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- Title
Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.
- Authors
Zhenji Gan; Rumsey, John; Hazen, Bethany C.; Ling Lai; Leone, Teresa C.; Vega, Rick B.; Hui Xie; Conley, Kevin E.; Auwerx, Johan; Smith, Steven R.; Olson, Eric N.; Kralli, Anastasia; Kelly, Daniel P.; Gan, Zhenji; Lai, Ling; Xie, Hui
- 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.
- Publication
Journal of Clinical Investigation, 2013, Vol 123, Issue 6, p2564
- ISSN
0021-9738
- Publication type
Academic Journal
- DOI
10.1172/JCI67652