Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress

Koutsoulidou, Andrie; Photiades, Marinos; Kyriakides, Tassos C.; Georgiou, Kristia; Prokopi, Marianna; Kapnisis, Konstantinos; Łusakowska, Anna; Nearchou, Marianna; Papadimas, George K.; Kyriakou, Kyriakos; Kararizou, Evangelia; Papanicolaou, Eleni Zamba; Phylactou, Leonidas A.

doi:10.1093/hmg/ddx212

Cited by 37 publications

(58 citation statements)

References 60 publications

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“…Researchers have only recently begun to assess the profiles of circulating EVs in differing physiological/pathological states, yet clear correlations between either disease types or stage of disease has emerged ( Melo et al, 2015 ; Koutsoulidou et al, 2017 ; Skotland et al, 2017 ). In this study, we used two indirect markers of muscle damage, CK and PMP, to confirm the occurrence of the physiological stressor, SkM damage.…”

Section: Discussionmentioning

confidence: 99%

Investigation of Circulating Extracellular Vesicle MicroRNA Following Two Consecutive Bouts of Muscle-Damaging Exercise

2018

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Background: Extracellular vesicles (EVs) are nano-sized vesicles that are known to be powerful mediators of intercellular communication via their microRNA (miR) content. A paucity of information on EV-mediated communication arising from skeletal muscle (SkM) in response to exercise-induced muscle damage is present in the published literature. Lack of such information inhibits our understanding of muscle injury and repair processes.Aims: To assess circulating EV levels and selected miR content within them, in response to two consecutive bouts of muscle-damaging exercise.Methods: Serum creatine kinase activity (CK) and EVs were analyzed from the blood of 9 healthy, untrained males at baseline, and at 2 and 24 h post-exercise. The exercise regimen consisted of a combination of plyometric jumping and downhill running. Perceived muscle pain (PMP) was assessed on a scale from 1 to 10. Plasma EVs were isolated using size exclusion columns and visualized with transmission electron microscopy (TEM). EV size and number were quantified using nanoparticle tracking analysis (NTA). miR expression was quantified using qPCR, with normalization to an exogenous control (cel-miR-39).Results: PMP and CK were significantly elevated post-exercise compared to baseline levels, providing indirect evidence for muscle damage. EV visualization using TEM revealed an abundant and heterogeneously sized pool of intact particles within the exosome size range (30–150 nm). No significant change in mean EV size or number was seen over time. The SkM-specific miR-206 in EVs was found to be variable among participants and no significant change occurred in SkM-important miRs; 1, 133a, 133b, 486, and 499a. However, EV miR-31 decreased from baseline to 24 h post-exercise (p = 0.027).Conclusion: Mild to moderate exercise-induced muscle damage altered the miR-31 profile of circulating EVs within the first 24 h post-exercise, but not that of myomiRs in EVs. These data demonstrate that EVs carry selectively packaged cargo which can be affected by exercise. Future research into the total miR content of EVs in response to exercise-induced muscle damage may reveal other miRs responsive to this relatively mild perturbation. More time points post-muscle-damaging exercise would provide a better understanding of the temporal EV myomiR response.

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Section: Discussionmentioning

confidence: 99%

Investigation of Circulating Extracellular Vesicle MicroRNA Following Two Consecutive Bouts of Muscle-Damaging Exercise

2018

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“…In DM, several studies have focused on proving that miRNAs are dysregulated in samples such as skeletal muscle biopsies, blood, serum, or plasma from DM1 patients (mainly adult form) when compared to the same type of samples from control individuals [42,43,44,45,46,47,50,54,81,82]. A rational starting point has been performed over muscle-specific myomiRs (miR-1, miR-133a, miR-133b, miR-206, miR-208b, miR-486, and miR-499).…”

