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      MicroRNAs in muscle wasting

      1 , , 1

      Journal of Cachexia, Sarcopenia and Muscle

      John Wiley and Sons Inc.

      Muscle wasting, MicroRNA, Cachexia

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          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.

          Abstract

          Introduction Skeletal muscle makes up approximately 40% of the total body mass; it is essential in providing structural support, to regulate motion and as an energy store, thereby playing a major role in the overall metabolism. Skeletal muscle retains a high plasticity in order to respond to various stimuli, which subsequently lead to changes in gene transcription and translation. Aside from the obvious transcription factors, non‐coding RNAs have received much attention over the last decade and can be subclassed into long non‐coding RNA and small non‐coding RNA termed microRNA (miR). These miRs are similar to mRNA when first transcribed as primary RNA and are subsequently processed by the endoribonuclease DROSHA associated with PASHA to a precursor miR, which is further processed by the endoribonuclease DICER1 to form mature miRs.1 The mature miR binds to its target mRNAs leading to a blocked translation or degradation thereby providing the cell with a post‐transcriptional control of gene expression.2, 3 While some miRs are expressed ubiquitously in most tissues and cell types, other miRs are highly and specifically enriched in certain tissues.4 MyomiRs comprise a group of miRs, who display an enriched expression in skeletal muscle including miR‐1, miR‐133a, miR‐133b, miR‐206, miR‐208, miR‐208b, miR‐486, and miR‐499. These miRs are under the transcriptional control of myogenic regulatory factors such as MyoD, myogenin, Myf5, and MRF4.5 The expression of MyomiRs is modulated in skeletal muscle growth, its development and maintenance, and during atrophy.5 Two key players of muscle wasting are the E3 ubiquitin ligases MAFbx and MuRF‐1, the latter being the only E3 ubiquitin ligase known to target contractile proteins in catabolic conditions6 and which can be inhibited by small molecules.7 The related proteins MuRF‐2 and MuRF‐3 bind to microtubules and are implicated in sarcomere formation with evident functional redundancy, which has proven to be important for the maintenance of skeletal muscle, as double knockout mice lead to myopathy, reduced fore generation, and fibre type shift.8 In contrast to healthy adaptation, not only myomiRs are regulated in cancer cachexia, a recent publication showed an up‐regulation of hsa‐miR‐3184‐3p, hsa‐miR‐423‐5p, hsa‐let‐7d‐3p, hsa‐miR‐1296‐5p, hsa‐miR‐345‐5p, hsa‐miR‐532‐5p, hsa‐miR‐423‐3p, and hsa‐miR‐199a‐3p, but no down‐regulation of miRs in skeletal muscle biopsies of patients with pancreatic and colorectal cancer (Table 1).9 In a rat model of paralysed muscle by spinal cord injury, a down‐regulation of miRs 23a, 23b, 27b, 145, and 206 was observed 56 days after injury,10 while injection of 30 μg of mir‐206 attenuated muscle loss in a rat denervation model.11 In patients with chronic obstructive pulmonary disease (COPD), an up‐regulation of miR‐542‐3p/5p in quadricep muscle has been described, which caused muscle wasting and reduced mitochondrial function when overexpressed in mice possibly due to a suppression of the mitochondrial ribosomal protein MRPS10, reduced 12S ribosomal RNA expression, and increased TGF‐b signalling.12 In patients with COPD with a low fat free mass, an increased expression of miR‐675 in quadricep muscle was shown to repress muscle regeneration in vitro.13 Moreover, quadricep