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

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          Abstract

          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.

          Conclusions

          Our study suggests that genetic intervention using a muscle‐directed miRNA delivery system has therapeutic efficacy in preventing Atrogin‐1‐mediated muscle atrophy in sarcopenia.

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          Most cited references73

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          The functions of animal microRNAs.

          MicroRNAs (miRNAs) are small RNAs that regulate the expression of complementary messenger RNAs. Hundreds of miRNA genes have been found in diverse animals, and many of these are phylogenetically conserved. With miRNA roles identified in developmental timing, cell death, cell proliferation, haematopoiesis and patterning of the nervous system, evidence is mounting that animal miRNAs are more numerous, and their regulatory impact more pervasive, than was previously suspected.
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            Frailty in older adults: evidence for a phenotype.

            Frailty is considered highly prevalent in old age and to confer high risk for falls, disability, hospitalization, and mortality. Frailty has been considered synonymous with disability, comorbidity, and other characteristics, but it is recognized that it may have a biologic basis and be a distinct clinical syndrome. A standardized definition has not yet been established. To develop and operationalize a phenotype of frailty in older adults and assess concurrent and predictive validity, the study used data from the Cardiovascular Health Study. Participants were 5,317 men and women 65 years and older (4,735 from an original cohort recruited in 1989-90 and 582 from an African American cohort recruited in 1992-93). Both cohorts received almost identical baseline evaluations and 7 and 4 years of follow-up, respectively, with annual examinations and surveillance for outcomes including incident disease, hospitalization, falls, disability, and mortality. Frailty was defined as a clinical syndrome in which three or more of the following criteria were present: unintentional weight loss (10 lbs in past year), self-reported exhaustion, weakness (grip strength), slow walking speed, and low physical activity. The overall prevalence of frailty in this community-dwelling population was 6.9%; it increased with age and was greater in women than men. Four-year incidence was 7.2%. Frailty was associated with being African American, having lower education and income, poorer health, and having higher rates of comorbid chronic diseases and disability. There was overlap, but not concordance, in the cooccurrence of frailty, comorbidity, and disability. This frailty phenotype was independently predictive (over 3 years) of incident falls, worsening mobility or ADL disability, hospitalization, and death, with hazard ratios ranging from 1.82 to 4.46, unadjusted, and 1.29-2.24, adjusted for a number of health, disease, and social characteristics predictive of 5-year mortality. Intermediate frailty status, as indicated by the presence of one or two criteria, showed intermediate risk of these outcomes as well as increased risk of becoming frail over 3-4 years of follow-up (odds ratios for incident frailty = 4.51 unadjusted and 2.63 adjusted for covariates, compared to those with no frailty criteria at baseline). This study provides a potential standardized definition for frailty in community-dwelling older adults and offers concurrent and predictive validity for the definition. It also finds that there is an intermediate stage identifying those at high risk of frailty. Finally, it provides evidence that frailty is not synonymous with either comorbidity or disability, but comorbidity is an etiologic risk factor for, and disability is an outcome of, frailty. This provides a potential basis for clinical assessment for those who are frail or at risk, and for future research to develop interventions for frailty based on a standardized ascertainment of frailty.
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              Identification of ubiquitin ligases required for skeletal muscle atrophy.

              Skeletal muscle adapts to decreases in activity and load by undergoing atrophy. To identify candidate molecular mediators of muscle atrophy, we performed transcript profiling. Although many genes were up-regulated in a single rat model of atrophy, only a small subset was universal in all atrophy models. Two of these genes encode ubiquitin ligases: Muscle RING Finger 1 (MuRF1), and a gene we designate Muscle Atrophy F-box (MAFbx), the latter being a member of the SCF family of E3 ubiquitin ligases. Overexpression of MAFbx in myotubes produced atrophy, whereas mice deficient in either MAFbx or MuRF1 were found to be resistant to atrophy. These proteins are potential drug targets for the treatment of muscle atrophy.
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                Author and article information

                Contributors
                kplee@kribb.re.kr
                kwonks@kribb.re.kr
                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
                03 June 2020
                October 2020
                : 11
                : 5 ( doiID: 10.1002/jcsm.v11.5 )
                : 1336-1350
                Affiliations
                [ 1 ] Aging Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea
                [ 2 ] Personalized Genomic Medicine Research Center Korea Research Institute of Bioscience and Biotechnology (KRIBB) Daejeon Korea
                [ 3 ] Department of Biology, College of Natural Sciences Gangneung‐Wonju National University Gangneung Korea
                [ 4 ] Department of Rehabilitation Medicine Seoul National University Bundang Hospital Gyeonggi‐do Korea
                [ 5 ] Department of Biomolecular Science, KRIBB School of Bioscience Korea University of Science and Technology (UST) Daejeon Korea
                [ 6 ] Department of Functional Genomics, KRIBB School of Bioscience Korea University of Science and Technology (UST) Daejeon Korea
                [ 7 ] Department of Medicinal Biotechnology, College of Health Sciences Dong‐A University Busan Korea
                [ 8 ] Department of New Drug Discovery and Development Chungnam National University Daejeon Korea
                [ 9 ] Internal Medicine Seoul National University Bundang Hospital Gyeonggi‐do Korea
                [ 10 ] Department of Genetics Albert Einstein College of Medicine NY USA
                [ 11 ] Department of Biochemistry and Molecular Biology Medical University of South Carolina Charleston SC USA
                Author notes
                [*] [* ] Correspondence to: Kwang‐Pyo Lee, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. Tel.: +82‐42‐860‐4146, Fax: +82‐42‐879‐8596, Email: kplee@kribb.re.kr; and Ki‐Sun Kwon, Aging Research Center, Korea Research Institute of Bioscience and Biotechnology (KRIBB), Daejeon 34141, Korea. Tel.: +82‐42‐860‐4143, Fax: +82‐42‐879‐8596, Email: kwonks@ 123456kribb.re.kr
                Author information
                https://orcid.org/0000-0003-0067-6898
                Article
                JCSM12578 JCSM-D-19-00263
                10.1002/jcsm.12578
                7567143
                32495509
                33d183c7-66ec-48fc-ab23-e57da8e8f453
                © 2020 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of 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.

                History
                : 13 June 2019
                : 16 March 2020
                : 22 April 2020
                Page count
                Figures: 6, Tables: 0, Pages: 15, Words: 7218
                Funding
                Funded by: KRIBB Research Initiative Program
                Funded by: National Research Foundation , open-funder-registry 10.13039/501100001321;
                Award ID: 2020R1A2C1005161
                Award ID: 2017M3A9D8048708
                Award ID: 2013M3A9B6076413
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                October 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.9.2 mode:remove_FC converted:16.10.2020

                Orthopedics
                dlk1‐dio3 mirna cluster,muscle aging,sarcopenia,atrophy,cachexia,atrogin‐1,mir‐376c‐3p
                Orthopedics
                dlk1‐dio3 mirna cluster, muscle aging, sarcopenia, atrophy, cachexia, atrogin‐1, mir‐376c‐3p

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