Celecoxib impairs primary human myoblast proliferation and differentiation independent of cyclooxygenase 2 inhibition

• Published in: Physiological reports 2022-11, Vol.10 (21), p.e15481-n/a
• Main Authors: Matheny, Ronald W., Kolb, Alexander L., Geddis, Alyssa V., Roberts, Brandon M.
• Format: Article
• Language: English
• Subjects: Aconitic acid; AKT protein; Antibodies; Automation; Celecoxib; Cell culture; Cell differentiation; Cell growth; Cell proliferation; Citric acid; cyclooxygenase; Cyclooxygenase-2; Drug dosages; Experiments; Fumaric acid; Glucose; Inflammation; Intermediates; Intracellular signalling; Malic acid; Membrane potential; Microscopy; Mitochondria; Musculoskeletal system; myoblast; Myoblasts; Myotubes; Nonsteroidal anti-inflammatory drugs; non‐steroidal anti‐inflammatory drug (NSAID); Original; Phosphorylation; Proteins; Pyruvic acid; Ribosomal protein S6; Skeletal muscle; Tricarboxylic acid cycle
• ISSN: 2051-817X
• DOI: 10.14814/phy2.15481

The use of non‐steroidal anti‐inflammatory drugs (NSAIDs) for treatment of musculoskeletal injuries is commonplace in the general, athletic, and military populations. While NSAIDs have been studied in a variety of tissues, the effects of NSAIDs on skeletal muscle have not been fully defined. To address this, we investigated the degree to which the cyclooxygenase (COX)‐2‐selective NSAID celecoxib affects muscle cell proliferation, differentiation, anabolic signaling, and mitochondrial function in primary human skeletal myoblasts and myotubes. Primary muscle cells were treated with celecoxib or NS‐398 (a pharmacological inhibitor of COX‐2) as a control. Celecoxib administration significantly reduced myoblast proliferation, viability, fusion, and myotube area in a dose‐dependent manner, whereas NS‐398 had no effect on any of these outcomes. Celecoxib treatment was also associated with reduced phosphorylation of ribosomal protein S6 in myoblasts, and reduced phosphorylation of AKT, p70S6K, S6, and ERK in myotubes. In contrast, NS‐398 did not alter phosphorylation of these molecules in myoblasts or myotubes. In myoblasts, celecoxib significantly reduced mitochondrial membrane potential and respiration, as evidenced by the decreased citric acid cycle (CAC) intermediates cis‐aconitic acid, alpha‐keto‐glutarate acid, succinate acid, and malic acid. Similar results were observed in myotubes, although celecoxib also reduced pyruvic acid, citric acid, and fumaric acid. NS‐398 did not affect CAC intermediates in myoblasts or myotubes. Together, these data reveal that celecoxib inhibits proliferation, differentiation, intracellular signaling, and mitochondrial function in primary human myoblasts and myotubes independent of its function as a COX‐2 inhibitor. Non‐steroidal anti‐inflammatory drugs (NSAIDs), including celecoxib, inhibit cyclooxygenase (COX) enzymes to reduce inflammation. Celecoxib is a widely‐consumed NSAID with high selectivity and potency toward COX‐2. We found that celecoxib inhibited proliferation, differentiation, intracellular signaling, and mitochondrial respiration in cultured primary human skeletal muscle cells through a mechanism independent of its COX‐2 inhibitory action. Our findings suggest that celecoxib may possess significant off‐target effects in skeletal muscle.