Abstract 9576: A Nuclear Receptor-microRNA Circuit Links Control of Muscle Fiber Type to Energy Metabolism
Muscle fitness deteriorates in many chronic diseases including heart failure. The mechanisms involved in the coordinate control of the energy metabolic and structural programs that determine muscle fitness are unknown. Recent studies indicate that the nuclear receptors PPARβ (δ) and PPARα exert opposing actions upon muscle endurance in transgenic mice (MCK-PPAR mice). We took advantage of the divergent effects of PPARβ and PPARα in muscle to delineate the regulatory circuitry that orchestrates control of muscle fiber type and energy metabolic programs. Muscle fiber typing and transcriptional profiling revealed that type I fibers were induced in MCK-PPARβ soleus muscle but markedly suppressed in MCK-PPARα muscle. Conversely, type I fibers were significantly increased in PPARα null gastrocnemius muscle whereas shRNA-mediated “knockdown” (KD) of PPARβ in primary skeletal myotubes reduced type I gene markers. Muscle microRNA (miR) profiling revealed that levels of miR-208b and miR-499 were increased in MCK-PPARβ muscle but dramatically reduced in MCK-PPARα muscle. miR-208b and miR-499, which are embedded in the Myh7 and Myh7b genes, respectively, have been shown to activate slow myofiber gene expression. Combined inhibition of miR-208b and miR-499 abolished the enhancing effects of PPARβ on slow myofiber gene expression in MCK-PPARβ myotubes, while transgenic overexpression of miR-499 in MCK-PPARα muscle prevented the PPARα-mediated repression of the type I fiber program, and reversed the poor exercise performance phenotype of the MCK-PPARα mice. PPARβ was shown to mediate its effects on Myh7/miR-208b and Myh7b/miR-499 expression and type I fiber composition in cooperation with the nuclear receptor ERRγ. Lastly, type I fibers were reduced in muscle-specific ERRβ/γ-deficient muscle together with a profound reduction of miR-499 and miR-208b. Taken together, we have identified a nuclear receptor-miRNA circuit that allows for bi-directional, coordinate, control of muscle slow fiber proportion and energy metabolic capacity. This network shows promise as a target for novel therapeutic approaches aimed at enhancing muscle fitness in conditions that lead to muscle de-training and heart failure.
- © 2012 by American Heart Association, Inc.