Ibuprofen delays senolytic effects of exercise in human skeletal muscle: A randomized control crossover trial

Abstract Background: Inflammation is required for muscle regeneration after injury. Purpose: To examine the role of inflammation on the exercise-induced senolytic effect in human skeletal muscle. Methods: Nonsteroidal anti-inflammatory treatments were administered using a placebo-controlled counterbalanced crossover trial (washout: > 3 weeks). Sedentary men (n = 12) aged 20-26 consumed ibuprofen (total dose: 1200 mg) or placebo before and after high-intensity interval exercise (HIIE) at 120% maximum aerobic power (total work ~ 70 kJ). Muscle biopsies were taken 3 hours and 24 hours after HIIE for tissue analysis compared to their pre-exercise baseline. Results: Following a 3-h recovery after HIIE, DNA strand breaks and γ-H2AX+ myofibers were comparable to baseline suggesting a quick post-exercise recovery without observed differences between placebo and ibuprofen. We found concurrent decreases in p16INK4a mRNA (-82%, p = 0.01, d = 1.23) and CD11b mRNA (-87%, p = 0.02, d = 1.03) within 3 hours, persisting for 24 hours. Immunohistochemistry analysis indicated that p16INK4a -expressing cells were located surrounding myofibers. Ibuprofen delayed both senolytic and anti-inflammatory effects of HIIE in muscle tissues. A strong correlation between p16INK4a mRNA and CD11b mRNA in muscle tissues (r = 0.88, p < 0.001) suggests the senolytic effect of exercise on lowering pro-inflammatory myeloid differentiation in human muscles. Conclusion: This study provides the first evidence suggesting high intensity exercise is a senolytic intervention to lower baseline inflammation persisting over an extended period. Pharmacological suppression of inflammation during muscle contraction delays this senolytic effect.