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

Table 2 Roles and targets of the myomiRs, miR-1, -206, -133a, -133b in other precursor cells and tissues

Factor(s)	Regulation	Regulator	Tissue/cell	Ref.
Nerve tissues
Pitx3	Pitx3 downregulated	miR-133b	Mammalian midbrain DNs	[73]
Exosome-mediated transfer of miR-133b from MSC to brain astrocytes	miR-133b transfer from multipotent mesenchymal stromal cells to neural cells	miR-133b upregulated	Mouse MSCs to neural cells	[47]
Ctgf and RhoA	Ctgf and RhoA downregulated	miR-133b upregulated	Multipotent MSCs/Rat brain parenchymal cells	[72]
miR-133b null mice: Striatum dopamine levels unchanged, Pitx3 expression unaffected; motor coordination unaltered	miR-133b has no significant role on mDA neuron development and maintenance in vivo	Normal numbers of mDA neurons during development and aging of miR-133b null mice	Mouse mDA neuron development in -/-miR-133b mutant mice	[45]
Acute or chronic morphine administration, or morphine withdrawal	miR-133b levels not affected		Rat VTA/ nucleus accumbens shell	[219]
GPM6A, a neuronal glycoprotein	microRNA-133b upregulation	Reduction in gmp6a at mRNA and protein level. Cell filopodium density was reduced	Hippocampus and prefrontal cortex of neonatal male rats stressed when in utero	[220]
Tac1 gene (neurotransmitter substance P)	Tac1 downregulated	miR-206 upregulated	MSCs-derived neural cells	[221]
Ketamine (antidepressive) administration	BDNF, a direct target gene of miR-206, was upregulated	miR-206 was downregulated by ketamine	Rat hippocampus tissue	[222]
Adipogenic tissues
IGF-1 and IGF-1R	IGF-1 signalling and miR-133b co-regulate ADSC differentiation via a feedback loop	miR-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
Pdrm16	miR-133a directly targets Prdm16.	Downregulation of miR-133 resultsin differentiation of pre-adipocyte precursors into BAT	Mouse adipocyte differentiation to BAT	[74]
Pdrm16	miR-133 directly targets Prdm16	Downregulation of miR-133 resulted in differentiation of pre-adipocyte precursors into BAT	Mouse primary brown adipocyte (and myogenic) progenitor cells - differentiate into BAT or SAT	[75]
Pdrm16	miR-133 targets Prdm16 controlling brown adipose determination in skeletal muscle satellite cells	miR-133 downregulates Prdm16	Adult mouse skeletal muscle stem cells (satellite cells) differentiate into BAT	[76]
HDAC4 downregulation directs SCs towards adipocyte differentiation	Brown adipose master regulator Prdm16 is upregulated, while its inhibitor miR-133 is also downregulated	HDAC4 downregulated in SCs differentiating into adipocyte progenitor cells	Myogenenic satellite SCs	[175]
GLUT4 expression	Both basal and insulin-stimulated glucose uptake are increased	KLF15	Mouse 3T3-L1 preadipocytes differentiating into adipocytes	[182]
Intrinsic insulin resistance	Elevated miR-133b	Undefined role	Adipose tissue of women with PCOS	[223]
Upregulation of LIM homeobox 8 and Zic family member 1 and downregulation of Homeobox C8 and Homeobox C9	Undefined relation of upregulated miR-206, miR-133b	Undefined relation with parallel upregulation of brite/beige markers, TBX1 and TMEM26	Human BAT from the supraclavicular region	[224]
Obesity development	Downregulation of miR-133b, miR-1	Undefined role	Adipose tissue from obese male C57BLJ6 mice	[225]
LXRα regulation of lipogenic genes	miR-1/miR-206 represses LXRα expression at both mRNA and protein levels	miR-1/miR-206-induces a decrease in lipogenic gene levels and lipid droplet accumulation	Mouse hepatocytes	[226]
Osteogenic tissues
Development of bone on organic or inorganic substrates		miR-133 differentially expressed in osteoblasts grown on different substrates	Osteoblast	[227]
Runx2	miR-133 directly down-regulates Runx2	miR-133 up-regulated	Osteogenic differentiation from C2C12 mesenchymal cells	[228]
