CALL FOR PAPERS Integrative and Translational Physiology: Inflammation and Immunity in Organ-System Physiology Prostaglandin and myokine involvement in the cyclooxygenase-inhibiting drug enhancement of skeletal muscle adaptations to resistance exercise in older adults

Trappe TA, Standley RA, Jemiolo B, Carroll CC, Trappe SW. Prostaglandin and myokine involvement in the cyclooxygenaseinhibiting drug enhancement of skeletal muscle adaptations to resistance exercise in older adults. Am J Physiol Regul Integr Comp Physiol 304: R198 –R205, 2013. First published December 5, 2012; doi:10.1152/ajpregu.00245.2012.—Twelve weeks of resistance training (3 days/wk) combined with daily consumption of the cyclooxygenase-inhibiting drugs acetaminophen (4.0 g/day; n 11, 64 1 yr) or ibuprofen (1.2 g/day; n 13, 64 1 yr) unexpectedly promoted muscle mass and strength gains 25–50% above placebo (n 12, 67 2 yr). To investigate the mechanism of this adaptation, muscle biopsies obtained before and 72 h after the last training bout were analyzed for mRNA levels of prostaglandin (PG)/cyclooxygenase pathway enzymes and receptors [arachidonic acid synthesis: cytosolic phospholipase A2 (cPLA2) and secreted phospholipase A2 (sPLA2); PGF2 synthesis: PGF2 synthase and PGE2 to PGF2 reductase; PGE2 synthesis: PGE2 synthase-1, -2, and -3; PGF2 receptor and PGE2 receptor-4], cytokines and myokines involved in skeletal muscle adaptation (TNF, IL-1 , IL-6, IL-8, IL-10), and regulators of muscle growth [myogenin, myogenic regulatory factor-4 (MRF4), myostatin] and atrophy [Forkhead box O3A (FOXO3A), atrogin-1, muscle RING finger protein 1 (MuRF-1), inhibitory B kinase (IKK )]. Training increased (P 0.05) cPLA2, PGF2 synthase, PGE2 to PGF2 reductase, PGE2 receptor-4, TNF, IL-1 , IL-8, and IKK . However, the PGF2 receptor was upregulated (P 0.05) only in the drug groups, and the placebo group upregulation (P 0.05) of IL-6, IL-10, and MuRF-1 was eliminated in both drug groups. These results highlight prostaglandin and myokine involvement in the adaptive response to exercise in older individuals and suggest two mechanisms underlying the enhanced muscle mass gains in the drug groups: 1) The drug-induced PGF2 receptor upregulation helped offset the drug suppression of PGF2 -stimulated protein synthesis after each exercise bout and enhanced skeletal muscle sensitivity to this stimulation. 2) The drug-induced suppression of intramuscular PGE2 production increased net muscle protein balance after each exercise bout through a reduction in PGE2-induced IL-6 and MuRF-1, both promoters of muscle loss.