Enhancement of phrenic long-term facilitation following repetitive acute intermittent hypoxia is blocked by the glycolytic inhibitor 2-deoxyglucose

Abstract

Moderate acute intermittent hypoxia (mAIH) elicits a form of respiratory motor plasticity known as phrenic long-term facilitation (pLTF). Preconditioning with modest protocols of chronic intermittent hypoxia enhances pLTF, demonstrating pLTF metaplasticity. Since "low-dose" protocols of repetitive acute intermittent hypoxia (rAIH) show promise as a therapeutic modality to restore respiratory (and nonrespiratory) motor function in clinical disorders with compromised breathing, we tested 1) whether preconditioning with a mild rAIH protocol enhances pLTF and hypoglossal (XII) LTF and 2) whether the enhancement is regulated by glycolytic flux. In anesthetized, paralyzed, and ventilated adult male Lewis rats, mAIH (three 5-min episodes of 10% O) elicited pLTF (pLTF at 60 min post-mAIH: 49 ± 5% baseline). rAIH preconditioning (ten 5-min episodes of 11% O/day with 5-min normoxic intervals, 3 times per week, for 4 wk) significantly enhanced pLTF (100 ± 16% baseline). XII LTF was unaffected by rAIH. When glycolytic flux was inhibited by 2-deoxy-d-glucose (2-DG) administered via drinking water (~80 mg·kg·day), pLTF returned to normal levels (58 ± 8% baseline); 2-DG had no effect on pLTF in normoxia-pretreated rats (59 ± 7% baseline). In ventral cervical (C) spinal homogenates, rAIH increased inducible nitric oxide synthase mRNA vs. normoxic controls, an effect blocked by 2-DG. However, there were no detectable effects of rAIH or 2-DG on several molecules associated with phrenic motor plasticity, including serotonin 2A, serotonin 7, brain-derived neurotrophic factor, tropomyosin receptor kinase B, or VEGF mRNA. We conclude that modest, but prolonged, rAIH elicits pLTF metaplasticity and that a drug known to inhibit glycolytic flux (2-DG) blocks pLTF enhancement.

The Bidirectional Relationship Between Obstructive Sleep Apnea and Metabolic Disease

“…Interestingly, oxygen and glucose signals can potentiate one another, leading to scenarios where dysregulation of glucose may lead to a dysregulation of O 2 and CO 2 sensing which in turn may affect breathing ( 137 ). Addition of 2-deoxy-d-glucose (2DG; a glucoprivic agent) in the drinking water of rats can prevent phrenic long-term facilitation, a form of respiratory motor plasticity, suggesting that alterations in glucose sensing can directly alter breathing ( 138 ). Work in this field is ongoing and shows great potential in elucidating bidirectional pathways between glucose control and disordered breathing via the sympathetic system.…”

Spinal AMP kinase activity differentially regulates phrenic motor plasticity

“…Recent studies from our laboratory demonstrate that moderate AIH-induced 5-HT 2 -dependent phrenic long-term facilita-tion is unaffected by systemic 2-DG (27). Conversely, 2-DG constrains respiratory metaplasticity (enhanced phrenic longterm facilitation) after 4 wk of repetitive AIH preconditioning (27). Although mechanisms underlying respiratory metaplasticity are largely unknown, a loss of cross-talk inhibition between the Q and S pathways to pMF has been postulated, leading to additive contributions from both the Q and S pathways (27).…”

“…Recent studies from our laboratory demonstrate that moderate AIH-induced 5-HT 2 -dependent phrenic long-term facilita-tion is unaffected by systemic 2-DG (27). Conversely, 2-DG constrains respiratory metaplasticity (enhanced phrenic longterm facilitation) after 4 wk of repetitive AIH preconditioning (27).…”

“…When activated by metabolic stress, such as severe hypoxia, AMPK inhibits mTORC1 signaling (4,5,7,20,37,43) and regulates certain forms of hippocampal synaptic plasticity (37). On the other hand, glycolytic flux inhibition with 2-deoxyglucose (2-DG), and presumed AMPK activation, has minimal impact on Q pathway-dependent pMF following moderate acute intermittent hypoxia (27). Thus, AMPK likely regulates some, but not all, forms of phrenic motor plasticity.…”

Carotid Bodies and the Integrated Cardiorespiratory Response to Hypoxia

“…An emerging goal of contemporary translational research is to identify safe and effective therapeutic strategies for management and treatment of the long-term consequences of adaptations to chronic intermittent hypoxia (106,143,153,236). Pharmacological and immunological approaches and gene therapy are being actively considered (145,148,182,236,243). Ablation or denervation of the carotid bodies for resistant hypertension is also being evaluated in preclinical research (106).…”