PGC-1α regulates a HIF2α-dependent switch in skeletal muscle fiber types

Abstract

The coactivator peroxisome proliferator-activated receptor-gamma coactivator 1 α (PGC-1α) coordinates a broad set of transcriptional programs that regulate the response of skeletal muscle to exercise. However, the complete transcriptional network controlled by PGC-1α has not been described. In this study, we used a qPCR-based screen of all known transcriptional components (Quanttrx) to identify transcription factors that are quantitatively regulated by PGC-1α in cultured skeletal muscle cells. This analysis identified hypoxia-inducible factor 2 α (HIF2α) as a major PGC-1α target in skeletal muscle that is positively regulated by both exercise and β-adrenergic signaling. This transcriptional regulation of HIF2α is completely dependent on the PGC-1α/ERRα complex and is further modulated by the action of SIRT1. Transcriptional profiling of HIF2α target genes in primary myotubes suggested an unexpected role for HIF2α in the regulation of muscle fiber types, specifically enhancing the expression of a slow twitch gene program. The PGC-1α–mediated switch to slow, oxidative fibers in vitro is dependent on HIF2α, and mice with a muscle-specific knockout of HIF2α increase the expression of genes and proteins characteristic of a fast-twitch fiber-type switch. These data indicate that HIF2α acts downstream of PGC-1α as a key regulator of a muscle fiber-type program and the adaptive response to exercise.

Myonectin (CTRP15), a Novel Myokine That Links Skeletal Muscle to Systemic Lipid Homeostasis

“…Exercise was confirmed by the expected reduction of fast-twitch muscle transcripts (troponin C2, myosin heavy chain polypeptide IIB (MHCIIB), and myosin heavy polypeptide 4 (MyoH4)) resulting from exercise-induced fiber type switch (supplemental Fig. S1) (38). In support of the in vitro data, myonectin expression was significantly induced in soleus and plantaris of mice given access to a running wheel for 2 weeks (Fig.…”

Inorganic Nitrate Mimics Exercise-Stimulated Muscular Fiber-Type Switching and Myokine and γ-Aminobutyric Acid Release

“…Rasbach et al identified that PGC1 induced fibertype switching requires functional, stabilized, HIFβ (14). Others have demonstrate that NO functions to stabilize HIF (6; 28).…”

“…Hypoxia-inducible factor β (HIFβ ) is a skeletal muscle-selective PGC1 transcriptional target that is positively regulated by exercise and has a key role in muscle function (14). HIFβ expression was increased in the soleus of nitrate treated rats ( (Fig.…”

“…Under normoxic conditions HIFβ protein is hydroxylated by prolyl hydroxylase domain containing enzymes (PHDs), ubiquitinated and degraded by the proteasome (27). HIFβ protein must be stabilized, following PGC1 -induced expression, to activate fiber-type switching (14); therefore the myotubes were also treated for 6 hours with 2,2-bipyridyl to inactivate PHDs and stabilize HIFβ . Expression of PGC1 was significantly and similarly increased in myotubes treated with either nitrate alone or nitrate in combination with 2,2-bipyridyl (Fig.…”

Mitochondrial Biogenesis through Activation of Nuclear Signaling Proteins

“…In mammalian cells, the PGC-1 family of coactivators (PGC-1a, PGC-1b, and PRC) potentiate the activity of several transcription factors involved in the basic functions of the mitochondrion as well as its rate of biogenesis (Puigserver and Spiegelman 2003;Kelly and Scarpulla 2004). Indeed, PGC1a and PGC-1b are sufficient to increase total mitochondrial mass, reactive oxygen species scavenging enzymes, oxidative phosphorylation components, mitochondrial metabolic pathways, protein import complexes, proteins involved in fission and fusion, and the levels of mitochondrial sirtuins (Mootha et al 2003;Uldry et al 2006;Cunningham et al 2007;Rasbach et al 2010;Handschin and Spiegelman 2011). This process occurs in part through the ability of PGC-1 proteins to potentiate the function of the NRFs, ERRs, and YY1.…”