Exercise Stimulates Pgc-1α Transcription in Skeletal Muscle through Activation of the p38 MAPK Pathway*

By T. Akimoto, S. Pohnert, Ping Li, Mei Zhang, C. Gumbs, Paul Rosenberg, R. S. Williams, Zhen Yan. Journal of Biological Chemistry, 2005

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Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α) promotes mitochondrial biogenesis and slow fiber formation in skeletal muscle. We hypothesized that activation of the p38 mitogen-activated protein kinase (MAPK) pathway in response to increased muscle activity stimulated Pgc-1α gene transcription as part of the mechanisms for skeletal muscle adaptation. Here we report that a single bout of voluntary running induced a transient increase of Pgc-1α mRNA expression in mouse plantaris muscle, concurrent with an activation of the p38 MAPK pathway. Activation of the p38 MAPK pathway in cultured C2C12 myocytes stimulated Pgc-1α promoter activity, which could be blocked by the specific inhibitors of p38, SB203580 and SB202190, or a dominant negative p38. Furthermore, the p38-mediated increase in Pgc-1α promoter activity was enhanced by increased expression of the downstream transcription factor ATF2 and completely blocked by ATF2ΔN, a dominant negative ATF2. Skeletal muscle-specific expression of a constitutively active activator of p38, MKK6E, in transgenic mice resulted in enhanced Pgc-1α and cytochrome oxidase IV protein expression in fast-twitch skeletal muscles. These findings suggest that contractile activity-induced activation of the p38 MAPK pathway promotes Pgc-1α gene expression and skeletal muscle adaptation.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/d7d39bf3ab38edbcff0c280b20aa96cc56944316

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Citations in the corpus

Fiber types in mammalian skeletal muscles. (2011, background): “The transcription of PGC-1 is regulated by calcium-dependent pathways, such as CaMK and calcineurin (316), by energy deprivation via AMPK activity (771, 786, 901) and by p38 MAPK via the transcription factor ATF2 (8).”
PGC-1 coactivators: inducible regulators of energy metabolism in health and disease. (2006, background): “Recently, the p38 MAPK and AMPK pathways have also been implicated in the control of PGC-1α expression in skeletal muscle after exercise training (43, 67).”
Meteorin-like is a hormone that regulates immune-adipose interactions to increase beige fat thermogenesis (2014, background): “PGC1a (now termed PGC1a1) itself is induced by endurance exercise in mice and humans (Akimoto et al., 2005; Mathai et al., 2008).”
Integrative biology of exercise. (2014, neutral): “, 2001) and also increases PGC-1a expression by phosphorylating the transcription factor ATF-2, which in turn increases PGC-1a protein abundance by binding to and activating the CREB site on the PGC-1a promoter (Akimoto et al., 2005).”
Transcriptional paradigms in mammalian mitochondrial biogenesis and function. (2008, background): “These changes are presumed to result from activation of a specific program of gene expression by PGC-1␤ through transcription factor targets such as MEF2, ERR␣, and PPAR␣ among others.”
The Molecular Bases of Training Adaptation (2007, background): “clear role for p38 in the adaptation response to exercise (Akimoto et al. 2005; Li et al. 2005; Lluis et al. 2006).”
Regulation of mitochondrial biogenesis (2010, background): “Transgenic mice specifi cally overexpressing p38 MAPK in skeletal muscle show enhanced PGC-1α expression and increased mitochondrial proteins [37].”
Metabolic Adaptations to Short-term High-Intensity Interval Training: A Little Pain for a Lot of Gain? (2008, background): “Furthermore, constitutive activation of p38 MAPK in fast muscle fibers results in enhanced mitochondrial enzyme expression (1), suggesting that p38 MAPK is an important mediator of the adaptive response to exercise.”