apoptotic pathways	Overexpression of miR-133	In vitro rat cardiomyocytes	[18]
Spred1	miR-1 directly targets Spred1	miR-1 is upregulated in hCMPCs during angiogenic differentiation	hCMPCs	[178]
miRNA-1 and miRNA-133a	miRNA-1 and miRNA-133a have antagonistic roles in the regulation of cardiac differentiation	Forced overexpression of miR-1 alone enhanced cardiac differentiation, in contrast overexpression of miR-133a reduced cardiac differentiation, compared to control cells	Pluripotent 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 Hand2	Cardiac myocytes show defective heart development, altered cardiac morphogenesis, channel activity, and cell cycling	miR-1-2-/- gene knockout	Cardiac myocytes with knockout of both miR-1-2 genes	[180]
mt-COX1 mRNA	3’-UTR of mt-COX1 mRNA bound by miR-181c and Ago1 factor	Overexpression of miR-181c significantly decreased mt-COX1 protein, but not mt-COX1 mRNA level	Overexpression of miR-181c increased mitochondrial respiration and reactive oxygen species in neonatal rat ventricular myocytes	[54]
mt-COX1 mRNA	In vivo elevation of miR-181c in rat heart, reduces levels of mt-COX1 protein	Results in reduced capacity for strenuous exercise and evidence of heart failure	Rat cardiac muscle	[55]
Carvedilol, a β-adrenergic blocker	Induces upregulation of miR-133	Cytoprotective effects against cardiomyocyte apoptosis	Rat cardiac tissue, in vivo	[18]
GLUT4, and SRF	Both miRs downregulate SRF and KLF15	Both miR-133a and miR-133b target KLF15	Mouse cardiac myocytes	[181]
GLUT4 expression	Both basal and insulin-stimulated glucose uptake are increased	KLF15	Mouse muscle cell lines	[182]
MEF2 transcription factor	MEF2 directly activates transcription of miR-1-2 and 133a-1 binding muscle-specific enhancer between the genes	Bicistronic primary transcript of miR-1-2 and 133a-1	Development of mammalian cardiac muscle	[9]
Myocardium tissue	Enriched in miR-1, miR-133b, miR-133a		Heart structures of rat, Beagle dog and cynomolgus monkey	[183]
Gelsolin	One common miR-133a isomiR targets gelsolin gene more efficiently than standard isomer; New second rat miR-1 gene	Many isomiRs were detected by deep sequencing at higher frequency than the canonical sequence in miRBase	miRNA/isomiR expression profiles in the left ventricular wall of rat heart	[184]
CTGF	CTGF downregulated by both miRs	Exogenous upregulation of miR-133b (and miR-30c)	Cultured cardiomyocytes and ventricular fibroblasts	[185]
MT1-MMP	miR-133a upregulated	miR-133a targets MT1-MMP	Human left ventricular fibroblasts	[186]
Injured and regenerating cardiac muscle
SERCA2a	Akt/FoxO3A-dependent pathway	Downregulation of miR-1 expression in failing heart muscle	Failing mouse heart muscle	[187]
	Activated SERC2a reduces phosphorylation of FoxO3a, allowing entry to nucleus and activation of miR-1 expression
IGF-1	IGF-1 signalling and miR-1 co-regulate differentiation of myoblasts via a feedback loop	IGF-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 Bmf	Only miR-133a expression enhanced under in vitro oxidative stress	miR-133a targets proapoptotic genes Bim and Bmf	Rat adult CPCs	[188]
			miR-1 favors differentiation of CPCs, whereas
Bim and Bmf	CPCs overexpressing miR-133a improved cardiac function by reducing Bim and Bmf	CPCs overexpressing miR-133a improved cardiac function, increasing vascularization and cardiomyocyte proliferation, reduced fibrosis and hypertrophy	CPCs overexpressing miR-133a in rat myocardial infarction model	[188]
