Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise

Abstract

It has been ∼40 yr since the discovery that PGs are produced by exercising skeletal muscle and since the discovery that inhibition of PG synthesis is the mechanism of action of what are now known as cyclooxygenase (COX)-inhibiting drugs. Since that time, it has been established that PGs are made during and after aerobic and resistance exercise and have a potent paracrine and autocrine effect on muscle metabolism. Consequently, it has also been determined that orally consumed doses of COX inhibitors can profoundly influence muscle PG synthesis, muscle protein metabolism, and numerous other cellular processes that regulate muscle adaptations to exercise loading. Although data from acute human exercise studies, as well as animal and cell-culture data, would predict that regular consumption of a COX inhibitor during exercise training would dampen the typical muscle adaptations, the chronic data do not support this conjecture. From the studies in young and older individuals, lasting from 1.5 to 4 mo, no interfering effects of COX inhibitors on muscle adaptations to resistance-exercise training have been noted. In fact, in older individuals, a substantial enhancement of muscle mass and strength has been observed. The collective findings of the PG/COX-pathway regulation of skeletal muscle responses and adaptations to exercise are compelling. Considering the discoveries in other areas of COX regulation of health and disease, there is certainly an interesting future of investigation in this re-emerging area, especially as it pertains to older individuals and the condition of sarcopenia, as well as exercise training and performance of individuals of all ages.

Keywords: PGE2; PGF2α; acetaminophen; ibuprofen; sarcopenia.

Fig. 1.

General schematic of the biosynthesis of the primary PGs in the PG/cyclooxygenase (COX) pathway and their associated receptors (53, 107, 108). The thicker arrows reflect conversions that are catalyzed by specific enzymes. Several other PGs are also made from the conversion (enzymatic or nonenzymatic) of those listed here: PGJ₂, Δ¹²-PGJ₂, 15-deoxy-Δ^12,14-PGJ₂, and 11-epi-PGF_2α are derived from PGD₂; PGA₂, PGB₂, and PGC₂ are derived from PGE₂; 15-keto-PGF_2α is derived from PGF_2α; 6-keto-PGF_1α and 6-keto-PGF₁ are derived from PGI₂. PGs are lipid molecules with a general chemical formula of C₂₀H_28–34O_3–6 and molecular weight range of 317–371 Da. See text for specific references related to the numerous aliases that exist for the variants and isoforms of the enzymes and receptors and for further understanding of the nomenclature. Although not a PG, thromboxane A₂ is also derived from the enzymatic conversion of PGH₂. This review focuses on the 2 primary PGs that influence skeletal muscle protein turnover (PGF_2α and PGE₂), which are discussed in the text and presented in further detail (see Fig. 2). DP1–2, EP1–4, FP, and IP, PG receptors.

Fig. 2.

Schematic of the portion of the PG/COX pathway involved in the regulation of skeletal muscle protein metabolism and adaptation. See text for specific references related to the enzymes, intermediates, and receptors of the COX pathway, as well as the studies that have delineated the factors and cellular processes regulated by the PGE₂ and PGF_2α receptors that influence skeletal muscle mass. See Trappe et al. (127) for nomenclature related to the PG synthases, reductase, and receptors. MuRF-1, muscle RING finger protein-1; PI3K/ERK/mTOR, phosphoinositide 3-kinase/ERK/mammalian target of rapamycin (62).