β-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1α in skeletal muscle

Abstract

-Adrenergic stimulation does not activate p38 MAP kinase or induce PGC-1␣ in skeletal muscle. Am J Physiol Endocrinol Metab 304: E844 -E852, 2013. First published March 5, 2013 doi:10.1152/ajpendo.00581.2012.-There are reports that the ␤-adrenergic agonist clenbuterol induces a large increase in peroxisome proliferator-activated receptor-␥ coactivator-1␣ (PGC-1␣) in skeletal muscle. This has led to the hypothesis that the increases in PGC-1␣ and mitochondrial biogenesis induced in muscle by endurance exercise are mediated by catecholamines. In the present study, we evaluated this possibility and found that injecting rats with clenbuterol or norepinephrine induced large increases in PGC-1␣ and mitochondrial proteins in brown adipose tissue but had no effect on PGC-1␣ expression or mitochondrial biogenesis in skeletal muscle. In brown adipocytes, the increase in PGC-1␣ expression induced by ␤-adrenergic stimulation is mediated by activation of p38 mitogenactivated protein kinase (p38 MAPK), which phosphorylates and activates the cAMP response element binding protein (CREB) family member activating transcription factor 2 (ATF2), which binds to a cyclic AMP response element (CRE) in the PGC-1␣ promoter and mediates the increase in PGC-1␣ transcription. Phospho-CREB does not have this effect. Our results show that the reason for the lack of effect of ␤-adrenergic stimulation on PGC-1␣ expression in muscle is that catecholamines do not activate p38 or increase ATF2 phosphorylation in muscle.phospho-ATF2; clenbuterol; norepinephrine; mitochondria; brown fat PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␥ coactivator 1␣ (PGC-1␣) was discovered during a study of the regulation of uncoupling protein-1 (UCP1) expression by the nuclear receptor PPAR␥ during induction of adaptive thermogenesis in brown fat (34) PGC-1␣ expression is powerfully induced in brown fat cells of mice exposed to cold (34). This effect is mediated by the cold-induced increase in catecholamine secretion and is mimicked by treatment with ␤ 2

Effects of Resveratrol and SIRT1 on PGC-1α Activity and Mitochondrial Biogenesis: A Reevaluation

“…This is in contrast to PGC-1α activation by phosphorylation by AMPK and/or p38 MAPK, which is associated with an increase in PGC-1α expression (Figure 3B) [22],[26]–[29]. A probable explanation for this difference is that AMPK and p38 MAPK do not just activate PGC-1, but also activate the transcription factors that induce increased PGC-1α expression.…”

Beta2‐adrenoceptor agonist salbutamol increases protein turnover rates and alters signalling in skeletal muscle after resistance exercise in young men

“…) and some studies report no effect of beta 2 ‐adrenergic stimulation on p38‐MAPK phosphorylation (Kim et al . ). Reports in mice also indicate that beta 2 ‐adrenergic stimulation does not phosphorylate mTOR Ser2448 , although it may phosphorylate mTOR Ser2481 (Sato et al .…”

The hitchhiker’s guide to PGC-1α isoform structure and biological functions

“…Moreover, detecting total Pgc-1α levels (which can be done by targeting exon 2, shared by all known isoforms except L-PGC-1α) will, in many cases, mask important changes in the levels of specific isoforms. For example, targeting exon 1a to analyse the effects of clenbuterol administration on mouse muscle PGC-1α expression will detect the overall change in isoforms expressed from the canonical promoter, but fail to measure the induction of the alternative promoter [59]. However, since most transcripts share part of their sequence, real-time PCR is not always a viable approach for reliably measuring PGC-1α isoform expression levels.…”