MT1-MMP activity increased in both. Ischemia and reperfusion regions	Interstitial miR-133a decreased with ischemia in vitro and in vivo; reperfusion returned to steady-state	Phosphorylated Smad2 increased within the ischemia-reperfusion region	Ischemia-reperfusion Yorkshire pigs (90 min ischemia/120 min reperfusion)	[186]
Cardiovascular disease
CNN2	Strong upregulation of CNN2 expression	miR-133b downregulated; miR-133b directly targets CNN2	Pre-inflammatory events in diseased cardiac tissues	[65]
Circulating platelet derived microparticles	Elevated miR-133		Patients with stable and unstable coronary artery disease	[189]
Acute MI causes upregulation of circulating serum miRs	miR-1, -133a, -133b, and -499-5p were about 15- to 140-fold elevated over control		Acute STEMI patients and experimental mouse MI model	[190]
Circulating miRNAs in serum of cardiovascular disease patients	Released miR-1 and miR-133a are localized in exosomes, and are released by Ca(2+) stimulation	Levels of miR-1, miR-133a, reduced in infarcted mouse myocardium model heart	miR release indicates myocardial damage	[191]
LVM after valve replacement in aortic stenosis	microRNA-133a is a significant positive predictor of LVM normalisation	miR-133 is a key element of the reverse remodelling process	Patients following valve replacement	[192]
Circulating levels of miR-133a	Elevated miR-133a (11-fold)		Troponin-positive acute coronary syndrome patients	[193]
Circulating levels of miR-133a	Elevated miR-133a	Improved potential regression of Left Ventricular Hypertrophy after valve replacement	Patients with aortic stenosis surgery	[194]
Apelin treatment reduces elevated circulating miRs	Elevated miR-133a, miR-208 and miR-1 reduced	High-fat diet elevated miRs and increased left ventricular diastolic and systolic diameters, and wall thickness	Obesity-associated cardiac dysfunction in mouse model	[195]
NAC treatment	Expressed miR-1, miR-499, miR-133a, and miR-133b were strongly depressed in the diabetic cardiomyocytes	NAC restored expression of miR-499, miR-1, miR-133a, and miR-133b significantly in the myocardium	Diabetic rat hearts	[196]
Myocardial junctin elevated	miR-1 targets junctin	NAC reduces junction levels	Development of diabetic cardiomyopathy in rat hearts	[196]
CAD associated ischemic heart failure	miR-133 expression decreased with increased severity of heart failure		Patients with CAD	[197]
Runx2	miR-133a targets Runx2		Transition of VSMCs to osteoblast-like cells	[198]
Increased alkaline phosphatase activity, osteocalcin secretion and Runx2 expression	miR-133a was decreased during osteogenic differentiation		Transition of VSMCs to osteoblast-like cells	[198]
Circulating miR-133a and 208a levels	Cardiac muscle-enriched microRNAs (miR-133a, miR-208a) elevated		Patients with coronary artery disease	[199]
Hypertrophic cardiac muscle
Cx43 increased	miR-1 targets Cx43	Downregulation of miR-1 mediates induction of pathologic cardiac hypertrophy	Hypertrophic rat cardiomyocytes in vitro and in vivo	[200]
Cx43 downregulated	miR-1 targets Cx43	Cx43 protein downregulated in miR-1 Tg mice compared to WT mice	Cardiac-specific miR-1 transgenic (Tg) mouse model	[201]
Twf1 upregulated	miR-1 targets Twf1	Strong downregulation of miR-1 in pathologic hypertrophic cardiac cells compared to normal, induces Twf1 expression	In vivo in hypertrophic mouse left ventricle; and in vitro in phenylephrine-induced hypertrophic cardiomyocytes	[202]
RhoA, Cdc42, Nelf-A/WHSC2	Increased levels of RhoA, Cdc42, Nelf-A/WHSC2	Reduction miR-133a	Hypertrophic cardiac muscle	[6]
Calcineurin, agonist of cardiac hypertrophy	Increased Calcineurin activity;	Reduced miR-133a;	Hypertrophic cardiac muscle;	[203]
	Cyclosporin A inhibits calcineurin	Prevents miR-133 down-regulation	Cardiac hypertrophy reduced
