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• W3174410114 abstract "Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disease. Focal weakness eventually progresses to global muscle weakness and paralysis, but the exact etiology of these events remains unknown. Epidemiological studies indicate that exposure to chronic intermittent hypoxia may trigger ALS in genetically predisposed patients. Mutations within the gene for optineurin (OPTN) was recently associated with ALS. OPTN has multiple roles in various biochemical pathways including regulation of inflammation and autophagy. Through these mechanisms OPTN appears to be neuroprotective but the exact mechanism by which loss of OPTN results in ALS is unknown. Using a novel Optn knock out (Optn−/−) mouse we sought to determine how OPTN deficiency results in ALS during a period of stress. We tested the hypothesis that stress with chronic intermittent hypoxia and hypercapnia (CIHH) exacerbates respiratory insufficiency in ALS and may even trigger earlier disease onset. Six month old wild type (WT) and Optn−/− mice were subjected to CIHH for 8 hours a day for 5 consecutive days. The day prior to CIHH and the day after completion of CIHH, breathing was assessed by whole body plethysmography (WBP) during normoxia (inspired oxygen fraction (FiO2) = 0.21; nitrogen balance) for baseline measures and during a “respiratory” challenge with 10% hypercapnia/hypoxia (FiO2 = 0.10; FiCO2 = 0.07; nitrogen balance). Mice were then euthanized and the diaphragm, tongue, medulla, spinal cord, phrenic nerves, and hypoglossal nerves were collected for histological and immunohistochemical assessment of neuromuscular junction integrity, motor neuron counts and nerve myelination. Spleens were collected to assess T cell mitochondria basal and maximal respiration in CIHH challenged Optn−/− mice. All animals survived the stress of CIHH. Breathing assessment revealed a significant decrease in peak inspiratory flow (PIF) in CIHH challenged Optn−/− mice compared to pre-challenge PIF and compared to WT PIF. Peak expiratory flow (PEF) was significantly decreased in CIHH challenged Optn−/− mice compared to pre-challenge PEF. PIF and PEF are an indirect measure of inspiratory and expiratory muscle strength. In addition, the frequency of breathing was statistically decreased in the Optn−/− CIHH challenged animals. Preliminary results from the mitochondrial oxidation studies reveal a blunted response to maximum mitochondrial stimulation in the Optn−/− CIHH challenged animals. Quantification of neuromuscular junction integrity in the diaphragm as well as hypoglossal and phrenic nerve myelination is ongoing. In conclusion, CIHH triggers early respiratory decline and exacerbates respiratory insufficiency in a novel OPTN deficient ALS mouse model. Support or Funding Information K08HD077040-07 (MKE), R21 NS098131-02 (MKE), This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal." @default.
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• W3174410114 date "2019-04-01" @default.
• W3174410114 modified "2023-09-27" @default.
• W3174410114 title "Chronic Intermittent Hypoxia and Hypercapnia Induces Respiratory Insufficiency in an Amyotrophic Lateral Sclerosis Mouse Model" @default.
• W3174410114 doi "https://doi.org/10.1096/fasebj.2019.33.1_supplement.551.19" @default.
• W3174410114 hasPublicationYear "2019" @default.
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