Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism
Abstract The mitogen-induced D-type cyclins (D1, D2 and D3) are regulatory subunits of the cyclin-dependent kinases CDK4 and CDK6 that drive progression through the G1 phase of the cell cycle. In skeletal muscle, cyclin D3 plays a unique function in controlling the proliferation/differentiation bala...
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| Format: | Article |
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Nature Portfolio
2018-08-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-018-31090-5 |
| _version_ | 1818428257039548416 |
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| author | Silvia Giannattasio Giacomo Giacovazzo Agnese Bonato Carla Caruso Siro Luvisetto Roberto Coccurello Maurizia Caruso |
| author_facet | Silvia Giannattasio Giacomo Giacovazzo Agnese Bonato Carla Caruso Siro Luvisetto Roberto Coccurello Maurizia Caruso |
| author_sort | Silvia Giannattasio |
| collection | DOAJ |
| description | Abstract The mitogen-induced D-type cyclins (D1, D2 and D3) are regulatory subunits of the cyclin-dependent kinases CDK4 and CDK6 that drive progression through the G1 phase of the cell cycle. In skeletal muscle, cyclin D3 plays a unique function in controlling the proliferation/differentiation balance of myogenic progenitor cells. Here, we show that cyclin D3 also performs a novel function, regulating muscle fiber type-specific gene expression. Mice lacking cyclin D3 display an increased number of myofibers with higher oxidative capacity in fast-twitch muscle groups, primarily composed of myofibers that utilize glycolytic metabolism. The remodeling of myofibers toward a slower, more oxidative phenotype is accompanied by enhanced running endurance and increased energy expenditure and fatty acid oxidation. In addition, gene expression profiling of cyclin D3−/− muscle reveals the upregulation of genes encoding proteins involved in the regulation of contractile function and metabolic markers specifically expressed in slow-twitch and fast-oxidative myofibers, many of which are targets of MEF2 and/or NFAT transcription factors. Furthermore, cyclin D3 can repress the calcineurin- or MEF2-dependent activation of a slow fiber-specific promoter in cultured muscle cells. These data suggest that cyclin D3 regulates muscle fiber type phenotype, and consequently whole body metabolism, by antagonizing the activity of MEF2 and/or NFAT. |
| first_indexed | 2024-12-14T14:58:44Z |
| format | Article |
| id | doaj.art-adf1b3c9b11f492ea0cdab5e5ffaa16c |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-12-14T14:58:44Z |
| publishDate | 2018-08-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-adf1b3c9b11f492ea0cdab5e5ffaa16c2022-12-21T22:56:55ZengNature PortfolioScientific Reports2045-23222018-08-018111810.1038/s41598-018-31090-5Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolismSilvia Giannattasio0Giacomo Giacovazzo1Agnese Bonato2Carla Caruso3Siro Luvisetto4Roberto Coccurello5Maurizia Caruso6National Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationNational Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationNational Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationUniversity of Tuscia, Department of Ecological and Biological SciencesNational Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationNational Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationNational Research Council (CNR), Institute of Cell Biology and Neurobiology, IRCCS Santa Lucia FoundationAbstract The mitogen-induced D-type cyclins (D1, D2 and D3) are regulatory subunits of the cyclin-dependent kinases CDK4 and CDK6 that drive progression through the G1 phase of the cell cycle. In skeletal muscle, cyclin D3 plays a unique function in controlling the proliferation/differentiation balance of myogenic progenitor cells. Here, we show that cyclin D3 also performs a novel function, regulating muscle fiber type-specific gene expression. Mice lacking cyclin D3 display an increased number of myofibers with higher oxidative capacity in fast-twitch muscle groups, primarily composed of myofibers that utilize glycolytic metabolism. The remodeling of myofibers toward a slower, more oxidative phenotype is accompanied by enhanced running endurance and increased energy expenditure and fatty acid oxidation. In addition, gene expression profiling of cyclin D3−/− muscle reveals the upregulation of genes encoding proteins involved in the regulation of contractile function and metabolic markers specifically expressed in slow-twitch and fast-oxidative myofibers, many of which are targets of MEF2 and/or NFAT transcription factors. Furthermore, cyclin D3 can repress the calcineurin- or MEF2-dependent activation of a slow fiber-specific promoter in cultured muscle cells. These data suggest that cyclin D3 regulates muscle fiber type phenotype, and consequently whole body metabolism, by antagonizing the activity of MEF2 and/or NFAT.https://doi.org/10.1038/s41598-018-31090-5 |
| spellingShingle | Silvia Giannattasio Giacomo Giacovazzo Agnese Bonato Carla Caruso Siro Luvisetto Roberto Coccurello Maurizia Caruso Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism Scientific Reports |
| title | Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism |
| title_full | Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism |
| title_fullStr | Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism |
| title_full_unstemmed | Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism |
| title_short | Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism |
| title_sort | lack of cyclin d3 induces skeletal muscle fiber type shifting increased endurance performance and hypermetabolism |
| url | https://doi.org/10.1038/s41598-018-31090-5 |
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