Section: Micro-rnas and Myotonic Dystrophymentioning

confidence: 99%

MicroRNA-Based Therapeutic Perspectives in Myotonic Dystrophy

Castel

Overby

Artero

2019

IJMS

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Myotonic dystrophy involves two types of chronically debilitating rare neuromuscular diseases: type 1 (DM1) and type 2 (DM2). Both share similarities in molecular cause, clinical signs, and symptoms with DM2 patients usually displaying milder phenotypes. It is well documented that key clinical symptoms in DM are associated with a strong mis-regulation of RNA metabolism observed in patient’s cells. This mis-regulation is triggered by two leading DM-linked events: the sequestration of Muscleblind-like proteins (MBNL) and the mis-regulation of the CUGBP RNA-Binding Protein Elav-Like Family Member 1 (CELF1) that cause significant alterations to their important functions in RNA processing. It has been suggested that DM1 may be treatable through endogenous modulation of the expression of MBNL and CELF1 proteins. In this study, we analyzed the recent identification of the involvement of microRNA (miRNA) molecules in DM and focus on the modulation of these miRNAs to therapeutically restore normal MBNL or CELF1 function. We also discuss additional prospective miRNA targets, the use of miRNAs as disease biomarkers, and additional promising miRNA-based and miRNA-targeting drug development strategies. This review provides a unifying overview of the dispersed data on miRNA available in the context of DM.

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“…Koutsoulidou et al demonstrated that appearance of miR-1, -133a, -133b, and -206 in serum correlated with the progression of muscle wasting in DM1 patients. All four miRNAs were found encapsulated within exosomes in the circulation ( 256 ). Cell and animal model studies suggest that MBNL expression is controlled by miR-277 and -304 ( 257 ), and miR-30-5p ( 258 ), and that this regulatory network could be involved in inhibition of myogenic differentiation in DM1.…”

Section: How Healthy and Dm Muscles Are Built And Maintainedmentioning

confidence: 99%

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy

et al. 2018

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Myotonic dystrophy type 1 (DM1) and 2 (DM2) are autosomal dominant degenerative neuromuscular disorders characterized by progressive skeletal muscle weakness, atrophy, and myotonia with progeroid features. Although both DM1 and DM2 are characterized by skeletal muscle dysfunction and also share other clinical features, the diseases differ in the muscle groups that are affected. In DM1, distal muscles are mainly affected, whereas in DM2 problems are mostly found in proximal muscles. In addition, manifestation in DM1 is generally more severe, with possible congenital or childhood-onset of disease and prominent CNS involvement. DM1 and DM2 are caused by expansion of (CTG•CAG)n and (CCTG•CAGG)n repeats in the 3′ non-coding region of DMPK and in intron 1 of CNBP, respectively, and in overlapping antisense genes. This critical review will focus on the pleiotropic problems that occur during development, growth, regeneration, and aging of skeletal muscle in patients who inherited these expansions. The current best-accepted idea is that most muscle symptoms can be explained by pathomechanistic effects of repeat expansion on RNA-mediated pathways. However, aberrations in DNA replication and transcription of the DM loci or in protein translation and proteome homeostasis could also affect the control of proliferation and differentiation of muscle progenitor cells or the maintenance and physiological integrity of muscle fibers during a patient’s lifetime. Here, we will discuss these molecular and cellular processes and summarize current knowledge about the role of embryonic and adult muscle-resident stem cells in growth, homeostasis, regeneration, and premature aging of healthy and diseased muscle tissue. Of particular interest is that also progenitor cells from extramuscular sources, such as pericytes and mesoangioblasts, can participate in myogenic differentiation. We will examine the potential of all these types of cells in the application of regenerative medicine for muscular dystrophies and evaluate new possibilities for their use in future therapy of DM.

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Identification of exosomal muscle-specific miRNAs in serum of myotonic dystrophy patients relating to muscle disease progress

Cited by 37 publications

References 60 publications

Investigation of Circulating Extracellular Vesicle MicroRNA Following Two Consecutive Bouts of Muscle-Damaging Exercise

Investigation of Circulating Extracellular Vesicle MicroRNA Following Two Consecutive Bouts of Muscle-Damaging Exercise

MicroRNA-Based Therapeutic Perspectives in Myotonic Dystrophy

Abnormalities in Skeletal Muscle Myogenesis, Growth, and Regeneration in Myotonic Dystrophy

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