Prostaglandin F2α promotes muscle cell survival and growth through upregulation of the inhibitor of apoptosis protein BRUCE

Abstract

During skeletal muscle growth and regeneration, the majority of differentiating myoblasts undergoes cell-cell fusion to form multinucleated myofibers, whereas a proportion of myoblasts undergoes apoptosis. The treatment of myoblasts with prostaglandin F2a (PGF2a) during myogenesis in vitro leads to the formation of large myotubes, but the mechanism by which PGF2a promotes myotube growth has not been investigated. Here, we demonstrate that PGF2a reduces cell death during myogenesis in vitro and in vivo. In addition, we show that PGF2a increases expression of the inhibitor of apoptosis protein (IAP) BRUCE through a pathway dependent on the nuclear factor of activated T cell 2 transcription factor. Importantly, PGF2a-mediated reduction in muscle cell death is dependent on BRUCE, and overexpression of BRUCE is sufficient to promote muscle cell survival and growth. These results establish a previously unrecognized link between NFAT signaling and regulation of IAP expression and are the first to identify a signaling pathway that increases BRUCE expression. In addition, our results provide evidence that increasing the pool of muscle cells available for fusion by inhibiting cell death enhances myotube growth.

Arachidonic acid supplementation enhances in vitro skeletal muscle cell growth via a COX-2-dependent pathway

“…Nevertheless, myonuclear accretion (number of nuclei per myotube) and myotube size were greatly enhanced by AA supplementation. These effects specific to later stages of myotube growth/development are consistent with previous reports of exogenous treatment with high doses of the single prostanoids, including PGF 2␣ (15,17) and PGI 2 (2). The fusion events that regulate the formation of multinucleated skeletal muscle cells involve two distinct phases: 1) myoblast-myoblast fusion to form small nascent myotubes containing few myo- Fig.…”

“…Under ex vivo conditions, however, supplemental AA increased protein degradation in absolute terms to a greater extent than protein synthesis, the net result being skeletal muscle protein catabolism (37). Despite the importance of satellite cell myogenesis in skeletal muscle regeneration/hypertrophy (20,25,30,38) and recent studies implicating specific individual PGs as important mediators of myoblast survival (17), proliferation (4,26,33,39), differentiation (26,39,56), and fusion (2,15,26,41), no study has investigated the direct net effect of heightened free AA availability on these processes.…”

“…High exogenous concentrations of individual PGs elicit class-specific physiological effects on multiple stages of skeletal muscle cell growth. For example, PGI 2 (2) and PGF 2␣ (15,17) enhance early and late muscle cell fusion events during myogenesis, respectively, leading to enhanced myonuclear accretion and increased myotube size. Conversely, PGD 2 exerts negative effects on early skeletal myogenesis, characterized by impairment of myocyte differentiation/fusion (56).…”

“…Similarly, PGF 2␣ and PGE 2 have opposing effects on skeletal muscle cell protein turnover in preexisting myotubes/myofibers, acting to increase rates of protein synthesis and protein degradation, respectively (37). Although the molecular mechanisms by which PGs may influence myogenesis/protein turnover remain poorly understood, the type F prostanoid receptor is coupled to intracellular skeletal muscle cell growth signaling via the nuclear factor of activated T cells C2 (15,17) and mammalian target of rapamycin (mTOR) (23) pathways. In addition to COX-derived PGs, LOX metabolites of AA have been implicated in the control of skeletal muscle cell growth.…”

Human inflammatory and resolving lipid mediator responses to resistance exercise and ibuprofen treatment

“…PGs and LTs may play an important role in regulating mobilization, activation, and migration of neutrophils during the early hours of postexercise recovery. Additionally, skeletal muscle cells themselves express PG and LT receptors and have been shown to respond to exogenous treatment with lipid mediators LTB 4 (92), PGF 2␣ (43,46,56), PGI 2 (6), or free AA substrate (55) with enhanced in vitro growth. Therefore, eicosanoids may be important autocrine/paracrine growth signaling molecules within skeletal muscle tissue during postexercise recovery, independent of their classical inflammatory roles.…”