title: High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice.
abstract: BACKGROUND
  Abnormal glucose metabolism is a central feature of disorders with increased rates of cardiovascular disease. Low levels of high-density lipoprotein (HDL) are a key predictor for cardiovascular disease. We used genetic mouse models with increased HDL levels (apolipoprotein A-I transgenic [apoA-I tg]) and reduced HDL levels (apoA-I-deficient [apoA-I ko]) to investigate whether HDL modulates mitochondrial bioenergetics in skeletal muscle.
  
  
  RESULTS
  ApoA-I ko mice exhibited fasting hyperglycemia and impaired glucose tolerance test compared with wild-type mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved glucose tolerance test, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of endurance capacity compared with wild-type mice. Circulating levels of fibroblast growth factor 21, a novel biomarker for mitochondrial respiratory chain deficiencies and inhibitor of white adipose lipolysis, were significantly reduced in apoA-I tg mice. Consistent with an increase in glucose utilization of skeletal muscle, genetically increased HDL and apoA-I levels in mice prevented high-fat diet-induced impairment of glucose homeostasis.
  
  
  CONCLUSIONS
  In view of impaired mitochondrial function and decreased HDL levels in type 2 diabetes mellitus, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of type 2 diabetes mellitus beyond cardiovascular disease.
authors.affiliation: Diabetes Research Department (IDO and IDR), Helmholtz Zentrum München, German Research Center for Environmental Health, München/Neuherberg, Germany (M.L., M.K., T.O., C.S., S.C., P.T.P., S.M.H.); Metabolic Diseases Institute, Division of Endocrinology, Department of Internal Medicine, University of Cincinnati, Cincinnati, OH (M.L., E.D., W.A., O.A.-M., K.M.H., J.W., C.R., J.M., S.S., C.T., R.K., S.M.G., R.A.G.D.S., D.D., W.S.D., S.M.H.); LIKES Research Center for Sport and Health Sciences, Jyväskylä, Finland (M.L.); Energy Metabolism Laboratory ETH Zurich (Swiss Federal Institute of Technology), Zurich, Switzerland (J.M.); Department of Pharmacology and Toxicology, Zydus Research Centre, Cadila Healthcare Limited, Ahmedabad, India (C.T.); Univ Paris Diderot, Sorbonne Paris Cité, Unité de Biologie Fonctionnelle et Adaptative, Paris, France (S.L., J.C., S.M.); Centre National de la Recherche Scientifique, Paris, France (S.L., J.C., S.M.); and Medizinische Klinik, Ludwig Maximilians University, Munich, Germany (S.M.H.).
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authors.initials: SM
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authors.lastname: Luquet
authors.forename: Julien
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authors.lastname: Castel
authors.forename: Sarah
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authors.lastname: Martinez
authors.forename: David
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authors.lastname: D'Alessio
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authors.initials: WS
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mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000235:genetics; D001786:Blood Glucose / Q000378:metabolism*; D019069:Cell Respiration / Q000502:physiology; D002478:Cells, Cultured; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D004195:Disease Models, Animal; D005230:Fatty Acids, Nonesterified / Q000097:blood; D005346:Fibroblast Growth Factors / Q000097:blood; D018149:Glucose Intolerance / Q000378:metabolism*; D006706:Homeostasis / Q000502:physiology; D006943:Hyperglycemia / Q000378:metabolism*; D008075:Lipoproteins, HDL / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008931:Mitochondria, Muscle / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism*; D010807:Physical Endurance / Q000502:physiology
chemical_list: D016632:Apolipoprotein A-I; D001786:Blood Glucose; D005230:Fatty Acids, Nonesterified; D008075:Lipoproteins, HDL; C414620:fibroblast growth factor 21; D005346:Fibroblast Growth Factors
keywords: cellular respiration; cholesterol, HDL; exercise; obesity