Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism Article

International Collaboration

cited authors

  • Gan, Zhenji, Rumsey, John, Hazen, Bethany C., Lai, Ling, Leone, Teresa C., Vega, Rick B., Xie, Hui, Conley, Kevin E., Auwerx, Johan, Smith, Steven R., Olson, Eric N., Kralli, Anastasia, Kelly, Daniel P.

funding text

  • This work was supported by NIH grants RO1DK045416 (to D.P. Kelly), R01AR41928 (to K.E. Conley), R01AG030226 (to S.R. Smith), and. R01DK095686 (to A. Kralli) and a postdoctoral fellowship (11POST7420013) from the American Heart Association (to Z. Gan). E.N. Olson was supported by grants from the Robert A. Welch Foundation, the American Heart Association, Jon Holden DeHaan Foundation, and the Fondation Leducq TransAtlantic Network of Excellence in Cardiovascular Research Program. J. Auwerx was supported by grants from the ERC, the Ecole Polytechnique Federale de Lausanne, and the Swiss National Science Foundation. S.R. Smith was supported by Novartis Clinical Innovation Fund. Special thanks to Leslie Leinwand (University of Colorado) for providing the 1.0-kb mouse Myh7b promoter-reporter vector, Ronald Evans (Salk Institute for Biological Studies) for the anti-ERR gamma antibody, Sudip Bajpeyi (PBRC) for the initial characterization of the human muscle samples, and the Analytical Genomics Core and the Histology Core at Sanford-Burnham Medical Research Institute at Lake Nona. We are grateful for Lorenzo Thomas for assistance with manuscript preparation, Xiaoman Li (University of Central Florida) for help with bioinformatics analyses, and Lauren Ashley Gabriel for assistance with animal studies.

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 PPAR beta/delta was shown to activate muscle endurance programs in transgenic mice. In contrast, muscle-specific transgenic overexpression of the related nuclear receptor, PPAR alpha, results in reduced capacity for endurance exercise. We took advantage of the divergent actions of PPAR beta/delta and PPAR alpha 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, PPAR beta/delta and PPAR alpha 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 gamma (ERR gamma). 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 ERR gamma 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.

authors

Publication Date

  • June 1, 2013

webpage

published in

category

start page

  • 2564

end page

  • 2575

volume

  • 123

issue

  • 6

WoS Citations

  • 92

WoS References

  • 53