High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice - PubMed (original) (raw)

. 2013 Nov 26;128(22):2364-71.

doi: 10.1161/CIRCULATIONAHA.113.001551. Epub 2013 Oct 29.

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 Castel, Sarah Martinez, David D'Alessio, W Sean Davidson, Susanna M Hofmann

Affiliations

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

Maarit Lehti et al. Circulation. 2013.

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.

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Figures

Figure 1

Figure 1

HDL modulates whole body glucose homeostasis through an direct effect on glycolytic muscle fibers: Fasting cholesterol (A) levels, lipoprotein profiles (B, HDL = fraction 40-53), hepatic triglyceride levels (C), glucose tolerance tests (D), fasting glucose levels (E) and HbA1c levels (F) (n=6-15 per goup); deoxyglucose uptake (G) in tibialis lateralis anterior (TLA) muscle, extensor digitorum longus (EDL) muscle, soleus (SOL) muscle , gastrocnemius (GAST) muscle , subcutaneous adipose tissue (ScAT), and liver under hyperinsulinemic-euglycemic clamp conditions (n = 6-8 per group); basal and insulin-induced AKT phosphorylation in quadriceps muscle (H, n = 2-3 per group), glycogen content in quadriceps (I) and liver (J) of chow fed and age-matched wt (open bars, filled circles), apoA-I tg (filled bars; open squares) and apoA-I ko mice (hatched bars; open triangles) (n=6-14 per group). AUC = area under the curve, sed = sedentary, exe = exercised. Data are expressed as means ± SEM. *P < 0.05; **P < 0.005; ***P < 0.0005 vs. wt mice and a = P < 0.05 vs. sedentary wt mice, b = P < 0.05 vs. sedentary apoA-I tg mice, c = P < 0.001 vs. exercised apoA-I ko mice.

Figure 2

Figure 2

Normal HDL levels are required for proper function of skeletal mitochondria: (A-C) Body composition, (D) distance covered during treadmill exercise to exhaustion test (n = 15 per group); (E) oxygen consumption rate (OCR) in mitochondria isolated from gastrocnemius muscle in basal state (State II), after addition of ADP (State III), and after addition of of the ATP synthase inhibitor oligomycin (State IVo); and protein expression of ATP synthase subunit A and B (F,G) in gastrocnemius muscle homogenates of chow fed wt (open bars), apoA-I tg (filled bars) and apoA-I ko mice (hatched bars) (n = 4 per group). Data are expressed as means ± SEM *P < 0.05; **P < 0.005, ***P < 0.0005 vs. wt mice.

Figure 3

Figure 3

HDL and apoA-I enhance cellular respiration of glucose in skeletal muscle and prevent age-induced decline of endurance capacity: (A and B) Extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) in C2C12 myoblasts incubated with glucose (5 mmol/L; open bars) and increasing amounts of HDL (closed bars). (C) ECAR in C2C12 myoblasts incubated with glucose (5 mmol/L, open bar), glucose and HDL (100 ug/ml; closed bars), LDL (100 ug/ml; hatched bars), phospholipid vesicles (100 ug/ml; hatched bars), and apoA-I (same protein concentration as HDL) (n= 7-12 per group). Data in A, B, and C are expressed as means ± SEM. a = P < 0.05, vs. cells incubated with glucose only. (D) fasting glucose, (E) fasting lactate, and (F) change of distance covered during treadmill exercise exhaustion tests performed 8 weeks apart in aging wt (open bars) and apoA-I transgenic mice (closed bars) (n = 15 per group). Data in D, E, and F are expressed as means ± SEM *P < 0.05; **P < 0.005 vs. wt mice.

Figure 4

Figure 4

Raising HDL levels decreases body fat mass in association with reduced circulating FGF21 levels and enhanced FFA release from white adipose tissue. (A) Fat mass of sedentary (dotted lines) and treadmill exercised (continuous lines) wt (circles) and apoA-I tg mice (squares) on chow. (B), Fasting hepatic FGF21 expression levels, (C) fasting circulating FGF21 levels, and (D) fasting FFA levels of sedentary wt (open bars) and apoA-I tg mice (closed bars) (n = 6-7 per group). Data are expressed as means ± SEM *P < 0.05; ***P < 0.0005 vs. wt mice.

Figure 5

Figure 5

Raising HDL protects against diet-induced hyperglycemia through increased glucose utilization. (A &B) body composition, fasting glucose (C) and fasting insulin (D) levels of diet-induced obese wt (open bars) and apoA-I tg (closed bars) mice. (E) glucose tolerance test in diet-induced obese wt (closed circles) and apoA-I tg mice (open quadrants) (n = 7-8 per group). AUC = area under the curve. Data are expressed as means ± SEM *P < 0.05; **P < 0.005, ***P < 0.0005 vs. wt mice.

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