MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

Sakai, Atsushi; Saitow, Fumihito; Maruyama, Motoyo; Miyake, Noriko; Miyake, Keisuke; Shimada, Takashi; Okada, Takashi; Suzuki, Hidenori

doi:10.1038/ncomms16079

Cited by 94 publications

(89 citation statements)

References 54 publications

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“…[59][60][61] Recent experiments have shown that coexpressed miRNA clusters consisting of three to six members can regulate a specific molecular pathway by targeting the same signalling pathway. 13,14 The miR-183 cluster (bearing miR-183,miR-96, and miR-182) and the miR-17-92 cluster (bearing miR-17,miR-18a,miR-19a, miR-19b, and miR-92a) controlled neuropathic pain by repressing auxiliary voltage-gated calcium channel subunits and multiple voltage-gated potassium channel subunits, respectively. Our results provide the first evidence of agedependent coexpression of the largest group of clustered miRNAs in the Dlk1-Dio3 locus (at least 15 in mice and seven in humans) to inhibit a common atrophy-related gene target, Atrogin-1.…”

Section: Discussionmentioning

confidence: 99%

“…9 MiRNAs are frequently arranged in polycistronic clusters and coexpressed at a specific genomic locus, showing a general tendency to cotarget the same complex or pathway. [10][11][12][13][14] We recently demonstrated that >50% of down-regulated miRNAs in aged mouse skeletal muscle and myoblasts are clustered in the delta-like homologue 1 and the type III iodothyronine deiodinase (Dlk1-Dio3) imprinted genomic region. [15][16][17] Dlk1-Dio3 is the largest known placental mammalian-specific miRNA cluster.…”

Section: Introductionmentioning

confidence: 99%

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A subset of microRNAs in the Dlk1‐Dio3 cluster regulates age‐associated muscle atrophy by targeting Atrogin‐1

Shin

Kwon

Lee

et al. 2020

J cachexia sarcopenia muscle

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Background The microRNAs (miRNAs) down-regulated in aged mouse skeletal muscle were mainly clustered within the delta-like homologue 1 and the type III iodothyronine deiodinase (Dlk1-Dio3) genomic region. Although clustered miRNAs are coexpressed and regulate multiple targets in a specific signalling pathway, the function of miRNAs in the Dlk1-Dio3 cluster in muscle aging is largely unknown. We aimed to ascertain whether these miRNAs play a common role to regulate age-related muscle atrophy. Methods To examine anti-atrophic effect of miRNAs, we individually transfected 42 miRNA mimics in fully differentiated myotubes and analysed their diameters. The luciferase reporter assay using target 3′ untranslated region (UTR) and RNA pull-down assay were employed to ascertain the target predicted by the TargetScan algorithm. To investigate the therapeutic potential of the miRNAs in vivo, we generated adeno-associated virus (AAV) serotype 9 expressing green fluorescent protein (GFP) (AAV9-GFP) bearing miR-376c-3p and infected it into the tibialis anterior muscle of old mice. We performed morphometric analysis and measured ex vivo isometric force using a force transducer. Human gluteus maximus muscle tissues (ages ranging from 25 to 80 years) were used to investigate expression levels of the conserved miRNAs in the Dlk1-Dio3 cluster. Results We found that the majority of miRNAs (33 out of 42 tested) in the cluster induced anti-atrophic phenotypes in fully differentiated myotubes with increasing their diameters. Eighteen of these miRNAs, eight of which are conserved in humans, harboured predicted binding sites in the 3′ UTR of muscle atrophy gene-1 (Atrogin-1) encoding a muscle-specific E3 ligase. Direct interactions were identified between these miRNAs and the 3′ UTR of Atrogin-1, leading to repression of Atrogin-1 and thereby induction of eIF3f protein content, in both human and mouse skeletal muscle cells. Intramuscular delivery of AAV9 expressing miR-376c-3p, one of the most effective miRNAs in myotube thickening, dramatically ameliorated skeletal muscle atrophy and improved muscle function, including isometric force, twitch force, and fatigue resistance in old mice. Consistent with our findings in mice, the expression of miRNAs in the cluster was significantly down-regulated in human muscle from individuals > 50 years old.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A subset of microRNAs in the Dlk1‐Dio3 cluster regulates age‐associated muscle atrophy by targeting Atrogin‐1

Shin

Kwon

Lee

et al. 2020

J cachexia sarcopenia muscle

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“…Moreover, the bioinformatic analysis showed a predicted interaction of RP11‐819C21.1 with 24 miRNAs and ZNRD1‐AS1 with 40 miRNAs. It is particularly interesting that both lncRNAs showed miR‐19a and miR19b as common target, since these miRNAs are involved in the modulation of multiple potassium channel α subunits and auxiliary subunits in DRG neurons of L5 SNL model of neuropathic pain (Sakai et al, ). Our data agree with Zhao and collaborators’ hypothesis, according to which the up‐regulation of Kcna2 antisense RNA reduces Kcna2 mRNA expression leading to diminished K + current in the injured DRG of rat model SNL (Zhao et al, ).…”

