2. Academic Validation
  3. ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

ERRγ Promotes Angiogenesis, Mitochondrial Biogenesis, and Oxidative Remodeling in PGC1α/β-Deficient Muscle

  • Cell Rep. 2018 Mar 6;22(10):2521-2529. doi: 10.1016/j.celrep.2018.02.047.
Weiwei Fan 1,  Nanhai He 1,  Chun Shi Lin 1,  Zong Wei 1,  Nasun Hah 1,  Wanda Waizenegger 1,  Ming-Xiao He 1,  Christopher Liddle 2,  Ruth T Yu 1,  Annette R Atkins 1,  Michael Downes 3,  Ronald M Evans 4
Affiliations

Affiliations

  • 1 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA.
  • 2 Storr Liver Centre, Westmead Institute for Medical Research and Sydney Medical School, University of Sydney, Westmead Hospital, Westmead, NSW 2145, Australia.
  • 3 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA. Electronic address: [email protected].
  • 4 Gene Expression Laboratory, Salk Institute for Biological Studies, La Jolla, CA, USA; Howard Hughes Medical Institute, Salk Institute for Biological Studies, La Jolla, CA, USA. Electronic address: [email protected].
PMID: 29514081 DOI: 10.1016/j.celrep.2018.02.047
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.

Keywords

ERR; PGC1; estrogen related receptor; exercise; fatty acid oxidation; glycolysis; mitochondria; muscle; muscle damage; vasculature.

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