@article{3a39e9012e67478d96fed451796dfa76,
title = "ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle",
abstract = "PGC1α is a pleiotropic co-factor that affects angiogenesis, mitochondrial biogenesis, and oxidative muscle remodeling via its association with multiple transcription factors, including the master oxidative nuclear receptor ERRγ. To decipher their epistatic relationship, we explored ERRγ gain of function in muscle-specific PGC1α/β double-knockout (PKO) mice. ERRγ-driven transcriptional reprogramming largely rescues muscle damage and improves muscle function in PKO mice, inducing mitochondrial biogenesis, antioxidant defense, angiogenesis, and a glycolytic-to-oxidative fiber-type transformation independent of PGC1α/β. Furthermore, in combination with voluntary exercise, ERRγ gain of function largely restores mitochondrial energetic deficits in PKO muscle, resulting in a 5-fold increase in running performance. Thus, while PGC1s can interact with multiple transcription factors, these findings implicate ERRs as the major molecular target through which PGC1α/β regulates both innate and adaptive energy metabolism. Fan et al. demonstrate that ERRγ improves mitochondrial energy metabolism in PGC1α/β-deficient muscle through its direct activation of target genes. Such ERRγ-induced effects are further boosted in combination with exercise training, suggesting ERRs are the major transcriptional modulator through which PGC1α/β regulates both innate and adaptive energy metabolism.",
keywords = "ERR, PGC1, estrogen related receptor, exercise, fatty acid oxidation, glycolysis, mitochondria, muscle, muscle damage, vasculature",
author = "Weiwei Fan and Nanhai He and Lin, {Chun Shi} and Zong Wei and Nasun Hah and Wanda Waizenegger and He, {Ming Xiao} and Christopher Liddle and Yu, {Ruth T.} and Atkins, {Annette R.} and Michael Downes and Evans, {Ronald M.}",
note = "Funding Information: 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. Funding Information: 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. Publisher Copyright: {\textcopyright} 2018 The Author(s)",
year = "2018",
month = mar,
day = "6",
doi = "10.1016/j.celrep.2018.02.047",
language = "English (US)",
volume = "22",
pages = "2521--2529",
journal = "Cell Reports",
issn = "2211-1247",
publisher = "Cell Press",
number = "10",
}