TY - JOUR
T1 - High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice
AU - Lehti, Maarit
AU - Donelan, Elizabeth
AU - Abplanalp, William
AU - Al-Massadi, Omar
AU - Habegger, Kirk M.
AU - Weber, Jon
AU - Ress, Chandler
AU - Mansfeld, Johannes
AU - Somvanshi, Sonal
AU - Trivedi, Chitrang
AU - Keuper, Michaela
AU - Ograjsek, Teja
AU - Striese, Cynthia
AU - Cucuruz, Sebastian
AU - Pfluger, Paul T.
AU - Krishna, Radhakrishna
AU - Gordon, Scott M.
AU - Silva, R. A.Gangani D.
AU - Luquet, Serge
AU - Castel, Julien
AU - Martinez, Sarah
AU - D'Alessio, David
AU - Davidson, W. Sean
AU - Hofmann, Susanna M.
PY - 2013/11/26
Y1 - 2013/11/26
N2 - 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.
AB - 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.
KW - Cellular respiration
KW - Cholesterol, HDL
KW - Exercise
KW - Obesity
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U2 - 10.1161/CIRCULATIONAHA.113.001551
DO - 10.1161/CIRCULATIONAHA.113.001551
M3 - Article
C2 - 24170386
AN - SCOPUS:84888645949
VL - 128
SP - 2364
EP - 2371
IS - 22
ER -