High-Density Lipoprotein Maintains Skeletal Muscle Function by Modulating Cellular Respiration in Mice

Abstract

Background Abnormal glucose metabolism is a central feature of disorders with increased rates of cardio-vascular disease (CVD). Low levels of high density lipoprotein (HDL) are a key predictor for CVD. We used genetic mouse models with increased HDL levels (apoA-I tg) and reduced HDL levels (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 (GTT) compared to wild type (wt) mice. Mitochondria isolated from gastrocnemius muscle of apoA-I ko mice displayed markedly blunted ATP synthesis. Endurance capacity (EC) during exercise exhaustion test was impaired in apoA-I ko mice. HDL directly enhanced glucose oxidation by increasing glycolysis and mitochondrial respiration rate (OCR) in C2C12 muscle cells. ApoA-I tg mice exhibited lower fasting glucose levels, improved GTT, increased lactate levels, reduced fat mass, associated with protection against age-induced decline of EC compared to wt mice. Circulating levels of fibroblast growth factor 21 (FGF21), 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 T2D, our findings indicate that HDL-raising therapies may preserve muscle mitochondrial function and address key aspects of T2D beyond CVD.

HDLs, Diabetes, and Metabolic Syndrome

“…In mice, the absence of ApoA-I leads to hyperinsulinemia and hyperglycemia as well as altered responses to insulin tolerance tests. Vice versa, ApoA-I transgenic mice exhibit lower fasting glucose levels and improved glucose tolerance test compared with wild-type mice (Han et al 2007;Lehti et al 2013). These data point to a modulating role of HDLs in maintaining normal glucose homeostasis.…”

“…HDLs were also found to directly enhance glucose oxidation by increasing glycolysis and mitochondrial respiration rate in C2C12 muscle cells (Lehti et al 2013). ATP synthesis was blunted in mitochondria isolated from the gastrocnemius muscle of ApoA-I knockout mice.…”

“…These data point to a modulating role of HDLs in maintaining normal glucose homeostasis. Moreover, genetically increased HDL cholesterol and ApoA-I levels in mice prevented high-fat diet-induced glucose homeostasis impairment (Lehti et al 2013).…”

“…Conversely, mice transgenically overexpressing human ApoA-I exhibited increased lactate levels, reduced fat mass, and protection against age-induced decline of endurance capacity. Circulating levels of fibroblast growth factor 21, a factor potentially involved in mitochondrial respiratory chain activity and inhibition of white adipose lipolysis, were significantly reduced in ApoA-I transgenic mice (Lehti et al 2013). …”

High-Density Lipoprotein

“…The recent work by Lehti and colleagues 11 appearing in this issue of Circulation uses a mouse model of apolipoprotein A-I (ApoA-I; the major protein component of HDL) knockout and overexpression (ApoA-I tg) to examine loss and gain of function effects on fasting plasma cholesterol, lipoprotein profile, glucose homeostasis, body composition, and exercise performance in vivo. From tissue extracts they examine liver and muscle glycogen, muscle AKT phosphorylation, mitochondrial function, and protein expression of mitochondrial ATP synthase subunits.…”