expression of miR‐422a was positively associated with muscle strength (maximal voluntary contraction r = 0.59, P < 0.001 and r = 0.51, P = 0.004, for COPD and aortic surgery, respectively) and inversely associated with the amount of muscle that would be lost in the first post‐operative week (r = −0.57, P < 0.001).14 Overexpression of miR‐23a/27a in muscle attenuated diabetes‐induced muscle cachexia and attenuates renal fibrosis lesions via muscle‐kidney crosstalk in streptozotocin‐induced diabetic mice.15 Recently, the lncRNA MAR1 has been shown to act as a miR‐487b scavenger to regulate Wnt5a protein expression leading to stimulated muscle differentiation and regeneration as well as increased strength in mice16 making the already complex miR regulatory system even more complicated. Table 1 Differential regulation of miR expression in skeletal muscle after exercise miR up‐regulated miR down‐regulated Exercise type Exercise duration Reference miR‐1, miR‐133a, miR‐133b, miR181a miR‐9, miR‐23a, miR‐23b, miR‐31 Acute exercise Acute bout of moderate‐intensity endurance cycling Russel et al.25 miR‐1, miR‐133a Acute resistance exercise 45 min of one‐legged knee extensor exercise Ringholm et al.26 miR‐1 12 weeks of training with two weekly resistance exercise sessions 12 weeks of training with two weekly resistance exercise sessions Mueller et al.27 miR‐1, miR‐133a, miR‐133b, miR‐206 Endurance Cycle ergometer five times per week frequency for 12 weeks Nielsen et al.28 miR‐1, miR‐29b Endurance 10 days of endurance training Russel et al.25 miR‐136, miR‐200c, miR‐376, miR‐377, miR‐499b, miR‐558 miR‐28, miR‐30d, miR‐204, miR‐330, miR‐345, miR‐375, miR‐449c, miR‐483, miR‐509, miR‐520a, miR‐548, miR‐628, miR‐653, miR‐670, miR‐889, miR‐1245a, miR‐1270, miR‐1280, miR‐1322, miR‐3180 Chronic resistance exercise 12‐week lower body resistance exercise Ogasawara et al.29 miR‐451 miR‐26a, miR‐29a, miR‐378 Resistance exercise 12‐week resistance exercise training program (pushing, pulling, and leg exercises, with 60 weight‐lifting sessions in total Davidsen et al.30 miR‐133a, miR‐378, miR‐486 Resistance exercise 8 × 5 unilateral leg press repetitions on each leg at 80% of the 1repitition maximum Fyfe et al.31 miRs can be actively secreted from a cell or leaking through the membrane in response to various stimuli and insults resulting in varying circulating miR levels in the blood, which are relatively stable making miRs interesting for the use as biomarkers and therapeutic targets.1 This is of particular importance in muscle wasting, as there are very few blood‐based biomarkers such as myostatin or agrinin that correlated with muscle mass.17, 18, 19, 20, 21 Several other circulating factors like GDF‐15,22 activin A,23 and low testosterone24 have been associated with muscle loss and survival in sarcopenia and cachexia and therefore can be considered potential biomarkers, but need to be validated in large trials. miRs could serve not only as biomarkers for muscle status and wasting but also as biomarkers to monitor muscle regeneration and therapy effects. Resistance exercise has been of particular interest in sarcopenia and also in cachexia.32, 33, 34, 35, 36, 37 Moreover, exercise mimetics such as trimetazidine are of interest in the therapy of muscle atrophy,38 but also need companion biomarkers. MyomiRs are strongly regulated in resistance exercise, and their expression patterns in muscle as well as their plasma pattern levels may have the potential to serve as biomarkers for exercise, and regular monitoring in sarcopenic or cachectic patients could prevent detrimental over‐exercise. Conflict of interest None declared.