HDAC4	HDAC4 downregulates Runx2	miR-1 targets HDAC4, increasing Runx2 activity	Chondrocyte proliferation in cartilage growth plate	[77]
Aggrecan	miR-1 promotes late-stage differentiation of growing cartilage cells	miR-1 targets Aggrecan gene expression	Chicken chondrocytes and human HCS-2/8 cells	[78]
Alveolar cells
VAMP2/ lung surfactant secretion	miR-206 targets VAMP-2	miR-206 overexpression decreased lung surfactant secretion	Lung alveolar type II cells	[229]
Hormonal regulation
L-thyroxine	miR-206/miR-133b downregulated	L-thyroxine treatment	L-thyroxine treated hypothroidic skeletal muscle from thyroidectomized patients	[230]
	miR-206/miR-133b upregulated	-	Hypothroidic human skeletal muscle
Thyroid hormone/TEAD1	Thyroid hormone inhibits the slow muscle phenotype by upregulation of miR-133a1 which downregulates TEAD1	miR-133a1 is enriched in fast-twitch muscle and regulates slow-to-fast muscle fiber type conversion	Mouse muscle	[231]
Thyroid hormone/miR-133a1 TEAD1	myosin heavy chain I expression downregulated	TH indirectly downregulates myosin heavy chain I via miR-133a/TEAD1	Mouse muscle	[232]
L-thyroxine	pre-miR-206 and pre-mir-133b downregulated	L-thyroxine	L-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 cardiomycetes	Downregulation KLF15, which downregulates GLUT4	Forced overexpression of miR-133a and miR-133b	Rat cardiac myocytes	[181]
Cardiac myocyte glucose metabolism	Upregulation KLF15, which upregulates GLUT4	Silencing endogenous miR-133	Rat cardiac myocytes	[181]
Metabolic control of glucose uptake by GLUT4 transporter	Downregulates KLF15, which results in downregulation of GLUT4 levels	Chronic heart failure has depressed miR-133a and -133b levels	Rat cardiac myocytes during chronic heart failure and cardiac hyperthrophy	[181]
Atrial natriuretic factor expression upregulation	Enhanced at LVH and dramatically increased at CHF stage	Both miR-133a and miR-133b downregulated at CHF stage	LVH and CHF in salt-sensitive Dahl rats	[181]
Estrogen	Estrogen replacement strongly decreased IGF-1 protein level in muscles at 1 wk		Ovariectomized rat skeletal muscle	[233]
Multiple targets	miR-133a upregulated in BTBR mice		Pancreatic 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 levels	miRNAs miR-1, miR-133a and miR-206 specifically expressed both in brown pre- and mature adipocytes	miRNAs miR-1, miR-133a and miR-206 were absent from white adipocytes	Mouse brown adipocytes	[235]
Foxl2	miR-133b targets Foxl2;	Foxl2 regulates StAR and CYP19A1 transcriptionally	Estradiol 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 astrocytes	miR-133b transfer from multipotent mesenchymal stromal cells to neural cells	miR-133b upregulated	Mouse multipotent MSCs to neural cells	[47]
Cell to cell transfer of exosome-enriched extracellular particles	mir-133b promotes neural plasticity and recovery of function after stroke induced damage	miR-133b upregulated	Rat multipotent MSCs via transfer of exosome-enriched extracellular particles	[72]
Transplanted stem cells
MSCs expressing miR-1	Upregulated miR-1	Increased rate of recovery, enhanced survival of transplanted MSCs and cardiomyogenic differentiation	Experimental ligation of the mouse left coronary artery to model myocardial infarction	[237]
Knockdown of Hes-1, member of Notch pathway	Upregulated miR-1 promotes the differentiation of MSCs into cardiac lineage	Role in survival of transplanted MSCs and cardiomyogenic differentiation	Mouse MSCs	[238]
Notch signalling and cardiomyocyte markers, Nkx2.5, GATA-4, cTnT, and Cx43	MSCs expressing exogenous miR-1		Mouse MSCs	[238]
Tissue inflammation
Selective release of miRs during inflammation into serum	miR-133 selectively released		Review	[239]
