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

Marion Pauly,Allan Assense,Hervé Dubouchaud,Josiane Castells,Patrice Flore,Amandine Thomas,Henri Benoit,Damien Freyssenet,Aurélie Rondon

doi:10.1038/srep43663

Abstract

Chronic intermittent hypoxia (IH) associated with obstructive sleep apnea (OSA) is a major risk factor for cardiovascular and metabolic diseases (insulin resistance: IR). Autophagy is involved in the pathophysiology of IR and high intensity training (HIT) has recently emerged as a potential therapy. We aimed to confirm IH-induced IR in a tissue-dependent way and to explore the preventive effect of HIT on IR-induced by IH. Thirty Swiss 129 male mice were randomly assigned to Normoxia (N), Intermittent Hypoxia (IH: 21–5% FiO2, 30 s cycle, 8 h/day) or IH associated with high intensity training (IH HIT). After 8 days of HIT (2*24 min, 50 to 90% of Maximal Aerobic Speed or MAS on a treadmill) mice underwent 14 days IH or N. We found that IH induced IR, characterized by a greater glycemia, an impaired insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver. Nevertheless, MAS and AKT phosphorylation were greater in muscle after IH. IH associated with HIT induced better systemic insulin sensitivity and AKT phosphorylation in liver. Autophagy markers were not altered in both conditions. These findings suggest that HIT could represent a preventive strategy to limit IH-induced IR without change of basal autophagy.

Highlights

Involved in the deleterious effects of intermittent hypoxia (IH) could help to provide new alternative or complementary treatment to CPAP in the management of Obstructive sleep apnea (OSA)-associated metabolic impairment
Thereafter the weight plateaued until the last day of exposure (Fig. 1B). This weight loss was paralleled by a decrease in food intake in both groups exposed to intermittent hypoxia (N: 5.2 ± 5.2; IH: 3.0 ± 0.1; IH HIT: 3.8 ± 0.1 g.day−1; p < 0.001; Fig. 1C)
We confirmed that intermittent hypoxia induces insulin resistance, characterized by greater fast glycemia, an impaired systemic insulin sensitivity and lower AKT phosphorylation in adipose tissue and liver in our model

Summary

Introduction

Involved in the deleterious effects of IH could help to provide new alternative or complementary treatment to CPAP in the management of OSA-associated metabolic impairment. It protects against cellular toxicity and death by recycling oxidized proteins and aged organelles It is finely regulated by more than 30 autophagy related genes and involves several steps after induction: generation of the nucleation complex, autophagosome formation, and cargo recognition[11]. Autophagy can be inhibited by the insulin pathway PI3K-AKT-mTOR and mTOR activation is regulated by AKT13. Hypoxia itself, via the transcription factor HIF-1, directly activates autophagy through BNIP3 regulation (allowing dissociation of Beclin from Bcl-2)[14]. The question whether the insulin resistance associated to OSA or IH is related to modulation of autophagy in a tissue dependent manner remains unanswered. We hypothesized that chronic IH exposure would fail to activate autophagy, in a tissue dependent manner, due to the alteration of insulin sensitivity in OSA

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Conclusion