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          Most cited references 39

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          Regulation of microRNA biogenesis.

           Nguyet M Ha,  V. Kim (2014)
          MicroRNAs (miRNAs) are small non-coding RNAs that function as guide molecules in RNA silencing. Targeting most protein-coding transcripts, miRNAs are involved in nearly all developmental and pathological processes in animals. The biogenesis of miRNAs is under tight temporal and spatial control, and their dysregulation is associated with many human diseases, particularly cancer. In animals, miRNAs are ∼22 nucleotides in length, and they are produced by two RNase III proteins--Drosha and Dicer. miRNA biogenesis is regulated at multiple levels, including at the level of miRNA transcription; its processing by Drosha and Dicer in the nucleus and cytoplasm, respectively; its modification by RNA editing, RNA methylation, uridylation and adenylation; Argonaute loading; and RNA decay. Non-canonical pathways for miRNA biogenesis, including those that are independent of Drosha or Dicer, are also emerging.
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            Ethical guidelines for publishing in the journal of cachexia, sarcopenia and muscle: update 2017

            Abstract This article details an updated version of the principles of ethical authorship and publishing in the Journal of Cachexia, Sarcopenia and Muscle (JCSM). At the time of submission to JCSM, the corresponding author, on behalf of all co‐authors, needs to certify adherence to these principles. The principles are as follows: All authors listed on a manuscript considered for publication have approved its submission and (if accepted) publication as provided to JCSM. No person who has a right to be recognized as author has been omitted from the list of authors on the submitted manuscript. Each author has made a material and independent contribution to the work submitted for publication. The submitted work is original and is neither under consideration elsewhere nor that it has been published previously in whole or in part other than in abstract form. All authors certify that the work is original and does not contain excessive overlap with prior or contemporaneous publication elsewhere, and where the publication reports on cohorts, trials, or data that have been reported on before these other publications must be referenced. All original research work has been approved by the relevant bodies such as institutional review boards or ethics committees. All conflicts of interest, financial or otherwise, that may affect the authors' ability to present data objectively, and relevant sources of funding have been duly declared in the manuscript. The manuscript in its published form will be maintained on the servers of JCSM as a valid publication only as long as all statements in the guidelines on ethical publishing remain true. If any of the aforementioned statements ceases to be true, the authors have a duty to notify the Editors of JCSM as soon as possible so that the available information regarding the published article can be updated and/or the manuscript can be withdrawn.
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              Cell-type-specific signatures of microRNAs on target mRNA expression.

              Although it is known that the human genome contains hundreds of microRNA (miRNA) genes and that each miRNA can regulate a large number of mRNA targets, the overall effect of miRNAs on mRNA tissue profiles has not been systematically elucidated. Here, we show that predicted human mRNA targets of several highly tissue-specific miRNAs are typically expressed in the same tissue as the miRNA but at significantly lower levels than in tissues where the miRNA is not present. Conversely, highly expressed genes are often enriched in mRNAs that do not have the recognition motifs for the miRNAs expressed in these tissues. Together, our data support the hypothesis that miRNA expression broadly contributes to tissue specificity of mRNA expression in many human tissues. Based on these insights, we apply a computational tool to directly correlate 3' UTR motifs with changes in mRNA levels upon miRNA overexpression or knockdown. We show that this tool can identify functionally important 3' UTR motifs without cross-species comparison.
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                Author and article information

                Contributors
                jochen.springer@med.uni-goettingen.de
                Journal
                J Cachexia Sarcopenia Muscle
                J Cachexia Sarcopenia Muscle
                10.1007/13539.2190-6009
                JCSM
                Journal of Cachexia, Sarcopenia and Muscle
                John Wiley and Sons Inc. (Hoboken )
                2190-5991
                2190-6009
                29 January 2019
                December 2018
                : 9
                : 7 ( doiID: 10.1002/jcsm.v9.7 )
                : 1209-1212
                JCSM12384 JCSM-D-18-00383
                10.1002/jcsm.12384
                6351673
                30697980
                © 2019 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society on Sarcopenia, Cachexia and Wasting Disorders

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

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                Figures: 0, Tables: 1, Pages: 4, Words: 874
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                jcsm12384
                December 2018 Supplement
                Converter:WILEY_ML3GV2_TO_NLMPMC version:5.5.7 mode:remove_FC converted:30.01.2019

                Orthopedics

                muscle wasting, cachexia, microrna

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