Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism

Silvia Giannattasio, Giacomo Giacovazzo, Agnese Bonato, Carla Caruso, Siro Luvisetto, Roberto Coccurello, Maurizia Caruso

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)12792
JournalScientific Reports
Volume8
Issue number1
DOIs
Publication statusPublished - Aug 24 2018

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Cyclin D3
Skeletal Muscle Fibers
Muscles
Cyclin D2
Phenotype
Cyclin-Dependent Kinases
Calcineurin
Cyclin D1
G1 Phase
Gene Expression Profiling
Mitogens
Muscle Cells
Energy Metabolism
Cultured Cells
Cell Cycle
Skeletal Muscle
Transcription Factors
Up-Regulation
Fatty Acids
Stem Cells

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Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism. / Giannattasio, Silvia; Giacovazzo, Giacomo; Bonato, Agnese; Caruso, Carla; Luvisetto, Siro; Coccurello, Roberto; Caruso, Maurizia.

In: Scientific Reports, Vol. 8, No. 1, 24.08.2018, p. 12792.

Research output: Contribution to journalArticle

Giannattasio, Silvia ; Giacovazzo, Giacomo ; Bonato, Agnese ; Caruso, Carla ; Luvisetto, Siro ; Coccurello, Roberto ; Caruso, Maurizia. / Lack of cyclin D3 induces skeletal muscle fiber-type shifting, increased endurance performance and hypermetabolism. In: Scientific Reports. 2018 ; Vol. 8, No. 1. pp. 12792.
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