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...

BackgroundBuilding both strength and endurance has been a challenge in exercise training in the elderly, but dietary supplements hold promise as agents for improving muscle adaptation. Here, we test a formulation of natural products (AX: astaxanthin, 12 mg and tocotrienol, 10 mg and zinc, 6 mg) with both anti‐inflammatory and antioxidant properties in combination with exercise. We conducted a randomized, double‐blind, placebo‐controlled study of elderly subjects (65–82 years) on a daily oral dose with interval walking exercise on an incline treadmill.MethodsForty‐two subjects were fed AX or placebo for 4 months and trained 3 months (3×/week for 40–60 min) with increasing intervals of incline walking. Strength was measured as maximal voluntary force (MVC) in ankle dorsiflexion exercise, and tibialis anterior muscle size (cross‐sectional area, CSA) was determined from magnetic resonance imaging.ResultsGreater endurance (exercise time in incline walking, >50%) and distance in 6 min walk (>8%) accompanied training in both treatments. Increases in MVC by 14.4% (±6.2%, mean ± SEM, P < 0.02, paired t‐test), CSA by 2.7% (±1.0%, P < 0.01), and specific force by 11.6% (MVC/CSA, ±6.0%, P = 0.05) were found with AX treatment, but no change was evident in these properties with placebo treatment (MVC, 2.9% ± 5.6%; CSA, 0.6% ± 1.2%; MVC/CSA, 2.4 ± 5.7%; P > 0.6 for all).ConclusionsThe AX formulation improved muscle strength and CSA in healthy elderly in addition to the elevation in endurance and walking distance found with exercise training alone. Thus, the AX formulation in combination with a functional training programme uniquely improved muscle strength, endurance, and mobility in the elderly.

Common cyclooxygenase (COX)-inhibiting drugs enhance resistance exercise induced muscle mass and strength gains in older individuals. The purpose of this investigation was to determine whether the underlying mechanism regulating this effect was specific to Type I or Type II muscle fibers, which have different contractile and metabolic profiles. Muscle biopsies (vastus lateralis) were obtained before and after 12 weeks of knee-extensor resistance exercise (3 days/week) from healthy older men who consumed either a placebo (n = 8; 64±2 years) or COX inhibitor (acetaminophen, 4 gram/day; n = 7; 64±1 years) in double-blind fashion. Muscle samples were examined for Type I and II fiber cross-sectional area, capillarization, and metabolic enzyme activities (glycogen phosphorylase, citrate synthase, β-hydroxyacyl-CoA-dehydrogenase). Type I fiber size did not change with training in the placebo group (304±590 μm(2)) but increased 28% in the COX inhibitor group (1,388±760 μm(2), p < .1). Type II fiber size increased 26% in the placebo group (1,432±499 μm(2), p < .05) and 37% in the COX inhibitor group (1,825±400 μm(2), p < .05). Muscle capillarization and enzyme activity were generally maintained in the placebo group. However, capillary to fiber ratio increased 24% (p < .1) and citrate synthase activity increased 18% (p < .05) in the COX inhibitor group. COX inhibitor consumption during resistance exercise in older individuals enhances myocellular growth, and this effect is more pronounced in Type I muscle fibers.

Prostaglandin E2 (PGE2) produced by the cyclooxygenase (COX) pathway regulates skeletal muscle protein turnover and exercise training adaptations. The purpose of this study was twofold: 1) define the PGE2/COX pathway enzymes and receptors in human skeletal muscle, with a focus on type I and II muscle fibers; and 2) examine the influence of aging on this pathway. Muscle biopsies were obtained from the soleus (primarily type I fibers) and vastus lateralis (proportionally more type II fibers than soleus) of young men and women (n = 8; 26 ± 2 yr), and from the vastus lateralis of young (n = 8; 25 ± 1 yr) and old (n = 12; 79 ± 2 yr) men and women. PGE2/COX pathway proteins [COX enzymes (COX-1 and COX-2), PGE2 synthases (cPGES, mPGES-1, and mPGES-2), and PGE2 receptors (EP1, EP2, EP3, and EP4)] were quantified via Western blot. COX-1, cPGES, mPGES-2, and all four PGE2 receptors were detected in all skeletal muscle samples examined. COX-1 (P < 0.1) and mPGES-2 were ∼20% higher, while EP3 was 99% higher and EP4 57% lower in soleus compared with vastus lateralis (P < 0.05). Aging did not change the level of skeletal muscle COX-1, while cPGES increased 45% and EP1 (P < 0.1), EP3, and EP4 decreased ∼33% (P < 0.05). In summary, PGE2 production capacity and receptor levels are different in human skeletal muscles with markedly different type I and II muscle fiber composition. In aging skeletal muscle, PGE2 production capacity is elevated and receptor levels are downregulated. These findings have implications for understanding the regulation of skeletal muscle adaptations to exercise and aging by the PGE2/COX pathway and related inhibitors.

Background Loss of mitochondrial function contributes to fatigue, exercise intolerance and muscle weakness, and is a key factor in the disability that develops with age and a wide variety of chronic disorders. Here, we describe the impact of a first-in-class cardiolipin-binding compound that is targeted to mitochondria and improves oxidative phosphorylation capacity (Elamipretide, ELAM) in a randomized, double-blind, placebo-controlled clinical trial. Methods Non-invasive magnetic resonance and optical spectroscopy provided measures of mitochondrial capacity (ATPmax) with exercise and mitochondrial coupling (ATP supply per O2 uptake; P/O) at rest. The first dorsal interosseous (FDI) muscle was studied in 39 healthy older adult subjects (60 to 85 yrs of age; 46% female) who were enrolled based on the presence of poorly functioning mitochondria. We measured volitional fatigue resistance by force-time integral over repetitive muscle contractions. Results A single ELAM dose elevated mitochondrial energetic capacity in vivo relative to placebo (ΔATPmax; P = 0.055, %ΔATPmax; P = 0.045) immediately after a 2-hour infusion. No difference was found on day 7 after treatment, which is consistent with the half-life of ELAM in human blood. No significant changes were found in resting muscle mitochondrial coupling. Despite the increase in ATPmax there was no significant effect of treatment on fatigue resistance in the FDI. Conclusions These results highlight that ELAM rapidly and reversibly elevates mitochondrial capacity after a single dose. This response represents the first demonstration of a pharmacological intervention that can reverse mitochondrial dysfunction in vivo immediately after treatment in aging human muscle.