Section: Discussionmentioning

confidence: 99%

ZNRD1‐AS and RP11‐819C21.1 long non‐coding RNA changes following painful laser stimulation correlate with laser‐evoked potential amplitude and habituation in healthy subjects: A pilot study

Santoro

Vollono

Pazzaglia

et al. 2020

European Journal of Pain

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Background Non‐coding RNAs (lncRNAs) are a group of non‐coding RNAs that act as regulators of gene expression; they are implicated in various human diseases and have been reported to be involved in the modulation of pain. We aimed to study whether: (a) lncRNAs modifications could be found in an experimental model of pain; (b) there was a correlation between lncRNA changes and laser evoked potential (LEP) amplitude/laser‐pain rating. Methods Laser evoked potentials were recorded from 11 healthy subjects to both left hand and perioral region stimulation. Three consecutive averages were calculated for each stimulation site in order to investigate the LEP amplitude habituation. Blood samples were obtained immediately before LEP recording (pre‐pain) and 30‐min after the recording of the last LEP average (post‐pain). Eighty‐four lncRNAs, involved in autoimmunity and human inflammatory response, were screened. The criteria used for lncRNAs analysis were fold change >2 and p < .05. By Real‐Time PCR, we identified two lncRNAs up‐regulated at the post‐pain time, as compared to the pre‐pain time: RP11‐819C21.1 (fold change = 8.2; p = .038) and ZNRD1 antisense RNA 1 non‐protein coding (ZNRD1‐AS; fold change = 6.3; p = .037). Results The ZNRD1‐AS up‐regulation was directly correlated with the N1 amplitude, while the RP11‐819C21.1 increase after pain showed a correlation with the reduced N2/P2 amplitude and laser‐pain habituation. Conclusion IncRNA changes in a human experimental phasic pain model. The correlation between lncRNA changes and LEP amplitude and habituation suggests that RP11‐819C21.1 and ZNRD1‐AS could be involved in the pathophysiology of painful diseases characterized by abnormal excitability of the cerebral cortex. Significance Long non‐coding RNAs are upregulated after experimental pain. RP11‐819C21.1 and ZNRD1 could be involved in the pathophysiology of diseases characterized by reduced habituation to pain.

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“…Since intrathecal miR-21 injection induces pain hypersensitivity in wild-type mice but not in mice with a global deletion of toll-like receptor 8 (Tlr8 −/− ), the TLR8 receptor appears to act as a downstream effector of miR-21 to maintain neuropathic pain; however, a direct targeting of the Tlr8 gene has not been validated yet [124]. miR-18, miR-19a, miR-19b as well as mir-92 are also up-regulated in neuropathic pain models and in turn down-regulate potassium channels including Kcna1, Kcna4, Kcnc4, Kcnd3 and Kcnq5 [73]. The suppression of potassium channels in general increases neuronal excitability and this may be a relevant mechanism causing nociceptor excitation and sensitization [125,126].…”

Section: Mirnas Deregulated In the Peripheral Nervementioning

confidence: 99%

Non-coding RNAs in neuropathic pain

2020

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Neuro-immune alterations in the peripheral and central nervous system play a role in the pathophysiology of chronic pain in general, and members of the non-coding RNA (ncRNA) family, specifically the short, 22 nucleotide microRNAs (miRNAs) and the long non-coding RNAs (lncRNAs) act as master switches orchestrating both immune as well as neuronal processes. Several chronic disorders reveal unique ncRNA expression signatures, which recently generated big hopes for new perspectives for the development of diagnostic applications. lncRNAs may offer perspectives as candidates indicative of neuropathic pain in liquid biopsies. Numerous studies have provided novel mechanistic insight into the role of miRNAs in the molecular sequelae involved in the pathogenesis of neuropathic pain along the entire pain pathway. Specific processes within neurons, immune cells, and glia as the cellular components of the neuropathic pain triad and the communication paths between them are controlled by specific miRNAs. Therefore, nucleotide sequences mimicking or antagonizing miRNA actions can provide novel therapeutic strategies for pain treatment, provided their human homologues serve the same or similar functions. Increasing evidence also sheds light on the function of lncRNAs, which converge so far mainly on purinergic signalling pathways both in neurons and glia, and possibly even other ncRNA species that have not been explored so far.

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MicroRNA cluster miR-17-92 regulates multiple functionally related voltage-gated potassium channels in chronic neuropathic pain

Cited by 94 publications

References 54 publications

A subset of microRNAs in the Dlk1‐Dio3 cluster regulates age‐associated muscle atrophy by targeting Atrogin‐1

A subset of microRNAs in the Dlk1‐Dio3 cluster regulates age‐associated muscle atrophy by targeting Atrogin‐1

ZNRD1‐AS and RP11‐819C21.1 long non‐coding RNA changes following painful laser stimulation correlate with laser‐evoked potential amplitude and habituation in healthy subjects: A pilot study

Non-coding RNAs in neuropathic pain

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