title: Hypoxia differentially regulates muscle oxidative fiber type and metabolism in a HIF-1α-dependent manner.
abstract: Loss of skeletal muscle oxidative fiber types and mitochondrial capacity is a hallmark of chronic obstructive pulmonary disease and chronic heart failure. Based on in vivo human and animal studies, tissue hypoxia has been hypothesized as determinant, but the direct effect of hypoxia on muscle oxidative phenotype remains to be established. Hence, we determined the effect of hypoxia on in vitro cultured muscle cells, including gene and protein expression levels of mitochondrial components, myosin isoforms (reflecting slow-oxidative versus fast-glycolytic fibers), and the involvement of the regulatory PPAR/PGC-1α pathway. We found that hypoxia inhibits the PPAR/PGC-1α pathway and the expression of mitochondrial components through HIF-1α. However, in contrast to our hypothesis, hypoxia stimulated the expression of slow-oxidative type I myosin via HIF-1α. Collectively, this study shows that hypoxia differentially regulates contractile and metabolic components of muscle oxidative phenotype in a HIF-1α-dependent manner.
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: i.slot@maastrichtuniversity.nl.
authors.forename: Ilse G M
authors.initials: IG
authors.lastname: Slot
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: a.schols@maastrichtuniversity.nl.
authors.forename: Annemie M W J
authors.initials: AM
authors.lastname: Schols
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: bettine.vosse@mumc.nl.
authors.forename: Bettine A H
authors.initials: BA
authors.lastname: Vosse
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: marco.kelders@maastrichtuniversity.nl.
authors.forename: Marco C J M
authors.initials: MC
authors.lastname: Kelders
authors.affiliation: Department of Respiratory Medicine, NUTRIM School for Nutrition, Toxicology and Metabolism, Maastricht University Medical Centre+, PO Box 5800, 6202 AZ Maastricht, The Netherlands. Electronic address: h.gosker@maastrichtuniversity.nl.
authors.forename: Harry R
authors.initials: HR
authors.lastname: Gosker
mesh_terms: D000818:Animals; D015687:Cell Hypoxia; D002460:Cell Line; D006019:Glycolysis; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism; D018485:Muscle Fibers, Skeletal / Q000166:cytology / Q000378:metabolism; D018995:Myosin Heavy Chains / Q000378:metabolism; D010085:Oxidative Phosphorylation; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; D020033:Protein Isoforms / Q000378:metabolism; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D047493:PPAR alpha; D047495:PPAR gamma; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C485290:Ppargc1a protein, mouse; D020033:Protein Isoforms; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D014157:Transcription Factors; D018995:Myosin Heavy Chains
keywords: C2C12; Fiber-type profile; Hypoxia; Oxidative phenotype