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. 2013 Nov 13;8(11):e80248.
doi: 10.1371/journal.pone.0080248. eCollection 2013.

Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men

Tzu-Pin Weng  1 , Shu-Chun Huang, Yu-Fen Chuang, Jong-Shyan Wang
Affiliations

Effects of interval and continuous exercise training on CD4 lymphocyte apoptotic and autophagic responses to hypoxic stress in sedentary men

Tzu-Pin Weng et al. PLoS One. .

Abstract

Exercise is linked with the type/intensity-dependent adaptive immune responses, whereas hypoxic stress facilitates the programmed death of CD4 lymphocytes. This study investigated how high intensity-interval (HIT) and moderate intensity-continuous (MCT) exercise training influence hypoxia-induced apoptosis and autophagy of CD4 lymphocytes in sedentary men. Thirty healthy sedentary males were randomized to engage either HIT (3-minute intervals at 40% and 80%VO2max, n=10) or MCT (sustained 60%VO2max, n=10) for 30 minutes/day, 5 days/week for 5 weeks, or to a control group that did not received exercise intervention (CTL, n=10). CD4 lymphocyte apoptotic and autophagic responses to hypoxic exercise (HE, 100 W under 12%O2 for 30 minutes) were determined before and after various regimens. The results demonstrated that HIT exhibited higher enhancements of pulmonary ventilation, cardiac output, and VO2 at ventilatory threshold and peak performance than MCT did. Before the intervention, HE significantly down-regulated autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions and acridine orange staining, and simultaneously enhanced apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels and phosphotidylserine exposure in CD4 lymphocytes. However, five weeks of HIT and MCT, but not CTL, reduced the extents of declined autophagy and potentiated apoptosis in CD4 lymphocytes caused by HE. Furthermore, both HIT and MCT regimens manifestly lowered plasma myeloperoxidase and interleukin-4 levels and elevated the ratio of interleukin-4 to interferon-γ at rest and following HE. Therefore, we conclude that HIT is superior to MCT for enhancing aerobic fitness. Moreover, either HIT or MCT effectively depresses apoptosis and promotes autophagy in CD4 lymphocytes and is accompanied by increased interleukin-4/interferon-γ ratio and decreased peroxide production during HE.

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Conflict of interest statement

Competing Interests: No conflicts of interest, financial or otherwise, are declared by the authors.

