Abstract
Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance. Paradoxically, LDs also amass in muscles of highly trained endurance athletes who are exquisitely insulin sensitive. Understanding the molecular mechanisms that mediate the expansion and appropriate metabolic control of LDs in the context of habitual physical activity could lead to new therapeutic opportunities. Herein, we show that acute exercise elicits robust upregulation of a broad program of genes involved in regulating LD assembly, morphology, localization, and mobilization. Prominent among these was perilipin-5, a scaffolding protein that affects the spatial and metabolic interactions between LD and their surrounding mitochondrial reticulum. Studies in transgenic mice and primary human skeletal myocytes established a key role for the exercise-responsive transcriptional coactivator PGC-1α in coordinating intramuscular LD programming with mitochondrial remodeling. Moreover, translational studies comparing physically active versus inactive humans identified a remarkably strong association between expression of intramuscular LD genes and enhanced insulin action in exercise-trained subjects. These results reveal an intimate molecular connection between intramuscular LD biology and mitochondrial metabolism that could prove relevant to the etiology and treatment of insulin resistance and other disorders of lipid imbalance.
Highlights
Intramuscular accumulation of triacylglycerol, in the form of lipid droplets (LD), has gained widespread attention as a hallmark of metabolic disease and insulin resistance
Shown by transmission electron microscopy, lipid droplets are larger and more numerous in red compared with white regions of mouse quadriceps, and in both fiber types the droplets are bordered by intermyofibrillar mitochondria (Fig. 1A, B)
PGC-1␣ is a promiscuous transcriptional coactivator that plays a prominent role in regulating mitochondrial genesis, oxidative metabolism, and muscle adaption to exercise [10, 24, 38, 39]
Summary
Institutional Animal Care and Use Committee using male and female C57/Bl6J mice or MCK-PGC-1␣ transgenic mice (kindly provided by Dr Bruce Spiegelman, Harvard University) and littermate controls. Mice were housed in a temperature-controlled environment with a 12:12 h light/dark cycle and provided ad libitum access to Purina standard chow (SC) or high-fat diet (HF; Research Diets 45% fat) and water. Transmission electron microscopy Tibialis anterior (TA) muscles from female C57/Bl6J mice on either SC or HF diets and MCK-PGC-1␣ transgenic mice were removed in the fed state after Nembutal, immersed in 2% formaldehyde/2.5% glutaraldehyde, and processed using standard methods [8] at the Translational Core Facility at UNC-Chapel Hill. Twelve-week-old male C57/Bl6j mice (n = 4) were habituated to the treadmill (3M/6M Columbus Instruments) for three days. Control and MCKPGC-1␣ transgenic mice were habituated but not exercised. Blots were normalized to total protein determined by Memcode Reversible Protein Stain (Thermo-Fisher Scientific)
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