The influence of anti-inflammatory medication on exercise-induced myogenic precursor cell responses in humans

Mackey, Abigail L.; Kjær, Michael; Dandanell, Sune; Mikkelsen, Kristian Hallundbæk; Holm, Lars; Døssing, Simon; Kadi, Fawzi; Koskinen, Satu; Jensen, Charlotte Harken; Langberg, Henning

doi:10.1152/japplphysiol.00157.2007

Cited by 165 publications

(174 citation statements)

References 49 publications

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“…Consistent with previous reports that NSAIDs may negatively influence skeletal muscle growth via deleterious effects on satellite cell myogenesis (22,26,28,29,31,39), we found basal C2C12 myogenesis to be impaired by nonselective and COX-2-selective NSAIDs. These findings support an important role of the COX-2 pathway in basal early myogenesis (4,26,39,41), despite the lack of a stimulatory effect of AA supplementation on this stage of muscle cell development.…”

Section: Discussionsupporting

confidence: 92%

“…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: 83%

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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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Section: Discussionsupporting

confidence: 92%

mentioning

confidence: 83%

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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“…MuSCs are crucial to development and regeneration (1-3, 24, 36-38), and their numbers dramatically increase in response to insults that damage the muscles in mice and humans (5,20,(39)(40)(41)(42). Injections of MuSCs into injured muscles lead to their exponential increase, whereas injection of their myoblast derivatives results in a decline in numbers, revealing a remarkable distinction in regenerative capacity of these two cell types (24).…”

Section: Discussionmentioning

confidence: 99%

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Palla

Blake

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

184

169

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This contribution is part of the special series of Inaugural Articles by members of the National Academy of Sciences elected in 2016.Contributed by Helen M. Blau, May 15, 2017 (sent for review April 3, 2017; reviewed by Douglas P. Millay and Fabio M. V. Rossi)Skeletal muscles harbor quiescent muscle-specific stem cells (MuSCs) capable of tissue regeneration throughout life. Muscle injury precipitates a complex inflammatory response in which a multiplicity of cell types, cytokines, and growth factors participate. Here we show that Prostaglandin E2 (PGE2) is an inflammatory cytokine that directly targets MuSCs via the EP4 receptor, leading to MuSC expansion. An acute treatment with PGE2 suffices to robustly augment muscle regeneration by either endogenous or transplanted MuSCs. Loss of PGE2 signaling by specific genetic ablation of the EP4 receptor in MuSCs impairs regeneration, leading to decreased muscle force. Inhibition of PGE2 production through nonsteroidal anti-inflammatory drug (NSAID) administration just after injury similarly hinders regeneration and compromises muscle strength. Mechanistically, the PGE2 EP4 interaction causes MuSC expansion by triggering a cAMP/phosphoCREB pathway that activates the proliferation-inducing transcription factor, Nurr1. Our findings reveal that loss of PGE2 signaling to MuSCs during recovery from injury impedes muscle repair and strength. Through such gain-or loss-of-function experiments, we found that PGE2 signaling acts as a rheostat for muscle stem-cell function. Decreased PGE2 signaling due to NSAIDs or increased PGE2 due to exogenous delivery dictates MuSC function, which determines the outcome of regeneration. The markedly enhanced and accelerated repair of damaged muscles following intramuscular delivery of PGE2 suggests a previously unrecognized indication for this therapeutic agent. muscle stem cells | PGE2 | regeneration | NSAIDs | strength

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“…This is supported by the robust, acute increases in MGF (4) and cyclin D1 (19) transcripts previously found in Xtr. Certainly there is evidence in humans that satellite cells proliferate in response to mechanical stress even when hypertrophy is not imminent (22), suggesting that forces other than eventual myonuclear addition drive expansion of the pool.…”

Section: Discussionmentioning

confidence: 99%

Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis

Petrella¹,

Kim²,

Mayhew³

et al. 2008

Journal of Applied Physiology

372

380

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Petrella JK, Kim J, Mayhew DL, Cross JM, Bamman MM. Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis. J Appl Physiol 104: 1736-1742, 2008. First published April 24, 2008 doi:10.1152/japplphysiol.01215.2007.-A present debate in muscle biology is whether myonuclear addition is required during skeletal muscle hypertrophy. We utilized K-means cluster analysis to classify 66 humans after 16 wk of knee extensor resistance training as extreme (Xtr, n ϭ 17), modest (Mod, n ϭ 32), or nonresponders (Non, n ϭ 17) based on myofiber hypertrophy, which averaged 58, 28, and 0%, respectively (Bamman MM, Petrella JK, Kim JS, Mayhew DL, Cross JM. J Appl Physiol 102: [2232][2233][2234][2235][2236][2237][2238][2239] 2007). We hypothesized that robust hypertrophy seen in Xtr was driven by superior satellite cell (SC) activation and myonuclear addition. Vastus lateralis biopsies were obtained at baseline and week 16. SCs were identified immunohistochemically by surface expression of neural cell adhesion molecule. At baseline, myofiber size did not differ among clusters; however, the SC population was greater in Xtr (P Ͻ 0.01) than both Mod and Non, suggesting superior basal myogenic potential. SC number increased robustly during training in Xtr only (117%; P Ͻ 0.001). Myonuclear addition occurred in Mod (9%; P Ͻ 0.05) and was most effectively accomplished in Xtr (26%; P Ͻ 0.001). After training, Xtr had more myonuclei per fiber than Non (23%; P Ͻ 0.05) and tended to have more than Mod (19%; P ϭ 0.056). Both Xtr and Mod expanded the myonuclear domain to meet (Mod) or exceed (Xtr) 2,000 m 2 per nucleus, possibly driving demand for myonuclear addition to support myofiber expansion. These findings strongly suggest myonuclear addition via SC recruitment may be required to achieve substantial myofiber hypertrophy in humans. Individuals with a greater basal presence of SCs demonstrated, with training, a remarkable ability to expand the SC pool, incorporate new nuclei, and achieve robust growth. strength training; skeletal muscle; neural cell adhesion molecule; myonucleus; myogenesis EACH MYONUCLEUS WITHIN THE multinucleated skeletal myofiber regulates gene transcription and subsequent protein synthesis over a finite volume of cytoplasm (6,7,23). This volume per nucleus, or myonuclear domain, is not a fixed quantity as evidenced during atrophy due to disuse (3, 24) or aging (25) as loss of cell volume exceeds nuclear shedding. Similarly, our laboratory and others have shown that some initial myofiber hypertrophy can expand the cytoplasmic volume associated with each myonucleus (17,25). This has led some to debate whether the addition of nuclei is required for skeletal myofiber hypertrophy (23). However, a ceiling size on the domain has been suggested (17, 23, 25) based on the concept that sufficient expansion of the myonuclear domain likely puts each nucleus under greater strain to supply the necessary gene products, driving a demand for the a...

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The influence of anti-inflammatory medication on exercise-induced myogenic precursor cell responses in humans

Cited by 165 publications

References 49 publications

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

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

Prostaglandin E2 is essential for efficacious skeletal muscle stem-cell function, augmenting regeneration and strength

Potent myofiber hypertrophy during resistance training in humans is associated with satellite cell-mediated myonuclear addition: a cluster analysis

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