NFATc4	NFAFc4 targetted by miR-133a	miR-133a	Cardiomyocyte hypertrophic repression	[204]
Interdependent Calcineurin-NFAT and MEK1-ERK1/2 signalling pathways in cardiomyocytes	MEK1-ERK1/2 signalling augments NFAT and NFAF gene expression; Activated calcineurin activates NFAT, inducing cardiac hypertrophy	MEK1 is part of mitogen-activated protein kinase (MAPK) cascade; MEK1 activates ERK directly	Hypertrophic growth response of mouse cardiomyocytes	[205]
Innervating skeletal muscle
Innervated skeletal muscle	MyoD, Myf5, Mrt4, nAChRα	Myogenin expression	Mouse skeletal muscle	[50,51]
	Each is strongly repressed
Denervated muscle (unstimulated)		Myogenin expression up-regulated MyoD, Myf5, Mrt4, nAChRα	Mouse skeletal muscle	[51]
		All strongly stimulated
Electrically stimulated - Denervated muscle	Myogenin, MyoD, Myf5, Mrt4, partly stimulated; nAChRα inhibited		Mouse skeletal muscle	[51]
HDAC4	miR-1 promotes myogenesis by targetting HDAC4	miR-133 enhances myoblast proliferation by targetting SRF	Skeletal muscle proliferation and differentiation in myoblast cultures	[7]
SRF
Neural activity effect on muscle (HDAC4 - MEF2 Axis)	Loss of neural input leads to concomitant nuclear accumulation of HDAC4	HDAC4 inhibits activation of muscle transcription factor MEF2; results in progressive muscle dysfunction	MEF-2 activity strongly inhibited in denervated mouse skeletal muscle and in ALS muscle	[49]
Innervation and formation of airway smooth muscle	Sonic hedgehog (Shh) /miR-206/ BDNF	Shh signalling blocks miR-206 expression, which in turn increases BDNF protein	Shh coordinates innervation and formation of airway smooth muscle	[206]
nAChR subunits (UNC-29 and UNC-63); retrograde signalling	Subunits UNC-29, UCR-63 and MEF2 downregulated	miR-1 upregulated	C. elegans muscle at the neuromuscular junction	[34]
MEF2	Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated	miR-206 upregulated	Rat skeletal muscle/re-innervating muscle	[43]
HDAC4	HDAC4 (miR-206 target, prospective miR-133b target) downregulated	miR-206/-133b upregulated (and miR-1/-133a downregulated)	Mouse fast twitch skeletal muscle/re-innervating muscle	[12]
Regenerating injured muscle
Hnrpu and Npy downregulated	miR-1 upregulated	miR-1, -133a, downregulated 1 mo after denervation, then increased 2 × at 4 mo after re-innervation	Rat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation	[43]
Ptprd downregulated	miR-133a upregulated
Hnrpu, Lsamp, MGC108776, MEF2, Npy, and Ppfibp2 downregulated	3 × increase in miR-206 1 mo later, after reinnervation; elevated at least 4 mo	Predominant type II fiber at 4 mo, after nerve re-innervation	Rat skeletal soleus muscle after sciatic nerve injury and subsequent re-innervation	[43]
PP2A B56a	PP2A B56a downregulated	133a upregulated	Canine heart failure model: myocytes	[207]
CaMKII-dependent hyperphosphorylation of RyR2	VF myocytes had increased reactive oxygen species and increased RyR oxidation	miR-1 upregulated	Canine post-myocardial infarction model	[208]
Collagen upregulated	TGF-b1 and TGFbRII: upregulated	miR-133a or miR-590: downregulated	Canine model of acute nicotine exposure. Atrial fibrosis in vivo; cultured canine atrial fibroblasts in vitro	[209]
miR-208 upregulated	miR-1 and miR-133a downregulated		Human MI compared to healthy adult hearts	[210]
Myogenic proteins, MyoD1, myogenin and Pax7	Induced expression of MyoD1, myogenin and Pax7 several days after miR injection	Exogenous injection of miR-1, -133 and -206 promotes myotube differentiation	Regenerating injured mouse skeletal muscle	[211]
Cyclin D1/ Sp1	Cyclin D1/ Sp1 downregulated	miR-1/133 upregulated	Regenerating rat skeletal muscle	[212]
