PPAR coactivator-1 contributes to exercise-induced regulation of intramuscular lipid droplet programming in mice and humans

University of Vermont, Burlington, Vermont, United States
The Journal of Lipid Research (Impact Factor: 4.42). 11/2012; 54(2). DOI: 10.1194/jlr.P028910
Source: PubMed


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 that 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 co-activator, 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 other disorders of lipid imbalance.

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    • "These findings are consistent with those of Schenk and Horowitz, who observed that acute exercise increased triglyceride synthesis concurrent with improved insulin resistance (Schenk and Horowitz 2007). Second is the observation that highly trained athletes, that arguably display the greatest muscle insulin sensitivity, also have substantial intramuscular triglyceride storage (Amati et al. 2011; Koves et al. 2013), suggesting that the toxic effects of lipids can be rescued if mitochondrial oxidative capacity is high or if lipid turnover is high (i.e., following repeated bouts of endurance exercise). Alternatively, the type of accumulated lipid, or how the lipid is packaged within the myocyte , may be an important factor determining insulin sensitivity. "
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    • "This study is the first to demonstrate that mitochondrial PLIN5 content in skeletal muscle is increased after 30 min of electrically stimulated contraction that induced lipolysis. As PLIN5 is higher in the mitochondrial fraction with contraction, it is consistent with a role for PLIN5 in coordinating the release of fatty acids from the lipid droplet and their subsequent oxidation in the mitochondria (Wang et al. 2011; Bosma et al. 2013; Koves et al. 2013). Other novel findings are that PLIN3 protein can be detected in skeletal muscle mitochondria, and the net mitochondrial PLIN3 protein content remained unchanged following contraction. "
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