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

Circulation. 2013 Nov 26;128(22):2364-71. doi: 10.1161/CIRCULATIONAHA.113.001551. Epub 2013 Oct 29.

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.

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.

Keywords: cellular respiration; cholesterol, HDL; exercise; obesity.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apolipoprotein A-I / genetics
  • Blood Glucose / metabolism*
  • Cell Respiration / physiology
  • Cells, Cultured
  • Diabetes Mellitus, Type 2 / metabolism
  • Disease Models, Animal
  • Fatty Acids, Nonesterified / blood
  • Fibroblast Growth Factors / blood
  • Glucose Intolerance / metabolism*
  • Homeostasis / physiology
  • Hyperglycemia / metabolism*
  • Lipoproteins, HDL / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mitochondria, Muscle / metabolism
  • Muscle, Skeletal / metabolism*
  • Physical Endurance / physiology

Substances

  • Apolipoprotein A-I
  • Blood Glucose
  • Fatty Acids, Nonesterified
  • Lipoproteins, HDL
  • fibroblast growth factor 21
  • Fibroblast Growth Factors