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Estrogen‐related Receptor α Overexpression Drives a Metabolic and Gene Expression Program Mimicking Aerobic Exercise in Skeletal Muscle
Author(s) -
Huss Janice M.,
Hamilton Angelica,
Li Jing
Publication year - 2018
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2018.32.1_supplement.857.3
Subject(s) - mitochondrial biogenesis , endocrinology , skeletal muscle , citrate synthase , medicine , pdk4 , biology , beta oxidation , mitochondrion , gene expression , microbiology and biotechnology , biochemistry , metabolism , gene , enzyme
Aerobic exercise is considered one of the most effective interventions to prevent obesity and type 2 diabetes (T2D). Exercise increases skeletal muscle insulin sensitivity by stimulating mitochondrial respiration and fatty acid oxidation through coordinated regulation of metabolic genes. Transcriptional pathways that regulate exercise‐induced metabolic gene programs present an attractive class of therapeutic targets to combat obesity and related metabolic diseases. We and others have shown that the Estrogen‐related Receptor α (ERRα) nuclear receptor regulates mitochondrial biogenesis, respiration and fatty acid oxidation and is required for metabolic reprogramming in response to exercise training. The objective of these studies is to determine whether ERRα over‐expression is sufficient to mediate exercise‐induced adaptations in muscle. We generated a conditional ERRα transgenic mouse line that expresses the Flag‐tagged human ERRα in skeletal muscle‐specific manner when crossed with Mck‐Cre recombinase mice (ERRαMOE). We examined gene expression (trancript and protein) and characterized the metabolic phentoype of the ERRαMOE mice. ERRαMOE mice exhibited a reddening of the superficial gastrocnemius and quadriceps, characteristic of oxidative muscles, accompanied by a reciprocal change in myosin heavy chain (MHC) IIb (−35%) and IIa (+80%) expression. Mitochondrial content was higher in skeletal muscle and heart, but not in non‐muscle tissues, based on mtDNA quantitation and citrate synthase protein expression. Consistently, basal (+32%) and maximal (+70%) O 2 consumption rates were increased in FDB fibers isolated from ERRα‐MOE compared to WT. Signaling through the AMP‐activated kinase (AMPK) pathway, which mediates exercise‐dependent metabolic reprogramming, was unchanged in the basal state; however, maximal activation by AICAR was enhanced in ERRα‐overexpressing myotubes. We assessed systemic glucose homeostasis in adult chow fed mice. Although fasting glucose (6 hr) was slightly lower in ERRαMOE, no significant difference in glucose tolerance was observed. However, the results of insulin tolerance tests showed that ERRαMOE mice were more insulin sensitive than WT. In future studies we will investigate whether ERRα activation in skeletal muscle protects against high fat diet‐induced insulin resistance. Based on the results from these studies, ERRα over‐expression mimics the effects of exercise on skeletal muscle mitochondrial respiratory capacity and improves whole body insulin sensitivity. Support or Funding Information Supported by Diabetes and Metabolic Research Institute (DMRI) and Shared Resource Pilot Awards from the City of Hope and NIH U24DK097748 This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .