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

Published

Journal Article

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.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.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.

Full Text

Duke Authors

Cited Authors

  • Lehti, M; Donelan, E; Abplanalp, W; Al-Massadi, O; Habegger, KM; Weber, J; Ress, C; Mansfeld, J; Somvanshi, S; Trivedi, C; Keuper, M; Ograjsek, T; Striese, C; Cucuruz, S; Pfluger, PT; Krishna, R; Gordon, SM; Silva, RAGD; Luquet, S; Castel, J; Martinez, S; D'Alessio, D; Davidson, WS; Hofmann, SM

Published Date

  • November 2013

Published In

Volume / Issue

  • 128 / 22

Start / End Page

  • 2364 - 2371

PubMed ID

  • 24170386

Pubmed Central ID

  • 24170386

Electronic International Standard Serial Number (EISSN)

  • 1524-4539

International Standard Serial Number (ISSN)

  • 0009-7322

Digital Object Identifier (DOI)

  • 10.1161/CIRCULATIONAHA.113.001551

Language

  • eng