Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle

Mikkelsen, Ulla Ramer; Helmark, I. C.; Kjær, Michael; Langberg, Henning

doi:10.1152/japplphysiol.01016.2007

Cited by 21 publications

(18 citation statements)

References 17 publications

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“…However, the intramuscular levels reported in that study are similar to those reported in middle-aged and younger individuals (29,49,50). In addition, low-level muscular work does not increase PGE 2 levels (30, 50), whereas resistance and aerobic exercise stimulate the muscle to produce PGE 2 and/or PGF 2␣ during and/or after exercise (15,49,50,67,123,126). Furthermore, increasing the workload during aerobic exercise increases the muscle production of PGE 2 (15,49).…”

supporting

confidence: 75%

“…There are somewhat limited data on PG synthesis and muscle protein metabolism at rest or after exercise in response to oral consumption of over-the-counter COX inhibitors (82,126,128). Mikkelsen et al (67) have shown that an intramuscular infusion of a relatively low dose of the prescription COX inhibitor indomethacin reduced PGE 2 levels in the muscle during and after resistance exercise by ϳ85%. This same COX-inhibitor delivery approach during and for a few hours after resistance exercise did not influence muscle protein synthesis measured near the infusion site 24 h later (69).…”

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confidence: 99%

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

Trappe

Liu

2013

Journal of Applied Physiology

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Trappe TA, Liu SZ. Effects of prostaglandins and COX-inhibiting drugs on skeletal muscle adaptations to exercise. J Appl Physiol 115: 909 -919, 2013. First published March 28, 2013 doi:10.1152/japplphysiol.00061.2013.-It has been ϳ40 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. PGE 2; PGF2␣; acetaminophen; ibuprofen; sarcopenia PGS PRODUCED BY the cyclooxygenase (COX) enzyme are ubiquitous in human physiology and regulate numerous processes (105, 108), including muscle protein metabolism (78,93,106,126,128). As a result, PGs regulate adaptations to muscular exercise, and COX-inhibiting drugs can alter the acute and chronic responses to exercise. Because of the continuum of acute responses and chronic adaptations that exists from lowerintensity, longer-duration exercise to higher-intensity, shorterduration exercise, it is difficult to adopt a "one-mechanismfits-all" approach to PG and COX involvement in skeletal muscle exercise adaptations. This is also true when distinguishing between muscle injury and muscular exercise for health and performance.COX-inhibiting drugs are one of the most commonly consumed classes of drugs in the world. In the United States, the COX inhibitors, acetaminophen, ibuprofen, and aspirin, are the top three consumed drugs of young, middle-aged, and older individuals, with ϳ50 million individuals using each of these drugs during any given week (52, 129). Interestingly, two of these drugs (acetaminophen...

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confidence: 75%

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confidence: 99%

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

Trappe

Liu

2013

Journal of Applied Physiology

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“…Mechanical stimulation of skeletal muscle cells promotes local membrane PL cleavage, free intracellular AA accumulation, PG synthesis/release, and cell growth (45,54,55). Consistently, inhibition of PG synthesis via NSAID administration in young healthy humans in vivo blunts adaptive myofiber protein synthesis (52,53) and satellite cell proliferation (22,27,28) responses to resistance exercise. In contrast, skeletal muscle wasting associated with chronic inflammatory conditions, including cancer cachexia (24,44,47), arthritis (10), and aging-associated sarcopenia (36,51), has been reported to be improved by systemic NSAID treatment.…”

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confidence: 84%

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

Markworth

Cameron‐Smith

2013

American Journal of Physiology-Cell Physiology

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[e.g., prostaglandins (PGs), leukotrienes, and hydroxyeicosatetraenoic acids] has been implicated in skeletal muscle cell growth and development. The collective role of AA-derived metabolites in physiological states of skeletal muscle growth/atrophy remains unclear. The present study aimed to determine the direct effect of free AA supplementation and subsequent eicosanoid biosynthesis on skeletal myocyte growth in vitro. C2C12 (mouse) skeletal myocytes induced to differentiate with supplemental AA exhibited dose-dependent increases in the size, myonuclear content, and protein accretion of developing myotubes, independent of changes in cell density or the rate/extent of myogenic differentiation. Nonselective (indomethacin) or cyclooxygenase 2 (COX-2)-selective (NS-398) nonsteroidal anti-inflammatory drugs blunted basal myogenesis, an effect that was amplified in the presence of supplemental free AA substrate. The stimulatory effects of AA persisted in preexisting myotubes via a COX-2-dependent (NS-389-sensitive) pathway, specifically implying dependency on downstream PG biosynthesis. AAstimulated growth was associated with markedly increased secretion of PGF 2␣ and PGE2; however, incubation of myocytes with PG-rich conditioned medium failed to mimic the effects of direct AA supplementation. In vitro AA supplementation stimulates PG release and skeletal muscle cell hypertrophy via a COX-2-dependent pathway. arachidonic acid; C2C12; growth; nonsteroidal anti-inflammatory drug; skeletal muscle ARACHIDONIC ACID (AA) is a polyunsaturated -6 fatty acid [20:4(6)], present in the diet, that is incorporated into cell membrane phospholipids (PLs) (19). Dietary change elicits rapid alterations in PL fatty acid composition, with supplemental AA increasing plasma PL abundance within days (42). In response to cellular perturbation (e.g., mechanical trauma, cytokines, or growth factors), AA is cleaved from PL molecules via the action of the enzyme PLA 2 . Free intracellular AA serves as a key transient cell-signaling intermediate, undergoing rapid enzymatic conversion to a diverse array of inflammatory autocrine/paracrine eicosanoid lipid mediators. Parallel cyclooxygenase (COX-1/COX-2) and lipoxygenase (5-LOX/ 12-LOX/15-LOX) pathways catalyze the oxidation of AA to ultimately produce the PGs (PGD 2 , PGE 2 , PGF 2␣ , PGI 2 , and thromboxane A 2 ) and the leukotriene (LT)/lipoxin (LX) families of eicosanoids, respectively. Nonsteroidal anti-inflammatory drugs (NSAIDs) are thought to exert their anti-inflammatory, analgesic, and antipyretic action, specifically by inhibition of the COX branch of the AA pathway, indicative of a central role of PG species in mediating the inflammatory response.Skeletal muscle cells express the COX genes COX-1 and COX-2 (49) and locally synthesize/release AA-derived PGs, including PGD 2 (56), PGE 2 /PGF 2␣ (33,40,41,54), and PGI 2 (2). NSAID treatment is associated with deleterious effects on adaptive skeletal muscle growth/regeneration (3, 4, 31, 39 -41, 46), consistent with the inflammatory res...

