Life-long reduction in myomiR expression does not adversely affect skeletal muscle morphology

Vechetti, Ivan J.; Wen, Yan; Chaillou, Thomas; Murach, Kevin A.; Alimov, Alexander P.; Figueiredo, Vandré Casagrande; Dal-Pai-Silva, Maeli; McCarthy, John J.

doi:10.1038/s41598-019-41476-8

Cited by 35 publications

(39 citation statements)

References 51 publications

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“…Our data showed that the muscle-enriched miRNAs were highly stable in the TA muscle of the iDicer KO mice (Figure 1B), which is consistent with our previous report [19]. Similarly, recent data on tamoxifen-inducible, skeletal muscle-specific Dicer knockout (HSA-MCM; Dicer fl/fl ) mice showed that the expression levels of miRNAs including miR-1, miR-133a and miR-206 were slightly affected by the Dicer depletion [32]. Several lines of evidence indicate that the mature miRNAs expressed in liver, heart, and neuron are also stable in vivo [33,34,35].…”

Section: Discussionsupporting

confidence: 90%

Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

Oikawa

Lee

Akimoto

2019

IJMS

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Skeletal muscle has a remarkable regenerative capacity, which is orchestrated by multiple processes, including the proliferation, fusion, and differentiation of the resident stem cells in muscle. MicroRNAs (miRNAs) are small noncoding RNAs that mediate the translational repression or degradation of mRNA to regulate diverse biological functions. Previous studies have suggested that several miRNAs play important roles in myoblast proliferation and differentiation in vitro. However, their potential roles in skeletal muscle regeneration in vivo have not been fully established. In this study, we generated a mouse in which the Dicer gene, which encodes an enzyme essential in miRNA processing, was knocked out in a tamoxifen-inducible way (iDicer KO mouse) and determined its regenerative potential after cardiotoxin-induced acute muscle injury. Dicer mRNA expression was significantly reduced in the tibialis anterior muscle of the iDicer KO mice, whereas the expression of muscle-enriched miRNAs was only slightly reduced in the Dicer-deficient muscles. After cardiotoxin injection, the iDicer KO mice showed impaired muscle regeneration. We also demonstrated that the number of PAX7+ cells, cell proliferation, and the myogenic differentiation capacity of the primary myoblasts did not differ between the wild-type and the iDicer KO mice. Taken together, these data demonstrate that Dicer is a critical factor for muscle regeneration in vivo.

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Section: Discussionsupporting

confidence: 90%

Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

Oikawa

Lee

Akimoto

2019

IJMS

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“…With these disadvantages in mind, and due to the specificity of new molecular and genetic indicators, their use becomes more and more appealing. As seen in Table 2, quite a few studies have highlighted the upregulation of the same four miRNAs, namely miR-1, miR-133a, miR-208a/b, and miR-499, shortly after myocardial infarction [59,[203][204][205], which are classically referred to as the myomiR family [206].…”

Section: Mirnas In Cardiovascular Diseasementioning

confidence: 99%

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

Condrat

Thompson

Barbu

et al. 2020

Cells

858

583

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MicroRNAs (miRNAs) represent a class of small, non-coding RNAs with the main roles of regulating mRNA through its degradation and adjusting protein levels. In recent years, extraordinary progress has been made in terms of identifying the origin and exact functions of miRNA, focusing on their potential use in both the research and the clinical field. This review aims at improving the current understanding of these molecules and their applicability in the medical field. A thorough analysis of the literature consulting resources available in online databases such as NCBI, PubMed, Medline, ScienceDirect, and UpToDate was performed. There is promising evidence that in spite of the lack of standardized protocols regarding the use of miRNAs in current clinical practice, they constitute a reliable tool for future use. These molecules meet most of the required criteria for being an ideal biomarker, such as accessibility, high specificity, and sensitivity. Despite present limitations, miRNAs as biomarkers for various conditions remain an impressive research field. As current techniques evolve, we anticipate that miRNAs will become a routine approach in the development of personalized patient profiles, thus permitting more specific therapeutic interventions.Biogenesis of miRNA begins in the nucleus, where the transcription of its precursor, primary miRNA or pri-miRNA takes place under the influence of RNA polymerases II and III [11,12]. The resulting molecule is a hairpin-like structure, which contains a loop at one end [11]. This primordial mi-RNA precursor that is usually made up of hundreds of nucleotides is then processed consecutively by two RNase III enzymes [13][14][15]. The first enzyme to act upon the pri-miRNA, which still resides in the nucleus, is called Drosha or DCGR8, and turns it into a new hairpin-like structure of approximately 70 nucleotides, the Precursor-miRNA or pre-miRNA. The latter is then transported to the cytoplasm, with the help of Exportin-5, where it is cleaved again by the Ago2/Dicer complex leading to the short, mature miRNA double strands [16].Further on, one of the strands, usually known as the guide strand, will be integrated into the RNA-induced silencing complex (RISC), while the other one, known as the passenger strand, is going to be degraded, even though in some occasions it has been found to be also functional [17]. In most cases, the strand that contains the less stable 5 end or a uracil at the beginning is more likely to be selected as the guide strand [18][19][20]. In those situations, where the passenger strand is not degraded and both get incorporated into the miRISC complex, the mature miRNA in the guide strand will be the dominant one [21,22].The main role of miRNA in the human body is gene regulation [23] by mediating the degradation of mRNA and also by regulating transcription and translation through canonical and non-canonical mechanisms [4]. The canonical mechanism means that the miRISC complex containing the miRNA guide strand is exerting its action by binding to the targ...

