Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration

Luca, Edlira; Turcekova, Katarina; Hartung, Angelika; Mathes, Sebastian; Rehrauer, Hubert; Krützfeldt, Jan

doi:10.1016/j.molmet.2020.02.010

Cited by 11 publications

(13 citation statements)

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“…We have previously shown that miR-29a is a master regulator of muscle cell differentiation in vitro ( 21 ) and muscle regeneration in vivo ( 22 ). Interestingly, the inhibition of miR-29a in the muscle cell line C2C12 affected adipogenic differentiation of 3T3 cells in a coculture system ( Fig.…”

Section: Resultsmentioning

confidence: 99%

“…We used both trancriptomics and proteomics datasets in which miR-29a was down-regulated in human primary myoblasts and C2C12 myotubes, respectively. We have previously published an RNA deep sequencing dataset of human myotubes ( 21 ), which we now reanalyzed specifically for miR-29a targets. For the proteomics dataset, liquid chromatography–mass spectrometry (LC-MS/MS) was performed on the supernatants of C2C12 myotubes.…”

Section: Resultsmentioning

confidence: 99%

“…We declare that all data supporting the findings of this study are available within the article and its SI Appendix and have been deposited in Dryad (DOI: 10.5061/dryad.j6q573nf6 ) ( 74 ). The RNA sequencing data described in this report have been deposited in the Gene Expression Omnibus database ( GSE154254 ) ( 75 ). The mass spectrometry proteomics data have been deposited to the ProteomeXchange consortium via the Proteomics Identifications Database (PRIDE) partner repository with the dataset identifier PXD020575 ( 76 ).…”

Section: Data Availabilitymentioning

confidence: 99%

“…Here, we expose the fickle role of FGF-2, which participates not only in the growth of myogenic progenitors and fibers but also supports the differentiation of FAPs. By following upstream and downstream signaling events of a master regulator of myogenesis, microRNA (miR)-29a (21), we identified an intricate FGF-2 signaling pathway in muscle cells, which enhances differentiation of FAPs in vitro and promotes IMAT formation in vivo during muscle regeneration via the suppression of the myokine SPARC. Additionally, the FGF-2/miR-29a/SPARC pathway is enhanced in Significance A unique feature of muscle during aging, obesity, and type 2 diabetes is the appearance of adipose tissue between skeletal muscle fibers, the intramuscular adipose tissue (IMAT).…”

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confidence: 99%

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FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

Mathes

Fahrner

Ghoshdastider

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Aged skeletal muscle is markedly affected by fatty muscle infiltration, and strategies to reduce the occurrence of intramuscular adipocytes are urgently needed. Here, we show that fibroblast growth factor-2 (FGF-2) not only stimulates muscle growth but also promotes intramuscular adipogenesis. Using multiple screening assays upstream and downstream of microRNA (miR)-29a signaling, we located the secreted protein and adipogenic inhibitor SPARC to an FGF-2 signaling pathway that is conserved between skeletal muscle cells from mice and humans and that is activated in skeletal muscle of aged mice and humans. FGF-2 induces the miR-29a/SPARC axis through transcriptional activation of FRA-1, which binds and activates an evolutionary conserved AP-1 site element proximal in the miR-29a promoter. Genetic deletions in muscle cells and adeno-associated virus–mediated overexpression of FGF-2 or SPARC in mouse skeletal muscle revealed that this axis regulates differentiation of fibro/adipogenic progenitors in vitro and intramuscular adipose tissue (IMAT) formation in vivo. Skeletal muscle from human donors aged >75 y versus <55 y showed activation of FGF-2–dependent signaling and increased IMAT. Thus, our data highlights a disparate role of FGF-2 in adult skeletal muscle and reveals a pathway to combat fat accumulation in aged human skeletal muscle.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Data Availabilitymentioning

confidence: 99%

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confidence: 99%

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FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

Mathes

Fahrner

Ghoshdastider

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…These post-transcriptional gene regulators open a new field of research regarding the therapeutic role of CrM supplementation on health-related conditions. It needs to be noted that the osmosensing activation of MAPK via Sphk1/S1P is related to several miRNAs [ 142 ], as well as the notion that the effect of Cr on focal adhesion kinase [ 38 , 70 ] ( Figure A1 ) might control muscle cell differentiation through a small set of miRNAs that are connected to the focal adhesion signaling during muscle regeneration, as was reported recently [ 143 ]. Further experimental validation is warranted in the future.…”

