Prostaglandin F2α stimulates growth of skeletal muscle cells via an NFATC2-dependent pathway

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 F2α (PGF2α) as well as two analogues augment muscle cell size in vitro. This increased myotube size is not due to PGF2α-enhancing cell fusion that initially forms myotubes, but rather to PGF2α recruiting the fusion of cells with preexisting multinucleated cells. This growth is mediated through the PGF2α 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 PGF2α-enhanced cell growth was examined. We show that NFAT is activated by PGF2α, and the isoform NFATC2 is required for PGF2α-induced muscle cell growth and nuclear accretion, demonstrating the first intersection between prostaglandin receptor activation and NFAT signaling. Given this novel role for PGF2α 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.

Prostaglandin F2α inhibits adipocyte differentiation via a Gαq‐Calcium‐Calcineurin‐Dependent signaling pathway

“…Our principal finding is that PGF2a inhibits adipocyte differentiation via a Gaq Gprotein subunit and calcium-dependent signaling pathway involving the calcium/calmodulinregulated serine/threonine phosphatase calcineurin. This conclusion is consistent with previous reports that PGF2a can act via its specific Gq-coupled FP prostanoid receptor to activate calcineurin in a number of cell types [Horsley and Pavlath, 2003;Liang et al, 2004], as well as with our recent identification of calcineurin as a critical calcium-dependent negative regulator of adipocyte differentiation [Neal and Clipstone, 2002]. We presume that this pathway is likely to operate in vivo to influence adipocyte development under conditions where PGF2a levels are elevated, such as those that occur during chronic inflammatory conditions as a result of increased expression of cyclooxygenase-2.…”

Normal muscle regeneration requires tight control of muscle cell fusion by tetraspanins CD9 and CD81

“…It was originally described as a protein copurifying with a prostaglandin F2a-binding protein, and was subsequently suggested to negatively modulate the binding of PGF2a on its receptor 36,37 . Interestingly, PGF2a was shown to stimulate myoblast fusion 38 . However, the increased fusion observed after CD9P-1 silencing is not due to an increased stimulation of the PGF2a receptor as it is not blocked by inhibition of this receptor ( Supplementary Fig.…”

Intronic regulation of matrix metalloproteinase-2 revealed by in vivo transcriptional analysis in ischemia

“…There are no prior reports of intronic regulation of an MMP gene or of an NFAT transcription factor that regulates MMP-2 expression. NFAT regulation was initially described in T cell activation (18); however, recent reports describe NFAT family members as regulating skeletal muscle development (19), regeneration (20), and cardiac ischemia-reperfusion injury (21). Our laboratory recently reported that NFATc1 regulates MMP-14 (membrane-type 1-MMP) transcription in mesangial cells (15).…”