Gan, ZhenjiRumsey, JohnHazen, Bethany C.Lai, LingLeone, Teresa C.Vega, Rick B.Xie, HuiConley, Kevin E.Auwerx, JohanSmith, Steven R.Olson, Eric N.Kralli, AnastasiaKelly, Daniel P.2013-10-012013-10-012013-10-01201310.1172/Jci67652https://infoscience.epfl.ch/handle/20.500.14299/95272WOS:000320093100027The 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.text::journal::journal article::research article