title: Autophagy-associated atrophy and metabolic remodeling of the mouse diaphragm after short-term intermittent hypoxia.
abstract: BACKGROUND
  Short-term intermittent hypoxia (IH) is common in patients with acute respiratory disorders. Although prolonged exposure to hypoxia induces atrophy and increased fatigability of skeletal muscle, the response to short-term IH is less well known. We hypothesized that the diaphragm and limb muscles would adapt differently to short-term IH given that hypoxia stimulates ventilation and triggers a superimposed exercise stimulus in the diaphragm.
  
  
  METHODS
  We determined the structural, metabolic, and contractile properties of the mouse diaphragm after 4 days of IH (8 hours per day, 30 episodes per hour to a FiO2 nadir=6%), and compared responses in the diaphragm to a commonly studied reference limb muscle, the tibialis anterior. Outcome measures included muscle fiber size, assays of muscle proteolysis (calpain, ubiquitin-proteasome, and autophagy pathways), markers of oxidative stress and mitochondrial function, quantification of intramyocellular lipid and lipid metabolism genes, type I myosin heavy chain (MyHC) expression, and in vitro contractile properties.
  
  
  RESULTS
  After 4 days of IH, the diaphragm alone demonstrated significant atrophy (30% decrease of myofiber size) together with increased LC3B-II protein (2.4-fold) and mRNA markers of the autophagy pathway (LC3B, Gabarapl1, Bnip3), whereas active calpain and E3 ubiquitin ligases (MuRF1, atrogin-1) were unaffected in both muscles. Succinate dehydrogenase activity was significantly reduced by IH in both muscles. However, only the diaphragm exhibited increased intramyocellular lipid droplets (2.5-fold) after IH, along with upregulation of genes linked to activated lipid metabolism. In addition, although the diaphragm showed evidence for acute fatigue immediately following IH, it underwent an adaptive fiber type switch toward slow type I MyHC-expressing fibers, associated with greater intrinsic endurance of the muscle during repetitive stimulation in vitro.
  
  
  CONCLUSIONS
  Short-term IH induces preferential atrophy in the mouse diaphragm together with increased autophagy and a rapid compensatory metabolic adaptation associated with enhanced fatigue resistance.
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada; Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Giordano
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada; Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Christian
authors.initials: C
authors.lastname: Lemaire
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada; Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Tong
authors.initials: T
authors.lastname: Li
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada; Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: R John
authors.initials: RJ
authors.lastname: Kimoff
authors.affiliation: Meakins-Christie Laboratories and Respiratory Division, McGill University, Montreal, Quebec, Canada; Program for Translational Research in Respiratory Diseases, McGill University Health Centre Research Institute, Montreal, Quebec, Canada.
authors.forename: Basil J
authors.initials: BJ
authors.lastname: Petrof
mesh_terms: D000222:Adaptation, Physiological / Q000502:physiology; D000818:Animals; D001284:Atrophy / Q000473:pathology; D001343:Autophagy / Q000502:physiology*; D003964:Diaphragm / Q000378:metabolism / Q000473:pathology*; D000860:Hypoxia / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D009119:Muscle Contraction / Q000502:physiology; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D018995:Myosin Heavy Chains / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism
chemical_list: D046988:Proteasome Endopeptidase Complex; D018995:Myosin Heavy Chains