Senolytic effect of high intensity interval exercise on human skeletal muscle

Abstract

p16 INK4a expression is a robust biomarker of senescence for stem cells in human tissues. Here we examined the effect of exercise intensity on in vivo senescence in skeletal muscle, using a randomized counter-balanced crossover design. Biopsied vastus lateralis of 9 sedentary men (age 26.1 ± 2.5 y) were assessed before and after a single bout of moderate steady state exercise (SSE, 60% maximal aerobic power) and high intensity interval exercise (HIIE, 120% maximal aerobic power) on a cycloergometer accumulating same amount of cycling work (in kilojoule). Increases in cell infiltration (+1.2 folds), DNA strand break (+1.3 folds), and γ-H2AX + myofibers (+1.1 folds) occurred immediately after HIIE and returned to baseline in 24 h (p < 0.05). Muscle p16 Ink4a mRNA decreased 24 h after HIIE (−57%, p < 0.05). SSE had no effect on cell infiltration, p16 Ink4a mRNA, and DNA strand break in muscle tissues. Senescence-lowering effect of HIIE was particularly prominent in the muscle with high pre-exercise p16INK4a expression, suggesting that exercise intensity determines the level of selection pressure to tissue stem cells at late senescent stage in human skeletal muscle. This evidence provides an explanation for the discrepancy between destructive nature of high intensity exercise and its anti-aging benefits.

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

“…1D). We have previously shown increased γ-H2AX levels immediately after HIIE [15]. samples in this study (r = 0.88, p < 0.001) (Fig.…”

“…Neutrophils, featured by MPO expression, can speci cally recognize and clear senescent cells by phagocytosis, forming an innate feedback mechanism to maintain youthfulness of tissues [12,13]. The result of the present study, together with our previous ndings [15], suggests that a longer period of anti-in ammatory response in skeletal muscle can be attained by a transient pro-in ammatory stimulus from a short episode of HIIE. Senescent cell accumulation is a known contributor to chronic in ammation, evidenced by a prominent increase in the secretion of proin ammatory mediators [29].…”

“…HIIE is known to induce transient in ammation and DNA damage in skeletal muscle [15]. We have further found that the senolytic effect of exercise in human skeletal muscle occurs only at an intensity high enough to induce signi cant muscle in ammation (such as HIIE), as opposed to moderate intensity exercises with a similar amount of cycling work [15].…”

“…An acute bout of high intensity exercise can induce an immediate release of bone marrow stem cells into circulation [30]. We have previously shown increased bone-marrow stem cell homing and proliferation in muscle tissues 24 hours after HIIE [15,19]. Chronic in ammation is currently known as a common denominator of age-associated metabolic disorders [31].…”

“…We have recently reported a signi cant decrease in p16 INK4a mRNA levels in human skeletal muscle 24 hours after HIIE in young men aged ~ 26 y [15]. This senolytic outcome occurred after signi cant immune cell in ltration in muscle tissues immediately post-exercise.…”