Section: Discussionmentioning

confidence: 91%

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

et al. 2021

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Creatine (Cr) and phosphocreatine (PCr) are physiologically essential molecules for life, given they serve as rapid and localized support of energy- and mechanical-dependent processes. This evolutionary advantage is based on the action of creatine kinase (CK) isozymes that connect places of ATP synthesis with sites of ATP consumption (the CK/PCr system). Supplementation with creatine monohydrate (CrM) can enhance this system, resulting in well-known ergogenic effects and potential health or therapeutic benefits. In spite of our vast knowledge about these molecules, no integrative analysis of molecular mechanisms under a systems biology approach has been performed to date; thus, we aimed to perform for the first time a convergent functional genomics analysis to identify biological regulators mediating the effects of Cr supplementation in health and disease. A total of 35 differentially expressed genes were analyzed. We identified top-ranked pathways and biological processes mediating the effects of Cr supplementation. The impact of CrM on miRNAs merits more research. We also cautiously suggest two dose–response functional pathways (kinase- and ubiquitin-driven) for the regulation of the Cr uptake. Our functional enrichment analysis, the knowledge-based pathway reconstruction, and the identification of hub nodes provide meaningful information for future studies. This work contributes to a better understanding of the well-reported benefits of Cr in sports and its potential in health and disease conditions, although further clinical research is needed to validate the proposed mechanisms.

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MicroRNA profiling of different exercise interventions for alleviating skeletal muscle atrophy in naturally aging rats

Liang

Zhang

Zeng

et al. 2022

J cachexia sarcopenia muscle

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Background Exercise is an affordable and practical strategy to alleviate several detrimental outcomes from the aging process, including sarcopenia. The elucidation of molecular mechanisms to alleviate sarcopenia is one of the most important steps towards understanding human aging. Although microRNAs (miRNAs) regulate muscle growth, regeneration and aging, the potential role of exercise-mediated miRNAs during the prevention and rehabilitation of skeletal muscle atrophy upon exercise interventions remains unclear. Methods A miRNA profile by miRNA sequencing for gastrocnemius muscle of a 24-month-old aged male rat model mimicking the naturally aging process was established through screening the differentially expressed miRNAs (DEMs) for alleviating aging-induced skeletal muscle atrophy upon optimal exercise intervention. The screened miRNAs and hub genes, as well as biomarkers with the most significantly enriched pathways, were validated by quantitative real-time polymerase chain reaction and western blotting. ResultsThe sarcopenia index (SI) value and cross-sectional area (CSA) of rats from the old control (OC) group significantly decreased when compared with the youth control (YC) group (P < 0.001, P < 0.01), whereas an increased SI value and an enlarged CSA of rats from the old-aerobic exercise (OE), old-resistance exercise (OR) and old-mixed exercise (OM) groups were determined (P < 0.01, P < 0.001, P < 0.05; P < 0.01, P < 0.01, P < 0.05). Our results demonstrate that 764 known miRNAs, 201 novel miRNAs and 505 miRNA-mRNA interaction networks were identified to be related to aging-induced muscular atrophy. Among them, 13 miRNAs were differentially expressed (P < 0.05 and log 2 |fold change| > 1) between the YC group and the OC group. Compared with the OC group, 7, 2 and 11 miRNAs were differentially expressed in the OE, OR and OM groups after exercise interventions, respectively. Meanwhile, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses revealed that the identified DEMs were primarily related to apoptosis, autophagy and the NF-κB/MuRF1 signalling pathways (P < 0.05). Meanwhile,, six hub genes (Ar, Igf1, Hif1a, Bdnf, Fak and Nras) and several biomarkers (LC3, Beclin1, p62, Bax, Bcl-2 and NF-κB/MuRF1) with the most significantly enriched pathways were confirmed, which may play a key role in muscular atrophy during the aging process. Conclusions These findings are closely correlated with the progression of sarcopenia and could act as potential biomarkers for the diagnosis and interventional monitoring of aging-induced skeletal muscle atrophy.

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Genetic deletion of microRNA biogenesis in muscle cells reveals a hierarchical non-clustered network that controls focal adhesion signaling during muscle regeneration

Cited by 11 publications

References 73 publications

FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

FGF-2–dependent signaling activated in aged human skeletal muscle promotes intramuscular adipogenesis

A Convergent Functional Genomics Analysis to Identify Biological Regulators Mediating Effects of Creatine Supplementation

MicroRNA profiling of different exercise interventions for alleviating skeletal muscle atrophy in naturally aging rats

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