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  • Previously we have shown that the overexpression


    Previously, we have shown that the overexpression of ERRγ induces exercise-like oxidative muscle remodeling without engaging changes in the expression level or activity of PGC1α (Narkar et al., 2011). In this study, overexpression of ERRγ in PKO muscle reveals that ERRγ-activated target genes can achieve almost all aspects of oxidative muscle remodeling in the absence of PGC1α/β, including oxidative fiber-type transformation, angiogenesis, and increased mitochondrial Wnt-C59 metabolism. These data highly suggest that PGC1α and PGC1β are dispensable for ERRγ-induced oxidative muscle remodeling. Both oxidative fiber-type determination and angiogenesis are minimally affected in PKO muscle, with no significant reduction in genes involved in these pathways, suggesting PGC1α and PGC1β are not required for their basal functions. Our RNA-seq and ChIP-seq studies identify a network of 629 ERRγ directly controlled genes that are induced by its overexpression. These genes are highly enriched in all previously mentioned oxidative muscle remodeling processes, confirming the direct role of ERRγ in transcriptionally regulating oxidative muscle remodeling. PGC1α and PGC1β are transcriptional co-activators and require DNA binding TFs to activate downstream genes. PGC1α is known to drive oxidative muscle remodeling by activating the same set of genes that are ERRγ direct targets (Lin et al., 2002, Arany, 2008), indicating ERRα/γ as its primary partner TFs during PGC1α-induced oxidative muscle remodeling, although further studies are required to confirm this. We have also demonstrated that exercise training alone is sufficient to significantly restore mitochondrial energetic dysfunctions and improve running performance in PKO mice (Figure S4F). Surprisingly, these improvements are comparable to those achieved by ERRγ overexpression. This confirms that exercise has concurrent benefits on oxidative muscle remodeling that are PGC1α/β independent. Training, combined with ERRγ overexpression, further boosts mitochondrial energetic functions, resulting in a 5-fold increase in running time and indicating that ERRγ is not simply an exercise surrogate. In summary, these results suggest that while exercise activates PGC1α/β, many of its benefits can be achieved independently, with notable cross talk with ERRγ and its target genes (Figure 4F).
    Experimental Procedures
    Acknowledgments We thank C. Brondos and E. Ong for administrative assistance, Y. Dai and J. Nery for assistance with library preparation and sequencing, and H. Juguilon and J. Alvarez for technical assistance. This work was funded by grants from the NIH (DK057978, HL105278, HL088093, ES010337, and CA014195) and the National Health and Medical Research Council of Australia Project (512354 and 632886 to C.L. and M.D.), as well as the Leona M. and Harry B. Helmsley Charitable Trust (2017PG-MED001), the Samuel Waxman Cancer Research Foundation, Ipsen/Biomeasure, and the Glenn Foundation for Medical Research. R.M.E. is an investigator of the Howard Hughes Medical Institute and the March of Dimes Chair in Molecular and Developmental Biology at the Salk Institute. This work was sponsored by the Department of the Navy, Office of Naval Research, through grant N00014-16-1-3159. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the Office of Naval Research. Research reported in this publication was supported by the National Institute of Environmental Health Sciences of the National Institutes of Health under award number P42ES010337. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
    Main Text Glucose-stimulated insulin secretion (GSIS) is the ultimate effector in governing glucose homeostasis, and this indispensable ability of the mature β cell is empowered in the early postnatal period (Otonkoski et al., 1988). The functional maturation is associated with a transition from glycolysis to oxidative phosphorylation for the efficient glucose-induced ATP production through modifications in gene expression programs. Alterations in the extracellular milieu, such as the presence of thyroid hormone or the transition from weaning to consumption of a high-carbohydrate diet, are known to trigger functional maturation in vivo (Aguayo-Mazzucato et al., 2013, Stolovich-Rain et al., 2015). However, the key mechanism(s) during active β cell maturation has remained elusive. This is especially evident in current efforts to coax β-like cells, derived from human embryonic or induced pluripotent stem cells, to functional maturity in vitro.