Prostaglandin and myokine involvement in the cyclooxygenase-inhibiting drug enhancement of skeletal muscle adaptations to resistance exercise in older adults

Abstract

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 A(2) (cPLA(2)) and secreted phospholipase A(2) (sPLA(2)); PGF(2α) synthesis: PGF(2α) synthase and PGE(2) to PGF(2α) reductase; PGE(2) synthesis: PGE(2) synthase-1, -2, and -3; PGF(2α) receptor and PGE(2) receptor-4], cytokines and myokines involved in skeletal muscle adaptation (TNF-α, IL-1β, 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 κB kinase β (IKKβ)]. Training increased (P < 0.05) cPLA(2), PGF(2α) synthase, PGE(2) to PGF(2α) reductase, PGE(2) receptor-4, TNF-α, IL-1β, IL-8, and IKKβ. However, the PGF(2α) 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 PGF(2α) receptor upregulation helped offset the drug suppression of PGF(2α)-stimulated protein synthesis after each exercise bout and enhanced skeletal muscle sensitivity to this stimulation. 2) The drug-induced suppression of intramuscular PGE(2) production increased net muscle protein balance after each exercise bout through a reduction in PGE(2)-induced IL-6 and MuRF-1, both promoters of muscle loss.

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

“…The COX-inhibitor consumption also promoted an upregulation of the PGF 2␣ receptor in the muscle of the drug groups (127). This increase coupled with a general training increase in COX-1 and the PGF 2␣ -producing enzymes (PGF 2␣ synthase and PGE 2 -to-PGF 2␣ reductase) (125,127) would make the muscle less susceptible to the same, daily COX-inhibiting drug doses and more sensitive to any PGF 2␣ that was produced following exercise. Whether these responses and muscle adaptations are specific to older individuals and any potential basal inflammatory state or exaggerated response following exercise (21,26,36,80,89,117,118,124) is unclear and needs further investigation.…”

“…Follow-up studies on muscle biopsies obtained from these individuals (125,127) and subsequent ex vivo studies (110) provide some mechanistic clarity about these unexpected COX-inhibitor effects (Fig. 2).…”

“…This hypothesis is based on the data that show that low-level increases in IL-6 acutely inhibit muscle protein turnover (131), chronically promote muscle atrophy (12,37), and are associated with a reduction in muscle mass and functional independence in older individuals (6,25,28,99), as well as the proteolytic nature of the ubiquitin ligase MuRF-1 (20,98). The COX-inhibitor consumption also promoted an upregulation of the PGF 2␣ receptor in the muscle of the drug groups (127). This increase coupled with a general training increase in COX-1 and the PGF 2␣ -producing enzymes (PGF 2␣ synthase and PGE 2 -to-PGF 2␣ reductase) (125,127) would make the muscle less susceptible to the same, daily COX-inhibiting drug doses and more sensitive to any PGF 2␣ that was produced following exercise.…”

Does an NSAID a day keep satellite cells at bay?

“…This study suggests that the positive action of NSAIDs on muscle in the elderly could be through the lowering of a constantly elevated systemic level of inflammatory activity. Indeed NSAID ingestion by healthy elderly individuals performing a 12-wk program of resistance training has been shown to eliminate the increase in the muscle gene expression levels of the cytokines interleukin-6 and -10 observed in the placebo group (78). Further studies in humans are required, however.…”

“…Two recent studies of human skeletal muscle have reported abundant gene expression levels of EP4, which were observed to increase further with 12 wk of resistance training, while only infrequent or low gene expression levels of EP1, EP2, and EP3 were detected (62,78). Interestingly, the PGF 2␣ receptor was also detected at the gene level and observed to be upregulated in elderly individuals who performed resistance training for 12 wk in conjunction with ingestion of the NSAID ibuprofen or acetaminophen, while no change was detected in the placebo group (78). Shown in Fig.…”