Nuclear receptor/microRNA circuitry links muscle fiber type to energy metabolism
Zhenji Gan, … , Anastasia Kralli, Daniel P. Kelly
Zhenji Gan, … , Anastasia Kralli, Daniel P. Kelly
Published June 3, 2013; First published May 8, 2013
Citation Information: J Clin Invest. 2013;123(6):2564-2575. https://doi.org/10.1172/JCI67652.
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Research Article Muscle biology

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

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

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Figure 1

PPARβ/δ and PPARα regulate opposing muscle fiber-type programs.

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PPARβ/δ and PPARα regulate opposing muscle fiber-type programs. (A) Expr...
(A) Expression of the slow-twitch myosin Myh7 and representative slow/fast-twitch troponin genes (qRT-PCR) in soleus muscle from indicated genotypes (n = 5–13 mice per group). (B) Cross-section of soleus muscle from 3- to 4-month-old male MCK-PPARβ/δ and MCK-PPARα mice (n = 5 mice per group) stained for myosin I ATPase activity as well as MHC fiber typing by immunofluorescence (IF) of soleus of indicated genotypes (MHC1 [green], MHC2a [blue], MHC2b [red], and MHC2x [unstained]). Scale bar: 500 μm. (C) Quantification of immunofluorescence data shown in B expressed as mean percentage total muscle fibers. (D) Muscle fiber typing in GC of WT and PPARα-null (PPARα KO) mice (n = 5 mice per group) as described in B. Scale bar: 500 μm. (E) Quantification of contractile protein gene expression in GC from indicated genotypes (n = 6–9 mice per group). (F) qRT-PCR results and Western blot analysis of Myh expression in skeletal myotubes harvested from WT mice subjected to adenovirus-based overexpression of PPARβ/δ shRNA (KD) compared with control shRNA (con) (n = 3). *P < 0.05 vs. corresponding controls. All values represent mean ± SEM and are shown as arbitrary units (AU) normalized to corresponding controls.