Regulation of PPARGC1A gene expression in trained and untrained human skeletal muscle.

Daniil V Popov,Pavel A Makhnovskii,Olga L Vinogradova,Evgeny A Lysenko,Nadia S Kurochkina

doi:10.14814/phy2.13543

Abstract

Promoter‐specific expression of the PPARGC1A gene in untrained and trained human skeletal muscle was investigated. Ten untrained males performed a one‐legged knee extension exercise (for 60 min) with the same relative intensity both before and after 8 weeks of cycling training. Samples from the m. vastus lateralis of each leg were taken before and after exercise. Postexercise PPARGC1A gene expression via the canonical promoter increased by ~100% (P < 0.05) in exercised and nonexercised untrained muscles, but did not change in either leg after training program. In untrained and trained exercised muscle, PPARGC1A gene expression via the alternative promoter increased by two orders of magnitude (P < 0.01). We found increases in postexercise content of dephosphorylated (activated) CRTC2, a coactivator of CREB1, in untrained exercised muscle and in expression of CREB1‐related genes in untrained and trained exercised muscle (P < 0.01–0.05); this may partially explain the increased expression of PPARGC1A via the alternative promoter. In addition, comparison of the regulatory regions of both promoters revealed unique conserved motifs in the alternative promoter that were associated with transcriptional repressors SNAI1 and HIC1. In conclusion, in untrained muscle, exercise‐induced expression of the PPARGC1A gene via the canonical promoter may be regulated by systemic factors, while in trained muscle the canonical promoter shows constitutive expression at rest and after exercise. Exercise‐induced expression of PPARGC1A via the alternative promoter relates to intramuscular factors and associates with activation of CRTC2‐CREB1. Apparently, expression via the alternative promoter is regulated by other transcription factors, particularly repressors.

Highlights

In skeletal muscle, peroxisome proliferator-activated receptor c coactivator 1a (PGC-1a, encoded by the PPARGC1A gene) plays an important role in regulating mitochondrial biogenesis and in adaptation to aerobic training
Physiological Reports published by Wiley Periodicals, Inc. on behalf of The Physiological Society and the American Physiological Society
We found the increase in the basal phosphorylation of CaMKIIThr286 (P < 0.01) and CREB1Ser133 (P < 0.05) in endurance-trained muscle compared to untrained muscle (Fig. 6)

Summary

Introduction

Peroxisome proliferator-activated receptor c coactivator 1a (PGC-1a, encoded by the PPARGC1A gene) plays an important role in regulating mitochondrial biogenesis and in adaptation to aerobic training. Acute exercise activates PGC-1a, thereby modulating the transcriptional activity of its partners and regulating expression of genes involved in mitochondrial biogenesis, angiogenesis, and fat and carbohydrate metabolism (Scarpulla 2008; Lira et al 2010; Narkar et al 2011; Kupr and Handschin 2015). An increase in PPARGC1A gene expression and PGC-1a protein content occurs several hours after muscle activity, which may stimulate mitochondrial biogenesis at the later stages of recovery (Wright et al 2007; Ikeda et al 2008). In rodent and human skeletal muscle, the PPARGC1A gene can be expressed via the a 2017 The Authors.

Results

Discussion

Conclusion