Chronic intermittent hypoxia (IH), the major feature of obstructive sleep apnea (OSA) increases myocardial infarct size. Recent data demonstrate that IH-induced cardiomyocyte susceptibility to infarction could be explained by mitochondrial function and/or dynamics alterations. Moreover, AMP-activated protein kinase (AMPK), a major protein involved in cardiomyocyte metabolism is activated by IH in striated skeletal muscle. However, we recently found that AMPK failed to be activated in myocardium from mice exposed to IH.

We aimed at demonstrating whether AMPK activation can be beneficial for ischemia-reperfusion injury following chronic IH exposure.

Mice were exposed to 21days of IH (21-5% FiO₂, 60s-cycles, 8h/day), or normoxia (N) and treated or not with metformin (300mg.kg⁻¹.day⁻¹). Infarct size was measured after in vivo ischemia (45min) and reperfusion (90min). Mitochondrial function was assessed using oxygraphy and spectrofluorimetry. Mitochondrial dynamics and AMPK activation were assessed by Western blot. An insulin tolerance test was also performed.

Metformin abolished the IH-induced increase in infarct size whereas it did not improve systemic insulin sensitivity. Metformin activated AMPK and did not impact the decrease in mitochondrial respiration (O₂ maximal consumption in complex I and II and respiratory control ratio). However, AMPK activation by Metformin seems to reestablish the distinctive IH impact on mitochondrial dynamics (fission and mitophagy).

Metformin treatment is protective against ischemia-reperfusion injury induced by IH only. This suggests that metformin could be an alternative treatment to the currently restrictive one for apneic patients with a high CV risk. Ongoing studies will aim to better characterize the mechanisms by which metformin specifically decreases infarct size under IH.