Inflammation and cancer	MicroRNA, free radical, cytokine and p53 pathways		Review	[240]
Immunological switch which shapes tissue responses	TWEAK/Fn14 pathway		Review	[241]
Tumor biology	HMOX1		Review	[242]
GM-CSF	Direct supression of GM-CSF expression by miR-133	Elevated expression of miR-133a/-133b during oxidative stress	Mouse alveolar epithelial cells during oxidative stress	[82]
PI3K/Akt and IGF-1 pathways	Activation of PI3K/Akt and IGF-1 pathway activities	Downregulation of miR-133a (and other miRs) by AOM/DSS induced chronic inflammation	Mouse model: AOM/DSS-induced colitis-associated gastro-intestinal cancer	[83]
CTGF, SMA, and COL1A1	Increased expression of CTGF, SMA and COL1A1, which are miR-133b targets	Strong downregulation of miR-133b (and other miRs)	TGF-β treated rabbit corneal fibroblasts; Recovering mouse cornea after laser ablation,	[70]
IL-10 and TGF-β	Exogenous IL-10 and TGF-β induces miR-133b expression	Upregulation of miR-133b	Human tolerogenic dendritic cells during maturation	[79]
IL-17-producing T-cells	Upregulation of Il17a/f gene expression	miR-133b/-206 cistron transcription occurs along with nearby Il17a/f gene expression	Immunocompetent mouse Th17 cells	[80]
NLRP3 inflammasome which processes IL-1β by caspase-1 cleavage	miR-133a-1 suppresses activation of inflammasomes via suppression of expression of mitochondrial UCP2	miR-133a-1 overexpression in cells increases caspase-1 p10 and IL-1β p17 cleavage,	Differentiated mouse THP1 cells	[81]
Concanavalin A-induced fulminant hepatitis		miR-133a is the most strongly differentially upregulated miR	Mouse liver following ConA injection	[243]
Infection/immune response to influenza virus (H1N2)	miR-206 expression		Experimental 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 PASMCs	miR-206 targets HIF-1α directly. Hypoxia-induced down-regulation of miR-206 promotes PH in PASMCs	Hypoxia-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 activity	Astrocyte-associated inflammation during recovery from chronic central nervous system injury	[246]
Indirectly: inflammatory cytokines (IL6, IL1B, CCL5)
Cellular factors influencing myomir expression/activity
miR-1/miR-133a
Skeletal muscle
Positive regulator	Negative regulator	Regulated target miR	Tissue/cell	Ref.
Myogenin, MyoD		Upregulates miR-1-1 and miR-133a-2	Primary human myoblasts; C2C12 cells	[11]
		Upregulates miR-1-2 and miR-133a-1
SRF, MyoD and MEF2		Upregulates miR-1-2	Muscle somites	[30]
MEF2		Upregulates miR-1 and miR-133a	Skeletal muscle	[9]
KSRP (part of Drosha and Dicer complexes)	miR-206 binds 3’-UTR of KSRP and inhibits its expression	KSRP upregulates miR-1 expression	Skeletal muscle	[35,37]
RNA-binding protein LIN28		LIN28 upregulates miR-1 expression; LIN28 promotes pre-miR-1 uridylation by ZCCHC11 (TUT4)	Cardiac muscle of patients with muscular dystrophy	[36]
	MBNL1	MBNL1 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-1	Cardiac muscle of patients with muscular dystrophy	[36]
CX43 and CACNA1C calcium channel	CX43 and CACNA1C both increased in both DM1-/DM2-affected hearts, contributing to the cardiac dysfunctions	CX43 and CACNA1C are direct targets of miR-1 repression	Cardiac muscle of patients with muscular dystrophy;	[36]
			CACNA1C and CX43 encode the main calcium- and gap-junction channels in heart
Utrophin A	miR-206 and KSRP are negative regulators of utrophin A	Overexpression of miR-206 promotes the upregulation of utrophin A, via the downregulation of KSRP	Normal 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
	Myostatin	Downregulates miR-1, miR-133a, miR-133b, miR-206	Mouse (35 d) pectoralis skeletal muscle	[29]
	SRF	Downregulates miRs-133a	Skeletal muscle	[1,3]
Prmt5 and Prmt4		Upregulates myomiR expression during differentiation	Mouse skeletal muscle	[247]
