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

• Published in: The Journal of clinical investigation 2013-06, Vol.123 (6), p.2564-2575
• Main 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
• Format: Article
• Language: English
• Subjects: Animals; Bioenergetics; Biomedical research; Biopsy; Cell Line; Cell receptors; Energy Metabolism; Exercise; Gene Expression; Gene Regulatory Networks; Genetic aspects; Genetic engineering; Genomics; Humans; Metabolism; Mice; Mice, Inbred C57BL; Mice, Inbred CBA; Mice, Transgenic; MicroRNA; MicroRNAs - genetics; MicroRNAs - metabolism; Muscle Fibers, Slow-Twitch - metabolism; Muscle, Skeletal - cytology; Muscle, Skeletal - metabolism; Muscular system; Myosin Heavy Chains - genetics; Myosin Heavy Chains - metabolism; Physiological aspects; PPAR alpha - metabolism; PPAR delta - metabolism; PPAR-beta - metabolism; Promoter Regions, Genetic; Proteins; Receptors, Estrogen - genetics; Receptors, Estrogen - metabolism; Regulation; Signal-To-Noise Ratio; Studies
• ISSN: 0021-9738; 1558-8238
• DOI: 10.1172/JCI67652

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.