High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice

Maarit Lehti, Elizabeth Donelan, William Abplanalp, Omar Al-Massadi, Kirk M. Habegger, Jon Weber, Chandler Ress, Johannes Mansfeld, Sonal Somvanshi, Chitrang Trivedi, Michaela Keuper, Teja Ograjsek, Cynthia Striese, Sebastian Cucuruz, Paul T. Pfluger, Radhakrishna Krishna, Scott M. Gordon, R. A.Gangani D. Silva, Serge Luquet, Julien CastelSarah Martinez, David D'Alessio, W. Sean Davidson, Susanna M. Hofmann

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


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. METHODS AND 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.

Original languageEnglish
Pages (from-to)2364-2371
Number of pages8
Issue number22
StatePublished - 26 Nov 2013
Externally publishedYes


  • Cellular respiration
  • Cholesterol, HDL
  • Exercise
  • Obesity


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