SKELETAL MUSCLE PHOSPHATIDYLCHOLINE AND PHOSPHATIDYLETHANOLAMINE ARE RESPONSIVE TO EXERCISE AND RELATED TO INSULIN SENSITIVITY IN HUMANS

Abstract

Introduction: Phosphatidylcholine (PC) and phosphatidylethanolamine (PE) composition in skeletal muscle has been linked to insulin sensitivity. Aim: To evaluate relationships between skeletal muscle PC:PE ratio, physical exercise and insulin sensitivity in humans. Materials and Methods : PC and PE were measured in m. vastus lateralis biopsies obtained from subjects examined in different studies with different degrees of insulin sensitivity: type 2 diabetes (n=13), impaired glucose metabolism and untrained (n=13), impaired glucose metabolism and trained (n=13), obesity (n=13), untrained normal weight controls (n=13), trained normal weight controls (n=13) and endurance trained athletes (n=6). From a subset of the subjects (MyoGlu; n=26) biopsies were obtained at rest, immediately after 45 min of cycle ergometer at 70% maximum oxygen uptake, and 2 h post-exercise, before as well as after 12 weeks of combined endurance- and strength-exercise intervention. Insulin sensitivity was measured by euglycemic hyperinsulinemic clamp. In addition, several measures of physical fitness were obtained, global RNA-sequencing was performed on the biopsies, and mitochondria and lipid droplets were quantified using point counting on electron microscopic images. Results: Skeletal muscle PC:PE ratio was highest in the type 2 diabetic group and gradually lower in groups with increasing insulin sensitivity. The lowest ratio was observed among endurance athletes. Twelve weeks of exercise intervention enhanced skeletal muscle levels of PC by ~21% and PE by ~42%, and reduced the PC:PE ratio by ~16%; a reduction in the PC:PE ratio predicted increased insulin sensitivity (β=-1.6, P<0.001). Transcriptomic analyses indicated that enzymes involved in PC and PE synthesis may explain the increased levels of PC and PE and the reduction in the PC:PE ratio after 12 weeks of exercise. The PC:PE ratio also correlated with mRNA expression of genes related to insulin receptor, Akt/PkB and mTORC1 signaling, and to the fraction of lipid droplets and mitochondria within skeletal muscle cells. Mitochondrial volume was increased from 3.4-5.7% after 12 weeks of exercise intervention. Conclusion: Skeletal muscle PC:PE ratio is inversely related to insulin sensitivity. The molecular link between skeletal muscle PC:PE ratio and insulin sensitivity probably involves several mechanisms including, but not limited to, mitochondrial function.