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Prostaglandin F2(alpha) stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway.

Horsley V, Pavlath GK - J. Cell Biol. (2003)

Bottom Line: We demonstrate that prostaglandin F2alpha (PGF2alpha) as well as two analogues augment muscle cell size in vitro.We show that NFAT is activated by PGF2alpha, and the isoform NFATC2 is required for PGF2alpha-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling.Given this novel role for PGF2alpha in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.

View Article: PubMed Central - PubMed

Affiliation: Cell and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.

ABSTRACT
Skeletal muscle growth requires multiple steps to form large multinucleated muscle cells. Molecules that stimulate muscle growth may be therapeutic for muscle loss associated with aging, injury, or disease. However, few factors are known to increase muscle cell size. We demonstrate that prostaglandin F2alpha (PGF2alpha) as well as two analogues augment muscle cell size in vitro. This increased myotube size is not due to PGF2alpha-enhancing cell fusion that initially forms myotubes, but rather to PGF2alpha recruiting the fusion of cells with preexisting multinucleated cells. This growth is mediated through the PGF2alpha receptor (FP receptor). As the FP receptor can increase levels of intracellular calcium, the involvement of the calcium-regulated transcription factor nuclear factor of activated T cells (NFAT) in mediating PGF2alpha-enhanced cell growth was examined. We show that NFAT is activated by PGF2alpha, and the isoform NFATC2 is required for PGF2alpha-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling. Given this novel role for PGF2alpha in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.

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Related in: MedlinePlus

PGF2α-mediated muscle growth occurs through the FP receptor. (A) Primary myoblasts were induced to differentiate in the presence of vehicle, 10−6 M fluprostenol, or 10−6 M AL-8810 and immunostained for EMyHC after 48 h. Bar, 60 μm. (B) Cells were treated with the indicated doses of fluprostenol for 48 h and analyzed as in Fig. 1 E. (C) After 24 h in DM, cells were treated with indicated doses of AL-8810 for 24 h and analyzed as in Fig. 1 E. Data are mean ± SEM of three independent experiments. *Significantly different from vehicle, P < 0.05.
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fig2: PGF2α-mediated muscle growth occurs through the FP receptor. (A) Primary myoblasts were induced to differentiate in the presence of vehicle, 10−6 M fluprostenol, or 10−6 M AL-8810 and immunostained for EMyHC after 48 h. Bar, 60 μm. (B) Cells were treated with the indicated doses of fluprostenol for 48 h and analyzed as in Fig. 1 E. (C) After 24 h in DM, cells were treated with indicated doses of AL-8810 for 24 h and analyzed as in Fig. 1 E. Data are mean ± SEM of three independent experiments. *Significantly different from vehicle, P < 0.05.

Mentions: PGF2α primarily mediates its cellular effects by binding with high affinity (Ki= 3.4 nM) to the FP prostanoid receptor (Breyer et al., 2001). However, PGF2α can also bind with lower affinity to EP1 (Ki= 1,300 nM) and EP3 (Ki= 75 nM) receptors. To determine if muscle growth induced by the addition of PGF2α occurs through the FP receptor, cells were treated with a specific FP agonist (fluprostenol) that has a similar affinity for the FP receptor as PGF2α (Ki= 3.8 nM) but does not bind to other prostanoid receptors (Breyer et al., 2001). Fluprostenol induces an increase in muscle cell size (Fig. 2 A) as well as an increase in myonuclear number to the same extent as PGF2α at similar doses (Fig. 2 B).


Prostaglandin F2(alpha) stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway.

Horsley V, Pavlath GK - J. Cell Biol. (2003)

PGF2α-mediated muscle growth occurs through the FP receptor. (A) Primary myoblasts were induced to differentiate in the presence of vehicle, 10−6 M fluprostenol, or 10−6 M AL-8810 and immunostained for EMyHC after 48 h. Bar, 60 μm. (B) Cells were treated with the indicated doses of fluprostenol for 48 h and analyzed as in Fig. 1 E. (C) After 24 h in DM, cells were treated with indicated doses of AL-8810 for 24 h and analyzed as in Fig. 1 E. Data are mean ± SEM of three independent experiments. *Significantly different from vehicle, P < 0.05.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172881&req=5

fig2: PGF2α-mediated muscle growth occurs through the FP receptor. (A) Primary myoblasts were induced to differentiate in the presence of vehicle, 10−6 M fluprostenol, or 10−6 M AL-8810 and immunostained for EMyHC after 48 h. Bar, 60 μm. (B) Cells were treated with the indicated doses of fluprostenol for 48 h and analyzed as in Fig. 1 E. (C) After 24 h in DM, cells were treated with indicated doses of AL-8810 for 24 h and analyzed as in Fig. 1 E. Data are mean ± SEM of three independent experiments. *Significantly different from vehicle, P < 0.05.
Mentions: PGF2α primarily mediates its cellular effects by binding with high affinity (Ki= 3.4 nM) to the FP prostanoid receptor (Breyer et al., 2001). However, PGF2α can also bind with lower affinity to EP1 (Ki= 1,300 nM) and EP3 (Ki= 75 nM) receptors. To determine if muscle growth induced by the addition of PGF2α occurs through the FP receptor, cells were treated with a specific FP agonist (fluprostenol) that has a similar affinity for the FP receptor as PGF2α (Ki= 3.8 nM) but does not bind to other prostanoid receptors (Breyer et al., 2001). Fluprostenol induces an increase in muscle cell size (Fig. 2 A) as well as an increase in myonuclear number to the same extent as PGF2α at similar doses (Fig. 2 B).

Bottom Line: We demonstrate that prostaglandin F2alpha (PGF2alpha) as well as two analogues augment muscle cell size in vitro.We show that NFAT is activated by PGF2alpha, and the isoform NFATC2 is required for PGF2alpha-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling.Given this novel role for PGF2alpha in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.

View Article: PubMed Central - PubMed

Affiliation: Cell and Developmental Biology, Emory University School of Medicine, Atlanta, GA 30322, USA.

ABSTRACT
Skeletal muscle growth requires multiple steps to form large multinucleated muscle cells. Molecules that stimulate muscle growth may be therapeutic for muscle loss associated with aging, injury, or disease. However, few factors are known to increase muscle cell size. We demonstrate that prostaglandin F2alpha (PGF2alpha) as well as two analogues augment muscle cell size in vitro. This increased myotube size is not due to PGF2alpha-enhancing cell fusion that initially forms myotubes, but rather to PGF2alpha recruiting the fusion of cells with preexisting multinucleated cells. This growth is mediated through the PGF2alpha receptor (FP receptor). As the FP receptor can increase levels of intracellular calcium, the involvement of the calcium-regulated transcription factor nuclear factor of activated T cells (NFAT) in mediating PGF2alpha-enhanced cell growth was examined. We show that NFAT is activated by PGF2alpha, and the isoform NFATC2 is required for PGF2alpha-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling. Given this novel role for PGF2alpha in skeletal muscle cell growth, these studies raise caution that extended use of drugs that inhibit PG production, such as nonsteroidal antiinflammatory drugs, may be deleterious for muscle growth.

Show MeSH
Related in: MedlinePlus