Smooth muscle
Sp-1 transcription factor	pERK1/2	Upregulates miR-133(a)	VSMCs	[248]
Brg1		Upregulates miR-133 (ChIP complex with SRF)	Smooth muscle	[249]
Cardiac muscle
GATA4, Nkx2.5, Myocardin, SRF		Upregulates miR-1 and miR-133a	Differentiating cardiac muscle	[5]
SRF plus Myocardin		Upregulates miR-1-1 and miR-1-2	Cardiomycetes	[30]
	Calcineurin	Downregulates miR-133a	Hypertrophic cardiac muscle	[203]
miR-206/ miR-133b
Skeletal muscle
Mrf5		Upregulates miR-1, miR-206	Skeletal muscle	[171]
Myogenin, MyoD		Upregulates miR-206	Primary human myoblasts; C2C12 cells	[11]
MyoD		Upregulates linc MD1 (encodes miR-133b)	Differentiating myoblasts	[11, 38]
		Binds to (E-box) enhancer of miR-206, miR-133b	skeletal muscle (mouse)	[12,40]
		Upregulates miR-206/miR-133b	Differentiated human foetal skeletal muscle cells	[250]
	FGF2 allows upregulation of Sp1/Cyclin D1	Downregulates p38-mediated miR-1/133 expression	Regenerating rat skeletal muscle	[212]
	Myostatin	Downregulates miR-133a, mir-133b, miR-1, and miR-206	Mouse (35 d) pectoralis skeletal muscle	[29]
	TWEAK downregulates myoD and MEF2c	Downregulates miR-1-1 and miR-133	Degenerating/wasting skeletal muscle	[59]
	HMOX1 downregulates MyoD and myogenin	Downregulates all myomiRs	Inflamed skeletal muscle	[60]
L-Thyroxine treatment		Downregulation of pri-miR-206 and pri-miR-133b	Human skeletal muscle	[230]
		No effect on miR-1/miR-133a pairs
Smooth muscle
p-ERK	Activated extracellular signal-regulated kinase p-ERK inversely correlated with VSMC growth	Downregulates miR-133 expression	VSMCs	[248]
Other tissues
Myogenin		Binds miR-206 enhancer (ChIP)	Fibroblast cell line:	[40]
IGF-I signalling		Upregulates miR-133b	Mouse Adipose derived stem cells	[71]
L-Thyroxine deficiency	Upregulated Col5a3	Strong upregulation of miR-133a and -133b	Hypothyroid mouse liver	[232]
	Downregulated Slc17a8, Gp2, Phlda1, Klk1d3, Klk1 and Dmbt1	Strong upregulation of miRs -1, -206
	Upregulated Vldlr and Akr1c19, and downregulated Upp2, Gdp2, Mup1, Nrp1, and Serpini2
L-Thyroxine treatment	Pre-miR-206 and Pre-miR-133b down-regulated	Upregulation of Gdp2 andMup1	Hypothyroid mouse liver in vivo, and in vitro mouse hepatocyte AML12 cells	[232]
PA2G4, mps1, cdc37, cx43, cldn5; cx43 is a miR-133 target	Upregulation of cell cycle factors mps1, cdc37, and PA2G4, and cell junction components cx43 and cldn5	Suppression of miR-133a1 stimulates cardiac cell proliferation	Regeneration of damaged Zebrafish cardiac muscle, associated with reduced miR-133a1	[167]
Fgf	Upregulated Fgf	Downregulates miR-133	Zebrafish regenerating fin blastema	[67]
SHP (nuclear receptor)	Downregulation of miR-206 in nuclear receptor SHP(-/-) mice		SHP(-/-) mice strain, mouse liver	[251]
AP1 transcription factor complex	AP1 induced miR-206 promoter transactivity and expression; this is repressed by YY1	ChIP analysis shows physical association of AP1 (c-Jun) and YY1 with miR-206 promoter	SHP(-/-) nuclear receptor mice strain, mouse liver	[251]
NR3B3	YY1 promoter transactivated by ERRgamma; this inhibited by SHP (NROB2)	Nuclear receptor ERRgamma (NR3B3) binding site on the YY1 promoter	Mouse 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-206	Mouse liver	[251]
Il17a/f locus	miR-133b and miR-206 expression	Coregulated with IL-17 production	αβ and γδ T cells	[80]

IGF: Insulin-like growth factor; 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; VTA: Ventral tegmental area; BAT: Brown adipose tissue; SCs: Stem cells; PCOS: Polycystic ovary syndrome; LVH: Left cardiac ventricular hypertrophy; CHF: Chronic heart failure; DNs: Dopaminergic neurons; mDA: Midbrain dopaminergic; AOM: Azoxymethane; DSS: Dextran sulfate sodium; PH: Pulmonary hypertension; PASMCs: Pulmonary artery smooth muscle cells.