title: Partial Support Ventilation and Mitochondrial-Targeted Antioxidants Protect against Ventilator-Induced Decreases in Diaphragm Muscle Protein Synthesis.
abstract: Mechanical ventilation (MV) is a life-saving intervention in patients in respiratory failure. Unfortunately, prolonged MV results in the rapid development of diaphragm atrophy and weakness. MV-induced diaphragmatic weakness is significant because inspiratory muscle dysfunction is a risk factor for problematic weaning from MV. Therefore, developing a clinical intervention to prevent MV-induced diaphragm atrophy is important. In this regard, MV-induced diaphragmatic atrophy occurs due to both increased proteolysis and decreased protein synthesis. While efforts to impede MV-induced increased proteolysis in the diaphragm are well-documented, only one study has investigated methods of preserving diaphragmatic protein synthesis during prolonged MV. Therefore, we evaluated the efficacy of two therapeutic interventions that, conceptually, have the potential to sustain protein synthesis in the rat diaphragm during prolonged MV. Specifically, these experiments were designed to: 1) determine if partial-support MV will protect against the decrease in diaphragmatic protein synthesis that occurs during prolonged full-support MV; and 2) establish if treatment with a mitochondrial-targeted antioxidant will maintain diaphragm protein synthesis during full-support MV. Compared to spontaneously breathing animals, full support MV resulted in a significant decline in diaphragmatic protein synthesis during 12 hours of MV. In contrast, diaphragm protein synthesis rates were maintained during partial support MV at levels comparable to spontaneous breathing animals. Further, treatment of animals with a mitochondrial-targeted antioxidant prevented oxidative stress during full support MV and maintained diaphragm protein synthesis at the level of spontaneous breathing animals. We conclude that treatment with mitochondrial-targeted antioxidants or the use of partial-support MV are potential strategies to preserve diaphragm protein synthesis during prolonged MV.
authors.affiliation: Department of Kinesiology, Temple University, Philadelphia, Pennsylvania, United States of America.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Hudson
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Ashley J
authors.initials: AJ
authors.lastname: Smuder
authors.affiliation: Department of Natural Sciences, Ohio Dominican University, Columbus, Ohio, United States of America.
authors.forename: W Bradley
authors.initials: WB
authors.lastname: Nelson
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Wiggs
authors.affiliation: Department of Health and Kinesiology, Texas A&M University, College Station, Texas, United States of America.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Shimkus
authors.affiliation: Department of Health and Kinesiology, Texas A&M University, College Station, Texas, United States of America.
authors.forename: James D
authors.initials: JD
authors.lastname: Fluckey
authors.affiliation: Department of Pharmacology, Weill Cornell Medical College, New York, New York, United States of America.
authors.forename: Hazel H
authors.initials: HH
authors.lastname: Szeto
authors.affiliation: Department of Applied Physiology and Kinesiology, Center for Exercise Science, University of Florida, Gainesville, Florida, United States of America.
authors.forename: Scott K
authors.initials: SK
authors.lastname: Powers
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000378:metabolism* / Q000494:pharmacology; D003964:Diaphragm / Q000187:drug effects / Q000378:metabolism* / Q000503:physiopathology; D004195:Disease Models, Animal; D005260:Female; D000076222:Mechanistic Target of Rapamycin Complex 1; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D046912:Multiprotein Complexes / Q000378:metabolism; D018908:Muscle Weakness / Q000378:metabolism; D018384:Oxidative Stress / Q000187:drug effects; D014176:Protein Biosynthesis / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051381:Rats; D012119:Respiration; D012121:Respiration, Artificial / Q000009:adverse effects*; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D013997:Time Factors; D012122:Ventilators, Mechanical / Q000009:adverse effects
chemical_list: D000975:Antioxidants; D046912:Multiprotein Complexes; D000076222:Mechanistic Target of Rapamycin Complex 1; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases