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

Duke University, 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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    ABSTRACT: The prevalence of type 2 diabetes (T2D) has increased dramatically over the past two decades, not only among adults but also among adolescents. T2D is a systemic disorder affecting every organ system and is especially damaging to the cardiovascular system, predisposing individuals to severe cardiac and vascular complications. The precise mechanisms that cause T2D are an area of active research. Most current theories suggest that the process begins with peripheral insulin resistance that precedes failure of the pancreatic β-cells to secrete sufficient insulin to maintain normoglycemia. A growing body of literature has highlighted multiple aspects of mitochondrial function, including oxidative phosphorylation, lipid homeostasis, and mitochondrial quality control in the regulation of peripheral insulin sensitivity. Whether the cellular mechanisms of insulin resistance in adults are comparable to that in adolescents remains unclear. This review will summarize both clinical and basic studies that shed light on how alterations in skeletal muscle mitochondrial function contribute to whole body insulin resistance and will discuss the evidence supporting high-intensity exercise training as a therapy to circumvent skeletal muscle mitochondrial dysfunction to restore insulin sensitivity in both adults and adolescents.
    Biochemistry and Cell Biology 05/2015; DOI:10.1139/bcb-2015-0012 · 2.15 Impact Factor
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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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    ABSTRACT: Contraction-mediated lipolysis increases the association of lipid droplets and mitochondria, indicating an important role in the passage of fatty acids from lipid droplets to mitochondria in skeletal muscle. PLIN3 and PLIN5 are of particular interest to the lipid droplet–mitochondria interaction because PLIN3 is able to move about within cells and PLIN5 associates with skeletal muscle mitochondria. This study primarily investigated: 1) if PLIN3 is detected in skeletal muscle mitochondrial fraction; and 2) if mitochondrial protein content of PLIN3 and/or PLIN5 changes following stimulated contraction. A secondary aim was to determine if PLIN3 and PLIN5 associate and whether this changes following contraction. Male Long Evans rats (n = 21; age, 52 days; weight = 317 ± 6 g) underwent 30 min of hindlimb stimulation (10 msec impulses, 100 Hz/3 sec at 10–20 V; train duration 100 msec). Contraction induced a ~50% reduction in intramuscular lipid content measured by oil red-O staining of red gastrocnemius muscle. Mitochondria were isolated from red gastrocnemius muscle by differential centrifugation and proteins were detected by western blotting. Mitochondrial PLIN5 content was ~1.6-fold higher following 30 min of contraction and PLIN3 content was detected in the mitochondrial fraction, and unchanged following contraction. An association between PLIN3 and PLIN5 was observed and remained unaltered following contraction. PLIN5 may play a role in mitochondria during lipolysis, which is consistent with a role in facilitating/regulating mitochondrial fatty acid oxidation. PLIN3 and PLIN5 may be working together on the lipid droplet and mitochondria during contraction-induced lipolysis.
    10/2014; 2(10). DOI:10.14814/phy2.12154
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    • "The physiological relevance of the vibration-induced increase in intramuscular triglycerides is not clear. Elevated intramuscular triglyceride concentration has been associated with metabolic disease, however, it also increases in response to exercise training [72]. This latter non-pathological response could potentially be an advantageous adaptation induced by vibration training, but more work will need to be done. "
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    ABSTRACT: The objective of the study was to determine if low intensity, high frequency vibration training impacted the musculoskeletal system in a mouse model of Duchenne muscular dystrophy, relative to healthy mice. Three-week old wildtype (n = 26) and mdx mice (n = 22) were randomized to non-vibrated or vibrated (45 Hz and 0.6 g, 15 min/d, 5 d/wk) groups. In vivo and ex vivo contractile function of the anterior crural and extensor digitorum longus muscles, respectively, were assessed following 8 wks of vibration. Mdx mice were injected 5 and 1 days prior to sacrifice with Calcein and Xylenol, respectively. Muscles were prepared for histological and triglyceride analyses and subcutaneous and visceral fat pads were excised and weighed. Tibial bones were dissected and analyzed by micro-computed tomography for trabecular morphometry at the metaphysis, and cortical geometry and density at the mid-diaphysis. Three-point bending tests were used to assess cortical bone mechanical properties and a subset of tibiae was processed for dynamic histomorphometry. Vibration training for 8 wks did not alter trabecular morphometry, dynamic histomorphometry, cortical geometry, or mechanical properties (P≥0.34). Vibration did not alter any measure of muscle contractile function (P≥0.12); however the preservation of muscle function and morphology in mdx mice indicates vibration is not deleterious to muscle lacking dystrophin. Vibrated mice had smaller subcutaneous fat pads (P = 0.03) and higher intramuscular triglyceride concentrations (P = 0.03). These data suggest that vibration training at 45 Hz and 0.6 g did not significantly impact the tibial bone and the surrounding musculature, but may influence fat distribution in mice.
    PLoS ONE 08/2014; 9(8):e104339. DOI:10.1371/journal.pone.0104339 · 3.23 Impact Factor
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