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“…12 Our laboratory and others recently found that muscle-specific miRNAs (myomiRs) persist for prolonged periods in the absence of the miRNA processing enzyme Dicer. 13,14 If prolonged miRNA stability is a quality specific to skeletal muscle, 15 myomiRs could be good candidates as long-term epigenetic regulators of exercise adaptation, especially given their known function in regulating muscle mass. [16][17][18] In the current investigation, we provide evidence on myonuclear accretion and maintenance in skeletal muscles with different fibre type composition and function after 2 months of PoWeR training and prolonged 6-month detraining.…”

Section: Introductionmentioning

confidence: 99%

“…Beyond myonuclear number, recent evidence suggests that DNA methylation changes in skeletal muscle induced by training could be long‐lasting and represent a memory of prior training exposure that facilitates future adaptation 12 . Our laboratory and others recently found that muscle‐specific miRNAs (myomiRs) persist for prolonged periods in the absence of the miRNA processing enzyme Dicer 13,14 . If prolonged miRNA stability is a quality specific to skeletal muscle, 15 myomiRs could be good candidates as long‐term epigenetic regulators of exercise adaptation, especially given their known function in regulating muscle mass 16–18 …”

Section: Introductionmentioning

confidence: 99%

Muscle memory: myonuclear accretion, maintenance, morphology, and miRNA levels with training and detraining in adult mice

Murach

Mobley

Zdunek

et al. 2020

J cachexia sarcopenia muscle

Self Cite

111

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Background In the context of mass regulation, 'muscle memory' can be defined as long-lasting cellular adaptations to hypertrophic exercise training that persist during detraining-induced atrophy and may facilitate future adaptation. The cellular basis of muscle memory is not clearly defined but may be related to myonuclear number and/or epigenetic changes within muscle fibres. Methods Utilizing progressive weighted wheel running (PoWeR), a novel murine exercise training model, we explored myonuclear dynamics and skeletal muscle miRNA levels with training and detraining utilizing immunohistochemistry, single fibre myonuclear analysis, and quantitative analysis of miRNAs. We also used a genetically inducible mouse model of fluorescent myonuclear labelling to study myonuclear adaptations early during exercise. Results In the soleus, oxidative type 2a fibres were larger after 2 months of PoWeR (P ¼ 0.02), but muscle fibre size and myonuclear number did not return to untrained levels after 6 months of detraining. Soleus type 1 fibres were not larger after PoWeR but had significantly more myonuclei, as well as central nuclei (P < 0.0001), the latter from satellite cell-derived or resident myonuclei, appearing early during training and remaining with detraining. In the gastrocnemius muscle, oxidative type 2a fibres of the deep region were larger and contained more myonuclei after PoWeR (P < 0.003), both of which returned to untrained levels after detraining. In the gastrocnemius and plantaris, two muscles where myonuclear number was comparable with untrained levels after 6 months of detraining, myonuclei were significantly elongated with detraining (P < 0.0001). In the gastrocnemius, miR-1 was lower with training and remained lower after detraining (P < 0.002). Conclusions This study found that (i) myonuclei gained during hypertrophy are lost with detraining across muscles, even in oxidative fibres; (ii) complete reversal of muscle adaptations, including myonuclear number, to untrained levels occurs within 6 months in the plantaris and gastrocnemius; (iii) the murine soleus is resistant to detraining; (iv) myonuclear accretion occurs early with wheel running and can be uncoupled from muscle fibre hypertrophy; (v) resident (non-satellite cell-derived) myonuclei can adopt a central location; (vi) myonuclei change shape with training and detraining; and (vii) miR-1 levels may reflect a memory of previous adaptation that facilitates future growth.

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Life-long reduction in myomiR expression does not adversely affect skeletal muscle morphology

Cited by 35 publications

References 51 publications

Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

Conditional Deletion of Dicer in Adult Mice Impairs Skeletal Muscle Regeneration

miRNAs as Biomarkers in Disease: Latest Findings Regarding Their Role in Diagnosis and Prognosis

Muscle memory: myonuclear accretion, maintenance, morphology, and miRNA levels with training and detraining in adult mice

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