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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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PGF2α induces hypertrophy of NFATC2−/− myotubes expressing recombinant NFATC2. (A) Primary NFATC2−/− myoblasts were infected either with control (Cntl RV) or recombinant NFATC2 retrovirus (NFATC2 RV). Cells were induced to differentiate and treated with vehicle or 10−6 M PGF2α. After 48 h, the cells were immunostained for EMyHC. Bar, 60 μm. (B) Nuclear number assays were performed as in Fig. 1 E. Data are the mean ± SEM of three independent experiments. *Significantly different from vehicle-treated cells infected with Cntl RV, P < 0.05; **Significantly different from vehicle treated cells infected with NFATC2 RV, P < 0.05.
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fig6: PGF2α induces hypertrophy of NFATC2−/− myotubes expressing recombinant NFATC2. (A) Primary NFATC2−/− myoblasts were infected either with control (Cntl RV) or recombinant NFATC2 retrovirus (NFATC2 RV). Cells were induced to differentiate and treated with vehicle or 10−6 M PGF2α. After 48 h, the cells were immunostained for EMyHC. Bar, 60 μm. (B) Nuclear number assays were performed as in Fig. 1 E. Data are the mean ± SEM of three independent experiments. *Significantly different from vehicle-treated cells infected with Cntl RV, P < 0.05; **Significantly different from vehicle treated cells infected with NFATC2 RV, P < 0.05.

Mentions: To further test whether PGF2α requires NFATC2 to induce muscle growth, we determined if expression of a recombinant NFATC2 in NFATC2−/− muscle cells could rescue the inability of these cells to increase in cell size and nuclear number in response to PGF2α. When treated with 10−6 M PGF2α, NFATC2−/− muscle cells infected with control retrovirus do not increase in size (Fig. 6 A) or in the percentage of myotubes with five or more nuclei (Fig. 6 B). Consistent with previous results (Horsley et al., 2001), expression of a recombinant NFATC2 in NFATC2−/− muscle cells restores myotube growth. However, NFATC2−/− cells expressing a recombinant NFATC2 and treated with PGF2α exhibit a greatly enhanced cell size relative to similarly treated wild-type cells that is associated with an increase in nuclear number. These data further demonstrate that PGF2α-induced muscle growth is mediated through NFATC2-dependent pathways.


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

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

PGF2α induces hypertrophy of NFATC2−/− myotubes expressing recombinant NFATC2. (A) Primary NFATC2−/− myoblasts were infected either with control (Cntl RV) or recombinant NFATC2 retrovirus (NFATC2 RV). Cells were induced to differentiate and treated with vehicle or 10−6 M PGF2α. After 48 h, the cells were immunostained for EMyHC. Bar, 60 μm. (B) Nuclear number assays were performed as in Fig. 1 E. Data are the mean ± SEM of three independent experiments. *Significantly different from vehicle-treated cells infected with Cntl RV, P < 0.05; **Significantly different from vehicle treated cells infected with NFATC2 RV, P < 0.05.
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fig6: PGF2α induces hypertrophy of NFATC2−/− myotubes expressing recombinant NFATC2. (A) Primary NFATC2−/− myoblasts were infected either with control (Cntl RV) or recombinant NFATC2 retrovirus (NFATC2 RV). Cells were induced to differentiate and treated with vehicle or 10−6 M PGF2α. After 48 h, the cells were immunostained for EMyHC. Bar, 60 μm. (B) Nuclear number assays were performed as in Fig. 1 E. Data are the mean ± SEM of three independent experiments. *Significantly different from vehicle-treated cells infected with Cntl RV, P < 0.05; **Significantly different from vehicle treated cells infected with NFATC2 RV, P < 0.05.
Mentions: To further test whether PGF2α requires NFATC2 to induce muscle growth, we determined if expression of a recombinant NFATC2 in NFATC2−/− muscle cells could rescue the inability of these cells to increase in cell size and nuclear number in response to PGF2α. When treated with 10−6 M PGF2α, NFATC2−/− muscle cells infected with control retrovirus do not increase in size (Fig. 6 A) or in the percentage of myotubes with five or more nuclei (Fig. 6 B). Consistent with previous results (Horsley et al., 2001), expression of a recombinant NFATC2 in NFATC2−/− muscle cells restores myotube growth. However, NFATC2−/− cells expressing a recombinant NFATC2 and treated with PGF2α exhibit a greatly enhanced cell size relative to similarly treated wild-type cells that is associated with an increase in nuclear number. These data further demonstrate that PGF2α-induced muscle growth is mediated through NFATC2-dependent pathways.

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