Angela L. Roger , Meredith L. Huston , Madison Spaulding , Caroline M. Metz , Ryan Froeb , Raechel Wu , Sean Kehoe , Gordon S. Mitchell , Mai K. ElMallah
{"title":"急性间歇缺氧治疗可适度改善庞贝病患者的呼吸。","authors":"Angela L. Roger , Meredith L. Huston , Madison Spaulding , Caroline M. Metz , Ryan Froeb , Raechel Wu , Sean Kehoe , Gordon S. Mitchell , Mai K. ElMallah","doi":"10.1016/j.resp.2025.104489","DOIUrl":null,"url":null,"abstract":"<div><div>Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult <em>Gaa</em><sup><em>-/-</em></sup> mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in <em>Gaa</em><sup><em>-/-</em></sup> mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in <em>Gaa</em><sup><em>-/-</em></sup> may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.</div></div>","PeriodicalId":20961,"journal":{"name":"Respiratory Physiology & Neurobiology","volume":"338 ","pages":"Article 104489"},"PeriodicalIF":1.6000,"publicationDate":"2025-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":"{\"title\":\"Therapeutic acute intermittent hypoxia modestly improves breathing in Pompe disease\",\"authors\":\"Angela L. Roger , Meredith L. Huston , Madison Spaulding , Caroline M. Metz , Ryan Froeb , Raechel Wu , Sean Kehoe , Gordon S. Mitchell , Mai K. ElMallah\",\"doi\":\"10.1016/j.resp.2025.104489\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<div><div>Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult <em>Gaa</em><sup><em>-/-</em></sup> mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in <em>Gaa</em><sup><em>-/-</em></sup> mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in <em>Gaa</em><sup><em>-/-</em></sup> may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.</div></div>\",\"PeriodicalId\":20961,\"journal\":{\"name\":\"Respiratory Physiology & Neurobiology\",\"volume\":\"338 \",\"pages\":\"Article 104489\"},\"PeriodicalIF\":1.6000,\"publicationDate\":\"2025-09-09\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Respiratory Physiology & Neurobiology\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://www.sciencedirect.com/science/article/pii/S1569904825001004\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q3\",\"JCRName\":\"PHYSIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Respiratory Physiology & Neurobiology","FirstCategoryId":"3","ListUrlMain":"https://www.sciencedirect.com/science/article/pii/S1569904825001004","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q3","JCRName":"PHYSIOLOGY","Score":null,"Total":0}
Therapeutic acute intermittent hypoxia modestly improves breathing in Pompe disease
Pompe disease is an autosomal recessive neuromuscular disorder characterized by a deficiency of acid α-glucosidase (GAA), an enzyme responsible for lysosomal glycogen degradation in all cells. Respiratory distress is a common symptom among patients with Pompe disease resulting from weakness of primary respiratory neuromuscular units of the diaphragm and genioglossus and the motor neurons which innervate them. The only FDA approved treatment is enzyme replacement therapy (ERT) of recombinant human GAA (rhGAA) which slows the decline of motor function and extends life expectancy. However, ERT does not cross the blood-brain barrier and thus, is unable to treat the critical pathology present in motor neurons hindering long-term efficacy. In the present study, we sought to explore an alternative treatment for Pompe patients to improve breathing by improving the function of motor neurons. Therapeutic acute intermittent hypoxia (tAIH) is a non-invasive therapeutic modality which has had success in improving respiratory and non-respiratory motor function in patients with spinal cord injury, amyotrophic lateral sclerosis, multiple sclerosis, and stroke. Here, we treated adult Gaa-/- mice with a single, week-long tAIH protocol, followed by bi-weekly tAIH for 4 months. We report three critical findings: (1) both short and long-term tAIH therapy modestly improve breathing in Gaa-/- mice; (2) long-term tAIH-therapy in WT mice moderately elevates breathing responses; and (3) these trending improvements to respiration in Gaa-/- may be related to changes in chemoreflex activation, reduced kyphosis, and improved overlap of acetylcholine receptors and phrenic motor neuron axon terminals in the diaphragm muscle.
期刊介绍:
Respiratory Physiology & Neurobiology (RESPNB) publishes original articles and invited reviews concerning physiology and pathophysiology of respiration in its broadest sense.
Although a special focus is on topics in neurobiology, high quality papers in respiratory molecular and cellular biology are also welcome, as are high-quality papers in traditional areas, such as:
-Mechanics of breathing-
Gas exchange and acid-base balance-
Respiration at rest and exercise-
Respiration in unusual conditions, like high or low pressure or changes of temperature, low ambient oxygen-
Embryonic and adult respiration-
Comparative respiratory physiology.
Papers on clinical aspects, original methods, as well as theoretical papers are also considered as long as they foster the understanding of respiratory physiology and pathophysiology.