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Estrogen-related receptor ? regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway.

ABSTRACT: Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERR?'s role in regulating myocyte differentiation is not known. ERR? and peroxisome proliferator-activated receptor-? coactivator-1? (PGC-1?) are coordinately upregulated with metabolic and skeletal muscle-specific genes early in myogenesis. We analyzed effects of ERR? overexpression and loss of function in myogenic models. In C2C12 myocytes ERR? overexpression accelerated differentiation, whereas XCT790 treatment delayed myogenesis and resulted in myotubes with fewer mitochondria and disorganized sarcomeres. ERR?-/- primary myocytes showed delayed myogenesis, resulting in structurally immature myotubes with reduced sarcomeric assembly and mitochondrial function. However, sarcomeric and metabolic gene expression was unaffected or upregulated in ERR?-/- cells. Instead, ERR?-/- myocytes exhibited aberrant ERK activation early in myogenesis, consistent with delayed myotube formation. XCT790 treatment also increased ERK phosphorylation in C2C12, whereas ERR? overexpression decreased early ERK activation, consistent with the opposing effects of these treatments on differentiation. The transient induction of MAP kinase phosphatase-1 (MKP-1), which mediates ERK dephosphorylation at the onset of myogenesis, was lost in ERR?-/- myocytes and in XCT790-treated C2C12. The ERR?-PGC-1? complex activates the Dusp1 gene, which encodes MKP-1, and ERR? occupies the proximal 5' regulatory region during early differentiation in C2C12 myocytes. Finally, treatment of ERR?-/- myocytes with MEK inhibitors rescued normal ERK signaling and myogenesis. Collectively, these data demonstrate that ERR? is required for normal skeletal myocyte differentiation via modulation of MAP kinase signaling.

SUBMITTER: Murray J

PROVIDER: S-EPMC3174569 | biostudies-literature | 2011 Sep

REPOSITORIES: biostudies-literature

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Estrogen-related receptor α regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway.

Murray Jennifer J Huss Janice M JM

American journal of physiology. Cell physiology 20110511 3

Myocyte differentiation involves complex interactions between signal transduction pathways and transcription factors. The estrogen-related receptors (ERRs) regulate energy substrate uptake, mitochondrial respiration, and biogenesis and may target structural gene programs in striated muscle. However, ERRα's role in regulating myocyte differentiation is not known. ERRα and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC-1α) are coordinately upregulated with metabolic and skeletal ...[more]

PMID: 21562305

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Project description:In many skeletal diseases, including osteoporosis and disuse osteopenia, defective osteoblast differentiation is associated with increased marrow adipogenesis. The relative activity of two transcription factors, RUNX2 and PPARγ, controls whether a mesenchymal cell will differentiate into an osteoblast or adipocyte. Herein we show that the ERK/MAP kinase pathway, an important mediator of mechanical and hormonal signals in bone, stimulates osteoblastogenesis and inhibits adipogenesis via phosphorylation of RUNX2 and PPARγ. Induction of osteoblastogenesis in ST2 mesenchymal cells was associated with increased MAPK activity and RUNX2 phosphorylation. Under these conditions PPARγ phosphorylation also increased, but adipogenesis was inhibited. In contrast, during adipogenesis MAPK activity and phosphorylation of both transcription factors was reduced. RUNX2 phosphorylation and transcriptional activity were directly stimulated by MAPK, a response requiring phosphorylation at S301 and S319. MAPK also inhibited PPARγ-dependent transcription via S112 phosphorylation. Stimulation of MAPK increased osteoblastogenesis and inhibited adipogenesis, while dominant-negative suppression of activity had the opposite effect. In rescue experiments using Runx2(-/-) mouse embryo fibroblasts (MEFs), wild type or, to a greater extent, phosphomimetic mutant RUNX2 (S301E,S319E) stimulated osteoblastogenesis while suppressing adipogenesis. In contrast, a phosphorylation-deficient RUNX2 mutant (S301A,S319A) had reduced activity. Conversely, wild type or, to a greater extent, phosphorylation-resistant S112A mutant PPARγ strongly stimulated adipogenesis and inhibited osteoblastogenesis in Pparg(-/-) MEFs, while S112E mutant PPARγ was less active. Competition between RUNX2 and PPARγ was also observed at the transcriptional level. Together, these studies highlight the importance of MAP kinase signaling and RUNX2/PPARγ phosphorylation in the control of osteoblast and adipocyte lineages.

Dataset Information

Estrogen-related receptor ? regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway.

Publications

Estrogen-related receptor α regulates skeletal myocyte differentiation via modulation of the ERK MAP kinase pathway.

Similar Datasets

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