title: Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism.
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.
authors.affiliation: Diabetes and Obesity Research Center, Sanford-Burnham Medical Research Institute, Orlando, Florida 32827, USA.
authors.forename: Zhenji
authors.initials: Z
authors.lastname: Gan
authors.forename: John
authors.initials: J
authors.lastname: Rumsey
authors.forename: Bethany C
authors.initials: BC
authors.lastname: Hazen
authors.forename: Ling
authors.initials: L
authors.lastname: Lai
authors.forename: Teresa C
authors.initials: TC
authors.lastname: Leone
authors.forename: Rick B
authors.initials: RB
authors.lastname: Vega
authors.forename: Hui
authors.initials: H
authors.lastname: Xie
authors.forename: Kevin E
authors.initials: KE
authors.lastname: Conley
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.forename: Steven R
authors.initials: SR
authors.lastname: Smith
authors.forename: Eric N
authors.initials: EN
authors.lastname: Olson
authors.forename: Anastasia
authors.initials: A
authors.lastname: Kralli
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Kelly
mesh_terms: D000818:Animals; D002460:Cell Line; D004734:Energy Metabolism; D015870:Gene Expression; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D018657:Muscle Fibers, Slow-Twitch / Q000378:metabolism*; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000378:metabolism; D047494:PPAR delta / Q000378:metabolism; D048068:PPAR-beta / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011960:Receptors, Estrogen / Q000235:genetics / Q000378:metabolism; D059629:Signal-To-Noise Ratio
chemical_list: C490916:Esrrg protein, mouse; C573190:MIRN499 microRNA, mouse; D035683:MicroRNAs; C543978:Mirn208 microRNA, mouse; C551613:Myh7 protein, mouse; D047493:PPAR alpha; D047494:PPAR delta; D048068:PPAR-beta; D011960:Receptors, Estrogen; D018995:Myosin Heavy Chains