Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism
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, 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
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.
Trial registration: ClinicalTrials.gov NCT00401791.
Figures
![Figure 1. PPARβ/δ and PPARα regulate opposing…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f1.jpg)
![Figure 2. PPARβ/δ and PPARα control distinct…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f2.jpg)
![Figure 3. miR-208b and miR-499 mediate opposing…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f3.jpg)
![Figure 4. PPARβ/δ and ERRγ function cooperatively…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f4.jpg)
![Figure 5. ERRβ/ERRγ are required for type…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f5.jpg)
![Figure 6. The ERRγ/miRNA circuit is induced…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f6.jpg)
![Figure 7. ERRγ/miRNA axis is associated with…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f7.jpg)
![Figure 8. Model of nuclear receptor/miRNA circuit…](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/3668841/bin/JCI67652.f8.jpg)
Source: PubMed