High-Density Lipoprotein is Independently Associated with Muscle Mitochondrial Function in Healthy Humans.

High-density lipoprotein cholesterol (HDL-C) is well known to play an important anti-atherogenic role via reverse cholesterol transport. Increasing number of studies in mice have also suggested a protective role of HDL in preserving muscle mitochondrial function via ApoA1-induced enhancement of cellular respiration of glucose. However, data in humans are lacking. We therefore hypothesize that HDL levels and/or function are correlated with muscle mitochondrial function in humans. Accordingly, we conducted a cross-sectional study to determine the relationship between levels and function of HDL and skeletal muscle mitochondrial function in 31 healthy adults without diabetes mellitus or cardiovascular disease. To estimate muscle mitochondrial function, we measured the oxygen recovery time constant (Tau) during supra-systolic cuff-occlusions following 2 minutes of rhythmic handgrip exercise at 30% maximal voluntary contraction in the forearm muscle, using near infrared spectroscopy (NIRS). To assess cholesterol efflux capacity (CEC), we used J774 macrophages, radiolabeled cholesterol, and ApoB-depleted plasma to calculate cholesterol efflux normalized to a pooled sample. Of the 31 subjects, 13 (42%) were female, mean age was 40 +/- 16, mean BMI was 23.9 +/- 3.4 kg/m^2, and the mean total serum cholesterol was 198.4 +/- 43.1 mg/dL. We found a significant inverse correlation between HDL-C levels and Tau, with a correlation coefficient (r) of -0.51 (p < 0.01, Figure. 1a). As expected, a positive correlation is observed between BMI and Tau (r= 0.50, p < 0.01, Figure 1c). In contrast, no significant correlation between fasting triglyceride, plasma glucose, insulin levels or HDL efflux function with Tau were found (all p-values > 0.05). In conclusion, our study identifies a novel association between circulating HDL levels with muscle mitochondrial function. However, the CEC of our sample was not significantly correlated with Tau, therefore future investigations with larger studies or more measures of HDL function and composition may elucidate these findings. The association of HDL-C and muscle mitochondrial function may explain increased prevalence of physical inactivity among populations with low HDL-C, such as those with metabolic syndrome. Additionally, future studies are needed to determine if strategies to improve HDL-C levels will result in improved muscle mitochondrial function and exercise capacity.