title: Differential Effects of Sepsis and Chronic Inflammation on Diaphragm Muscle Fiber Type, Thyroid Hormone Metabolism, and Mitochondrial Function.
abstract: BACKGROUND
  The diaphragm is the main respiratory muscle, and its function is compromised during severe illness. Altered local thyroid hormone (TH) metabolism may be a determinant of impaired muscle function during illness.
  
  
  METHODS
  This study investigates the effects of bacterial sepsis and chronic inflammation on muscle fiber type, local TH metabolism, and mitochondrial function in the diaphragm. Two mouse models were used: sepsis induced by S. pneumoniae infection or chronic inflammation induced by subcutaneous turpentine injection. In vitro, the effect of bacterial endotoxin (LPS) on mitochondrial function in C2C12 myotubes was studied.
  
  
  RESULTS
  Sepsis induced a transient increase in the fiber type I profile and increased Dio3 expression while decreasing Dio2, Thra1, and Slc16a2 expression. Triiodothyronine positively regulated genes Tnni2 and Myog were decreased, indicating reduced TH signaling in the diaphragm. In contrast, chronic inflammation increased the fiber type II profile in the diaphragm as well as Thra1, Thrb1, and Myog expression while decreasing Dio3 expression, suggesting increased TH responsiveness during chronic inflammation. LPS-stimulated C2C12 myotubes showed decreased Dio2 expression and reduced basal oxygen consumption as well as non-mitochondrial respiration. The same respiratory profile was induced by Dio2 knockdown in myotubes.
  
  
  CONCLUSIONS
  The in vivo results show differential effects of sepsis and chronic inflammation on diaphragm muscle fiber type, TH metabolism, and mitochondrial function, while the in vitro results point to a causal role for altered TH metabolism in functional muscle impairment. These findings may be relevant for the pathogenesis of impaired respiratory function in critical illness.
authors.affiliation: 1 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam , Amsterdam, The Netherlands .|2 Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Flavia F
authors.initials: FF
authors.lastname: Bloise
authors.affiliation: 1 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Anne H
authors.initials: AH
authors.lastname: van der Spek
authors.affiliation: 1 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Olga V
authors.initials: OV
authors.lastname: Surovtseva
authors.affiliation: 2 Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro , Rio de Janeiro, Brazil .
authors.forename: Tania Maria
authors.initials: TM
authors.lastname: Ortiga-Carvalho
authors.affiliation: 1 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Eric
authors.initials: E
authors.lastname: Fliers
authors.affiliation: 1 Department of Endocrinology and Metabolism, Academic Medical Centre, University of Amsterdam , Amsterdam, The Netherlands .
authors.forename: Anita
authors.initials: A
authors.lastname: Boelen
mesh_terms: D000818:Animals; D005260:Female; D007249:Inflammation / Q000378:metabolism*; D007453:Iodide Peroxidase / Q000378:metabolism; D056892:Mediator Complex / Q000378:metabolism; D026901:Membrane Transport Proteins / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008928:Mitochondria / Q000378:metabolism*; D027501:Monocarboxylic Acid Transporters; D009132:Muscles / Q000378:metabolism*; D018008:Myogenin / Q000378:metabolism; D011008:Pneumococcal Infections / Q000378:metabolism; D012132:Respiratory Muscles / Q000503:physiopathology; D018805:Sepsis / Q000150:complications* / Q000382:microbiology; D027981:Symporters; D013963:Thyroid Hormones / Q000378:metabolism*; D013997:Time Factors; D019210:Troponin I / Q000378:metabolism; D000097564:Iodothyronine Deiodinase Type II
chemical_list: D007453:Iodide Peroxidase; D056892:Mediator Complex; D026901:Membrane Transport Proteins; D027501:Monocarboxylic Acid Transporters; D018008:Myogenin; D027981:Symporters; D013963:Thyroid Hormones; D019210:Troponin I; D000097564:Iodothyronine Deiodinase Type II; C519602:Med13 protein, mouse; C503801:Myog protein, mouse; C484257:Slc16a2 protein, mouse; C117274:iodothyronine deiodinase type III