PRP, source of pro-inflammatory cytokines	Stong 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-cristallin	Stimulated 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 TWEAK	TWEAK upregulated	miR-1-1, miR-1-2, miR-133a, miR-133b and miR-206 downregulated	Degenerating/wasting mouse skeletal muscle	[59]
HMOX1 mediated by codependent inhibition of c/EBPδ binding to myoD promoter	HMOX1 inhibits differentiation of myoblasts and modulates miRNA processing	Downregulation 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-206	Downregulation of MyoD, myogenin and myosin, and disturbed formation of myotubes. Upregulation of SDF-1 and miR-146a
Dystrophic muscular disease
Circulating serum microRNAs	miR-1, miR-133a, and miR-206 highly abundant in Mdx serum	miR-1, miR-133a, and miR-206 downregulated or modestly upregulated in muscle	Muscle tissue from patients with Duchenne muscular dystrophy (Mdx)	[213]
Laminin α2 chain deficiency	miR-1, miR-133a, and miR-206 are deregulated in laminin α2 chain-deficient muscle	Laminin α2 chain-deficient mouse	Congenital muscular dystrophy type 1A tissue	[214]
Dystrophic process advances from prominent inflammation with necrosis and regeneration to prominent fibrosis	Deficiency in calpain leads initially to accelerated myofiber formation followed by depletion of satellite cells	Pax7-positive SCs highest in the fibrotic patient group; correlated with down-regulation of miR-1, miR-133a, and miR-206	Muscle 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 heart	Normal skeletal muscle and heart development	Mdx 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 hybridization	Only miR-206 showed an over-expression in majority of DM1 patients	No 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 regeneration	HDAC inhibitors can activate FAPs towards muscle regeneration	Inhibition of HDAC induces MyoD and BAF60C expression, which causes up-regulation of miR-1-2, miR-133, and miR-206 expression	Early stage disease dystrophic mouse muscles, regeneration of myofibres	[62]
TDP-43	TDP-43 interacts with miR-1/-206 isomers, but not miR-133 isomers	Depleted miR-1/-206 allow targets IGF-1 and HDAC4 to accumulate in ALS muscle	Mouse ALS model injured motor neurons and muscle	[33]
Inflammation response in muscle
Inflammatory myopathies	Increased expression of TNFα	Associated with decreased expression of miR-1, miR-133a, and miR-133b	Inflammatory myopathies including dermatomyositis, polymyositis, and inclusion body myositis	[64]
hBSMCs sensitized with IL-13	Increased muscle RhoA	Reduction of muscle miR-133a	Sensitized human bronchial smooth muscle cells (hBSMCs)	[218]

IGF: Insulin-like growth factor; IGF-1R: IGF-1 receptor; MRFs: Muscle regulatory factors; PTB: Polypyrimidine tract-binding protein; Fstl1: Follistatin-like 1; Utrn: Utrophin; mTOR: Mechanistic target of rapamycin; pcRNA: Polycistronic RNAs; SRF: Serum response factor; Snai1: Snail family zinc finger-1; β1AR: β-adrenergic receptor; PKA: Protein kinase A; MDA: Malondialdehyde; Spred1: Sprouty-related EVH1 domain containing protein 1; mt-COX1: Mitochondrial cytochrome c oxidase subunit 1; SERCA2a: Sarcoplasmic reticulum calcium ATPase 2a; LVM: Left ventricular mass; NAC: N-acetylcysteine; CAD: Coronary artery disease; StAR: Steroidogenic acute regulatory protein; mES: Mouse embryonic stem; EBs: Endodermal bodies; SCs: Stem cells; CSCs: Cardiac stem cells; MI: Myocardial infarcted; hCMPCs: Human-derived cardiomyocyte progenitor cells; VSMCs: Vascular smooth muscle cells; CPCs: Cardiac progenitor cells; STEMI: ST-segment elevation MI.