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Dysregulation of the Energy‐sensing AMPK Pathway in Skeletal Muscle‐specific ERRα−/− Mice
Author(s) -
Huss Janice,
McDonald Marisa,
Hamilton Angie
Publication year - 2016
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.30.1_supplement.1008.4
Subject(s) - ampk , endocrinology , medicine , amp activated protein kinase , skeletal muscle , protein kinase a , chemistry , activator (genetics) , phosphorylation , receptor , biochemistry
The AMP‐activated protein kinase (AMPK) pathway is involved in both acute control and long‐term metabolic regulation in skeletal muscle. AMPK is activated during exercise and is required for many of the adaptive responses to endurance exercise, mediating its effects via transcription factors that control metabolic gene programs. We previously showed that the Estrogen‐related Receptor α (ERRα) is activated after an exercise bout and in response to AICAR, a pharmacologic AMPK activator. The muscle‐specific ERRα−/− mice (M‐ERRα−/−) exhibit a blunted metabolic response to endurance training. The aim of the present study is to test the hypothesis that AMPK signaling may be altered in ERRα‐deficient muscles and thus contribute to the exercise phenotype in these mice. M‐ERRα−/− and M‐ERRαWT (WT) mice were subjected to a single treadmill exercise bout (1hr) or an acute (30 min) AICAR treatment. M‐ERRα−/− muscles had reduced basal activity of both AMPK and its upstream kinase, LKB1, as assessed by western detection of the phosphorylated proteins. Despite reduced baseline activity, AMPK activation in response to acute exercise was maintained in the M‐ERRα−/− mice. Using IP‐activity assays we showed that AMPKα2 isoform specific activity was reduced at baseline in M‐ERRα−/− white vastus compared to WT. However, AMPKα2 was more robustly stimulated in the M‐ERRα−/− muscle in response to AICAR treatment (6.2‐fold, M‐ERRα−/− vs.2.3‐fold, WT). This is consistent with the greater reduction in blood glucose 30 min post‐AICAR administration observed in the M‐ERRα−/− mice, resulting from AMPK‐stimulated glucose uptake. Analysis of transcripts involved in AMPK signaling revealed that LKB1 and AMPKβ2 isoforms were consistently downregulated in ERRα‐deficient muscles or with ERRα inhibition in myocytes. We demonstrated that the regulatory regions of the Stk11 and Prkab2 genes that encode these transcripts, are directly regulated by ERRα in transient transfection experiments in myocytes. Thus, our data suggest that ERRα is involved in regulating AMPK pathway activity in skeletal muscle which can alter the responsiveness of the pathway to energetic and pharmacologic stimulation. Support or Funding Information Support by NIH R01DK74700 and Diabetes and Metabolic Research Institute, City of Hope..