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“…In studies where NSAID is consumed orally, PG release is blocked systemically at the whole body level. Inserting microdialysis catheters into the muscle allows the infusion of NSAID directly into the muscle to exert effects locally, which was confirmed by detection of reduced levels of PGE 2 in dialysate collected from catheters inserted at distances of 1 cm and 4 cm, respectively, away from the infusion catheter (46). It is not possible to compare the concentration of NSAID infused in this study directly with doses administered orally in other studies, but the PG levels appeared to be similar (47).…”

Section: Effects Of Nsaids On Satellite Cellsmentioning

confidence: 59%

“…In this study, no significant time ϫ drug interaction was detected, but the lack of increase in the NSAID group suggests that NSAID may exert a negative effect on the satellite cell response to exercise. This hypothesis was tested further, again in young healthy male volunteers, by a different approach, where NSAID was infused directly into the working muscle (46,47). In studies where NSAID is consumed orally, PG release is blocked systemically at the whole body level.…”

Section: Effects Of Nsaids On Satellite Cellsmentioning

confidence: 99%

Does an NSAID a day keep satellite cells at bay?

Mackey

2013

Journal of Applied Physiology

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Mackey AL. Does an NSAID a day keep satellite cells at bay? J Appl Physiol 115: 900-908, 2013. First published May 16, 2013 doi:10.1152/japplphysiol.00044.2013.-Nonsteroidal anti-inflammatory drugs (NSAIDs) are widely consumed by athletes worldwide, despite growing evidence for a negative influence on the adaptation of skeletal muscle to exercise, at least in young healthy individuals. This review focuses on the potential of NSAIDs to alter the activity of satellite cells, the muscle stem cell responsible for repair and maintenance of skeletal muscle. The signaling pathways that are potentially modified by NSAID exposure are also considered. Growth factors as well as inflammatory cells and connective tissue appear to be key factors in the response of muscle under conditions where cyclooxygenase and prostaglandin activity are blocked through NSAID ingestion or infusion. Discrepancies in the literature regarding the response of young and old individuals are addressed, where it appears that the elderly may benefit from NSAID ingestion, although this clearly requires further study. The long-term implications for the muscle of the apparent inhibitory effect of NSAIDs on satellite cells in younger individuals are not clear, and it is possible these may first become apparent with chronic use in athletes training at a high level or with advancing age. Reports of the potential for NSAIDs to alter prostaglandin and growth factor signaling provide a basis for further study of the mechanism of NSAID action on satellite cells. exercise; growth factor; muscle adaptation; NSAIDs; satellite cells SATELLITE CELLS (see Figs. 1 and 2) are a population of cells resident in adult skeletal muscle and have been proven to be essential for muscle repair (33, 67). The cycle of satellite cell activity (see Fig. 3) has been most widely studied in models of muscle injury or overload where the satellite cells are awoken from their dormant state. Briefly, the main steps involved include 1) activation to enter the cell cycle, and 2) proliferation, after which the cells either 3) undergo differentiation and fuse with a myofiber, or 4) return to quiescence (24,50,68,95). With the capacity to perform these two functions, namely repairing damaged tissue and replenishing their own cell pool, satellite cells have been ascribed the status of the muscle stem cell. While it appears that satellite cells in the muscle of elderly individuals are not as easily activated as in younger individuals (11), triggering activation and proliferation in vivo appears to be relatively easy, and many factors are now recognized as being capable of this. For example, mechanical stimuli in the form of stretch or forceful contractions, damage to the muscle, pharmacological agents, and inflammatory conditions are strong activators of satellite cells. It appears from the literature that nonsteroidal anti-inflammatory drugs (NSAIDs) can influence satellite cell activity, both directly and indirectly. This minireview will consider how NSAIDs can influence satellite cells at an...

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Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle

Abstract: Mikkelsen UR, Helmark IC, Kjaer M, Langberg H. Prostaglandin synthesis can be inhibited locally by infusion of NSAIDS through microdialysis catheters in human skeletal muscle.

Cited by 21 publications

References 17 publications

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

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

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

Does an NSAID a day keep satellite cells at bay?

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