Abstract |
The mechanisms involved in the coordinate regulation of the metabolic and structural programs controlling muscle fitness and endurance are unknown. Recently, the nuclear receptor PPARβ/δ was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPARα, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPARβ/δ and PPARα to explore the downstream regulatory circuitry that orchestrates the programs linking muscle fiber type with energy metabolism. Our results indicate that, in addition to the well-established role in transcriptional control of muscle metabolic genes, PPARβ/δ and PPARα participate in programs that exert opposing actions upon the type I fiber program through a distinct muscle microRNA ( miRNA) network, dependent on the actions of another nuclear receptor, estrogen-related receptor γ (ERRγ). Gain-of-function and loss-of-function strategies in mice, together with assessment of muscle biopsies from humans, demonstrated that type I muscle fiber proportion is increased via the stimulatory actions of ERRγ on the expression of miR-499 and miR-208b. This nuclear receptor/ miRNA regulatory circuit shows promise for the identification of therapeutic targets aimed at maintaining muscle fitness in a variety of chronic disease states, such as obesity, skeletal myopathies, and heart failure.
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Authors | Zhenji Gan, John Rumsey, Bethany C Hazen, Ling Lai, Teresa C Leone, Rick B Vega, Hui Xie, Kevin E Conley, Johan Auwerx, Steven R Smith, Eric N Olson, Anastasia Kralli, Daniel P Kelly |
Journal | The Journal of clinical investigation
(J Clin Invest)
Vol. 123
Issue 6
Pg. 2564-75
(Jun 2013)
ISSN: 1558-8238 [Electronic] United States |
PMID | 23676496
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Esrrg protein, mouse
- MIRN499 microRNA, mouse
- MicroRNAs
- Mirn208 microRNA, mouse
- Myh7 protein, mouse
- PPAR alpha
- PPAR delta
- PPAR-beta
- Receptors, Estrogen
- Myosin Heavy Chains
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Topics |
- Animals
- Cell Line
- Energy Metabolism
- Gene Expression
- Gene Regulatory Networks
- Humans
- Mice
- Mice, Inbred C57BL
- Mice, Inbred CBA
- Mice, Transgenic
- MicroRNAs
(genetics, metabolism)
- Muscle Fibers, Slow-Twitch
(metabolism)
- Muscle, Skeletal
(cytology, metabolism)
- Myosin Heavy Chains
(genetics, metabolism)
- PPAR alpha
(metabolism)
- PPAR delta
(metabolism)
- PPAR-beta
(metabolism)
- Promoter Regions, Genetic
- Receptors, Estrogen
(genetics, metabolism)
- Signal-To-Noise Ratio
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