High-intensity training reduces intermittent hypoxia-induced ER stress and myocardial infarct size

Abstract

Chronic intermittent hypoxia (IH) is described as the major detrimental factor leading to cardiovascular morbimortality in obstructive sleep apnea (OSA) patients. OSA patients exhibit increased infarct size after a myocardial event, and previous animal studies have shown that chronic IH could be the main mechanism. Endoplasmic reticulum (ER) stress plays a major role in the pathophysiology of cardiovascular disease. High-intensity training (HIT) exerts beneficial effects on the cardiovascular system. Thus, we hypothesized that HIT could prevent IH-induced ER stress and the increase in infarct size. Male Wistar rats were exposed to 21 days of IH (21-5% fraction of inspired O2, 60-s cycle, 8 h/day) or normoxia. After 1 wk of IH alone, rats were submitted daily to both IH and HIT (2 ϫ 24 min, 15-30m/min). Rat hearts were either rapidly frozen to evaluate ER stress by Western blot analysis or submitted to an ischemia-reperfusion protocol ex vivo (30 min of global ischemia/ 120 min of reperfusion). IH induced cardiac proapoptotic ER stress, characterized by increased expression of glucose-regulated protein kinase 78, phosphorylated protein kinase-like ER kinase, activating transcription factor 4, and C/EBP homologous protein. IH-induced myocardial apoptosis was confirmed by increased expression of cleaved caspase-3. These IH-associated proapoptotic alterations were associated with a significant increase in infarct size (35.4 Ϯ 3.2% vs. 22.7 Ϯ 1.7% of ventricles in IH ϩ sedenary and normoxia ϩ sedentary groups, respectively, P Ͻ 0.05). HIT prevented both the IH-induced proapoptotic ER stress and increased myocardial infarct size (28.8 Ϯ 3.9% and 21.0 Ϯ 5.1% in IH ϩ HIT and normoxia ϩ HIT groups, respectively, P ϭ 0.28). In conclusion, these findings suggest that HIT could represent a preventive strategy to limit IHinduced myocardial ischemia-reperfusion damages in OSA patients.obstructive sleep apnea; intermittent hypoxia; ischemia-reperfusion; high-intensity aerobic training; endoplasmic reticulum stress NEW & NOTEWORTHYWe demonstrated that intermittent hypoxia induced cardiac proapoptotic ER stress and increased infarct size, which were prevented by high-intensity aerobic training. These results strengthen the need for early identification of patients with sleep apnea at risk for cardiovascular complications and suggest that exercise can be used as a new preventive strategy for these patients.

High intensity aerobic exercise training improves chronic intermittent hypoxia-induced insulin resistance without basal autophagy modulation

“…Furthermore, we cannot exclude a greater maximal cardiac output. However this hypothesis is not consistent with the rather deleterious cardiac effects of IH24.…”

“…Whether in rodents or humans, exercise improves liver insulin resistance. Moreover, since IH can disturb glucose homeostasis via sympathetic hyperactivity2938, we cannot exclude the well-known decrease in sympathetic activity induced by exercise training in the improvement of IR24.…”

“…Intense exercise intensity (high intensity training: HIT) seems suitable and more efficient to get rapid benefits on metabolic health on whole body insulin sensitivity and some of its contributors such muscle microvascular density and eNOS protein2223. In previous studies performed on rat24 and in mice (unpublished results), we assessed metabolic and functional variables to determine which protocol (moderate intensity aerobic endurance training or high-intensity aerobic endurance training (HIT)) of equal volume (i.e. total energy expenditure although different intensity) promoted more beneficial outcomes after short-term training.…”

Imbalance of ER and Mitochondria Interactions: Prelude to Cardiac Ageing and Disease?

“…In an aged rat model, a combination of intermittent ladder-climbing exercise training and a reduced caloric intake were found to decrease the levels of ER stress-related proteins, including phosphorylated PERK and CHOP, proteins that contribute to cardiac muscle damage in ageing [94]. Moreover, high-intensity training can improve cardiac function and reduce cardiac infarction by decreasing the expression of GRP78, phosphorylated PERK, phosphorylated eIF2α, ATF4, ATF6, XBP1, CHOP, and cleaved caspase-3 in an intermittent I/R rat model [95,96]. In addition, treadmill exercise has been shown to ameliorate ER stress by down-regulating phosphorylated eIF2α and ATF6 in diabetic mice [97].…”

Chronic intermittent hypoxia and obstructive sleep apnea: an experimental and clinical approach

“…Preconditioning is a procedure by which potentially deleterious stimuli are applied near and/or below the threshold of damage to the organism. Mice exposed for a short period of just once a day survived longer than mice exposed to long and severe hypoxia with less cellular and tissue injury at lung, cerebral, and myocardium levels 14,28. After this procedure, tissues and organs can develop resistance or tolerance to the same noxious stimuli preventing or reducing the injury of IH 17.…”