COX-2 inhibitor reduces skeletal muscle hypertrophy in mice

Abstract

Anti-inflammatory strategies are often used to reduce muscle pain and soreness that can result from high-intensity muscular activity. However, studies indicate that components of the acute inflammatory response may be required for muscle repair and growth. The hypothesis of this study was that cyclooxygenase (COX)-2 activity is required for compensatory hypertrophy of skeletal muscle. We used the synergist ablation model of skeletal muscle hypertrophy, along with the specific COX-2 inhibitor NS-398, to investigate the role of COX-2 in overload-induced muscle growth in mice. COX-2 was expressed in plantaris muscles during compensatory hypertrophy and was localized mainly in or near muscle cell nuclei. Treatment with NS-398 blunted the increases in mass and protein content in overloaded muscles compared with vehicle-treated controls. Additionally, the COX-2 inhibitor decreased activity of the urokinase type plasminogen activator, macrophage accumulation, and cell proliferation, all of which are required for hypertrophy after synergist ablation. Expression of insulin-like growth factor-1 and phosphorylation of Akt, mammalian target of rapamycin, and p70S6K were increased following synergist ablation, but were not affected by NS-398. Additionally, expression of atrogin-1 was reduced during hypertrophy, but was also not affected by NS-398. These results demonstrate that COX-2 activity is required for skeletal muscle hypertrophy, possibly through facilitation of extracellular protease activity, macrophage accumulation, and cell proliferation.

Systematic review of the synergist muscle ablation model for compensatory hypertrophy

“…Rats are often used due to their considerable activity and their larger size in comparison to mice. The mean weight of the animals used in the studies analyzed was 220 ± 12 g. [1][2][3][4][5]7,[14][15][16]18 Among the models described in the literature for changes in muscle demand, different protocols of mechanical loading have been used: resistance training (RT) and compensatory hypertrophy after ablation and tenotomy.…”

“…Tenotomy has the disadvantage of the rapid reconnection of the cut tendon, which limits functionality. 65 Most commonly studied muscles Compensatory hypertrophy by the ablation of synergists is an efficient model for studies on muscle hypertrophy, 2,3,7,[10][11][12][13][14][15][16][17][18][19][20] as the fast increase in muscle mass reduces the duration of the experiment. In recent years, changes have occurred in the standard of surgery (bilateral or unilateral) and the relationship between the number of days and increase in muscle mass, which justifies this systematic review.…”

“…[1][2][3][4][5]7,[14][15][16]18 In the 1980s and 1990s, the model most often employed was the entire removal of the tibialis anterior to generate overload of the digitorum longus. 15 Currently, the most used muscles in such models are the soleus and plantar muscle and compensatory hypertrophy commonly involves the removal of the distal portion of the gastrocnemius.…”

“…The muscle adaptation process can be induced by stretching/ immobilization, 44,46 compensatory mechanisms (chronic). 1,[2][3][4][5][6]8,9,12,14,[18][19][20][61][62][63][64][65] and exercise/training. 33,46 Evidence of this is derived from a large number of studies demonstrating that overload leads to an increase in muscle mass and cross-sectional area of the muscle fibers and induces chronic changes in the balance between the synthesis and degradation of proteins.…”

“…2,3,7,[10][11][12][13][14][15][16][17][18][19][20] The most studied muscles are plantar flexors in the rear paw of rats. As skeletal muscle has different types of fibers (type I [slow--twitch] and type II [fast-twitch -IIa, IIb, IIx/IId]), 21 a number of authors justify the choice of the plantaris muscle due to its diversity of fiber types (type I: 8 ± 2%; type IIA: 19 ± 3%; type IIB/D: 74 ± 4%) and its different adaptation possibilities.…”