Figures

Figure 1
Figure 1. Design and time course of the experiment.
Subjects (n=30) were randomly divided into three groups: control (CTL; n=10), high-intensity interval training (HIT, n=10), and moderate continuous training (MCT, n=10). Subjects in three groups were confront inactive (CTL group), or trained on a bicycle ergometer for five cycles 3-min at 80% of VO2max interspersed with a 3-min active recovery at 40% of VO2max (HIT group), or continuous at 60% of VO2max for 30 min/day, 5 days/week, for 5 weeks. Each subject had to perform 1) graded exercise tests (GXT) 4 days before and 4 days after the intervention, 2) hypoxic exercise test (HE) on the second day before and on the second day after the intervention. At rest and immediately after the HE test, blood samples were collected. Grey cyclist, graded exercise test; striped cyclist, hypoxic (12%O2) exercise test; black cyclist, 5-week exercise intervention.
Figure 2
Figure 2. Flow cytometric analysis of apoptosis and autophagy in CD4 lymphocyte (Day 0).
Graph showing the flow cytometric analysis of high intensity-interval (HIT) (A) and moderate intensity-continuous (MCT) (B) exercise training effects on main biomarkers of apoptosis and autophagy [i.e., LAMP-2, active caspase -3, and annexin V staining (phosphotidylserine exposure)] in untreated CD4 lymphocytes (Day 0). Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0).
Figure 3
Figure 3. Flow cytometric analysis of apoptosis and autophagy in CD4 lymphocyte (Day 1).
Graph showing the flow cytometric analysis of high intensity-interval (HIT) (A) and moderate intensity-continuous (MCT) (B) exercise training effects on main biomarkers of apoptosis and autophagy [i.e., LAMP-2, active caspase -3, and annexin V staining (phosphotidylserine exposure)] in rapamycin-treated CD4 lymphocytes (Day 1). Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0).
Figure 4
Figure 4. Effects of various interventions on levels of mTOR and phospho-Bcl-2 in CD4 lymphocytes.
(A-C) mTOR; (D-F) phospho-Bcl-2; HIT, high-intensity interval training group (A, D); MCT, moderate continuous training group (B, E) ; CTL, control group (C, F); Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0); Vehicle and Rap, CD4 lymphocytes treated in the absence and presence of rapamycin (500nM) for 24 h (Day 1), respectively. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post; ‡P<0.05, HIT or MCT vs. CTL. Values were mean±SE. n=10 in each group.
Figure 5
Figure 5. Effects of various interventions on levels of Atg-1 and Beclin-1 in CD4 lymphocytes.
(A-C) Atg-1; (D-F) Beclin-1; HIT, high-intensity interval training group (A, D); MCT, moderate continuous training group (B, E) ; CTL, control group (C, F); Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0); Vehicle and Rap, CD4 lymphocytes treated in the absence and presence of rapamycin (500nM) for 24 h (Day 1), respectively. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post; ‡P<0.05, HIT or MCT vs. CTL. Values were mean±SE. n=10 in each group.
Figure 6
Figure 6. Effects of various interventions on levels of Atg-12, LC3-II, and LAMP-2 in CD4 lymphocytes.
(A-C) Atg-12; (D-F) LC3-II; (G-I) LAMP-2; HIT, high-intensity interval training group (A, D, G); MCT, moderate continuous training group (B, E, H); CTL, control group (C, F, I); Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0); Vehicle and Rap, CD4 lymphocytes treated in the absence and presence of rapamycin (500nM) for 24 h (Day 1), respectively. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post; ‡P<0.05, HIT or MCT vs. CTL. Values were mean±SE. n=10 in each group.
Figure 7
Figure 7. Effects of various interventions on levels of acridine orange (AO)-labeled and phosphatidylserine (PS)-exposed in CD4 lymphocytes.
(A-C) AO-labeled; (D-F) PS-exposed; HIT, high-intensity interval training group (A, D); MCT, moderate continuous training group (B, E) ; CTL, control group (C, F); Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0); Vehicle and Rap, CD4 lymphocytes treated in the absence and presence of rapamycin (500nM) for 24 h (Day 1), respectively. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post; ‡P<0.05, HIT or MCT vs. CTL. Values were mean±SE. n=10 in each group.
Figure 8
Figure 8. Effects of various interventions on levels of active caspase 9 and caspase 3 in CD4 lymphocytes.
(A-C) caspase 9; (D-F) caspase 3; HIT, high-intensity interval training group (A, D); MCT, moderate continuous training group (B, E) ; CTL, control group (C, F); Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test; Basal, untreated CD4 lymphocytes (Day 0); Vehicle and Rap, CD4 lymphocytes treated in the absence and presence of rapamycin (500nM) for 24 h (Day 1), respectively. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post; ‡P<0.05, HIT or MCT vs. CTL. Values were mean±SE. n=10 in each group.
Figure 9
Figure 9. Effects of various interventions on levels of interleukin-4 (IL-4) and interferon-γ (INF-γ) and ratio of IL-4 to INF-γ in plasma.
(A) IL-4; (B) INF-γ; (C) ratio of IL-4 to INF-γ; HIT, high-intensity interval training group; MCT, moderate continuous training group; CTL, control group; Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post. Values were mean±SE. n=10 in each.
Figure 10
Figure 10. Effects of various interventions on levels of interleukin-6 (IL-6) and myeloperoxidase (MPO) in plasma.
(A) IL-6; (B) MPO; HIT, high-intensity interval training group; MCT, moderate continuous training group; CTL, control group; Pre, pre-intervention; Post, post-intervention; Rest, resting; HE, hypoxic (12%O2) exercise test. *P<0.05, Rest vs. HE; +P<0.05, Pre vs. Post. Values were mean±SE. n=10 in each group.
Figure 11
Figure 11. Possible mechanisms of improved aerobic capacity and modulated CD4 lymphocyte autophagic and apoptotic responses to hypoxic stress by various exercise regimens.
High-intensity interval training (HIT) is more effective for enhancing aerobic capacity (VO2max) by increasing cardiac output response to exercise, compared to moderate continuous training (MCT) does. A bout of 12%O2 exercise (HE) suppresses the initiation, elongation, maturation, and fusion of autophagy by decreased beclin-1, Atg-1, LC3-II, Atg-12, and LAMP-2 expressions, and simultaneously enhances the initiation and execution of apoptosis by increased phospho-Bcl-2 and active caspase-9/-3 levels in CD4 lymphocytes. However, five weeks of HIT and MCT attenuate the extents of declined autophagy and potentiated apoptosis in CD4 lymphocyte caused by HE, possibly by (1) down-regulating mTOR expression, (2) lowering Th2 cytokine (indicated by a decrease in interleukin-4, IL-4) production, and (3) depressing elevation of oxidative stress by HE. Besides, HIT, but not MCT, further depresses resting myeloperoxidase (MPO) and IL-4 levels in plasma.
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This work was supported by the National Science Council of Taiwan (grant number NSC 100-2314-B-182-004-MY3), Chang Gung Medical Research Program (grant number CMRPG 280241) and the Healthy Aging Research Center, Chang Gung University (grant number EMRPD1A0841). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
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