Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis

Center for Autophagy Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
Nature (Impact Factor: 41.46). 01/2012; 481(7382):511-5. DOI: 10.1038/nature10758
Source: PubMed

ABSTRACT Exercise has beneficial effects on human health, including protection against metabolic disorders such as diabetes. However, the cellular mechanisms underlying these effects are incompletely understood. The lysosomal degradation pathway, autophagy, is an intracellular recycling system that functions during basal conditions in organelle and protein quality control. During stress, increased levels of autophagy permit cells to adapt to changing nutritional and energy demands through protein catabolism. Moreover, in animal models, autophagy protects against diseases such as cancer, neurodegenerative disorders, infections, inflammatory diseases, ageing and insulin resistance. Here we show that acute exercise induces autophagy in skeletal and cardiac muscle of fed mice. To investigate the role of exercise-mediated autophagy in vivo, we generated mutant mice that show normal levels of basal autophagy but are deficient in stimulus (exercise- or starvation)-induced autophagy. These mice (termed BCL2 AAA mice) contain knock-in mutations in BCL2 phosphorylation sites (Thr69Ala, Ser70Ala and Ser84Ala) that prevent stimulus-induced disruption of the BCL2-beclin-1 complex and autophagy activation. BCL2 AAA mice show decreased endurance and altered glucose metabolism during acute exercise, as well as impaired chronic exercise-mediated protection against high-fat-diet-induced glucose intolerance. Thus, exercise induces autophagy, BCL2 is a crucial regulator of exercise- (and starvation)-induced autophagy in vivo, and autophagy induction may contribute to the beneficial metabolic effects of exercise.

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Available from: Kai Sun, Sep 27, 2015
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    • "Generation of Mitochondrial Acetyl-CoA In most mammalian cells, acetyl-CoA is predominantly generated in the mitochondrial matrix by various metabolic circuitries, namely glycolysis, b-oxidation, and the catabolism of branched amino acids (Figure 1A). Glycolysis culminates in the generation of cytosolic pyruvate, which is imported into mitochondria by the mitochondrial pyruvate carrier (MPC), a heterodimer of MPC1 and MPC2 (Herzig et al., 2012). Mitochondrial pyruvate is decarboxylated to form acetyl-CoA, CO 2 , and NADH by the so-called pyruvate dehydrogenase complex (PDC), a large multicomponent system that in humans is composed of (1) three proteins that are directly involved in CoA-and NAD + -dependent pyruvate decarboxylation , i.e., pyruvate dehydrogenase (lipoamide) (PDH, which in exists in three isoforms), dihydrolipoamide S-acetyltransferase (DLAT), and dihydrolipoamide dehydrogenase (DLD); (2) two regulatory components, i.e., pyruvate dehydrogenase kinase (PDK, which also exists in four isoforms) and pyruvate dehydrogenase phosphatase (PDP, a heterodimer involving either of two catalytic subunits and either of two regulatory subunits); and (3) one non-enzymatic subunit, i.e., pyruvate dehydrogenase complex , component X (PDHX) (Patel et al., 2014). "
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    ABSTRACT: Acetyl-coenzyme A (acetyl-CoA) is a central metabolic intermediate. The abundance of acetyl-CoA in distinct subcellular compartments reflects the general energetic state of the cell. Moreover, acetyl-CoA concentrations influence the activity or specificity of multiple enzymes, either in an allosteric manner or by altering substrate availability. Finally, by influencing the acetylation profile of several proteins, including histones, acetyl-CoA controls key cellular processes, including energy metabolism, mitosis, and autophagy, both directly and via the epigenetic regulation of gene expression. Thus, acetyl-CoA determines the balance between cellular catabolism and anabolism by simultaneously operating as a metabolic intermediate and as a second messenger. Copyright © 2015 Elsevier Inc. All rights reserved.
    Cell metabolism 06/2015; 21(6):805-821. DOI:10.1016/j.cmet.2015.05.014 · 17.57 Impact Factor
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    • "In this sense, recent findings have demonstrated that acute aerobic exercise increases proteolysis in the skeletal muscle through ubiquitin– proteasome and autophagy systems [23] [47]. Both systems maintain cellular quality control mechanisms, recycling damaged organelles (mainly via autophagy) or myofibrillar proteins (mainly via proteasome degradation ) and allowing new synthesis. "
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    ABSTRACT: Aerobic exercise training (AET) induces several skeletal muscle changes, improving aerobic exercise capacity and health. Conversely, to the positive effects of AET, the cachexia syndrome is characterized by skeletal muscle wasting. Cachexia is a multifactorial disorder that occurs and is associated with other chronic diseases such as heart failure and cancer. In these diseases, an overactivation of ubiquitin-proteasome and autophagy systems associated with a reduction in protein synthesis culminates in severe skeletal muscle wasting and, in the last instance, patient's death. In contrast, AET may recycle and enhance many protein expression and enzyme activities, counteracting metabolism impairment and muscle atrophy. Therefore, the aim of the current review was to discuss the supposed therapeutic effects of AET on skeletal muscle wasting in both cardiac and cancer cachexia. Copyright © 2014. Published by Elsevier Inc.
    Life Sciences 12/2014; 125. DOI:10.1016/j.lfs.2014.11.029 · 2.70 Impact Factor
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    • "To get further insights into the molecular machinery controlled by leptin in the context of autophagy, we analyzed the interaction between the anti-autophagy Bcl-2 protein and Beclin-1, a key element of the autophagic cascade [28–30]. Of note, in our experimental conditions, we found that Bcl-2 co-immunoprecipitated with Beclin-1, thus suggesting a physical interaction between the anti-autophagy Bcl-2 and Beclin-1 (Fig. 3C left). "
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    ABSTRACT: Objective In this report we show that the adipocytokine leptin directly modulates autophagy in human CD4+CD25− conventional (Tconv) T cells. Results In vitro treatment with recombinant human leptin determined an inhibition of autophagy during T cell receptor (TCR) stimulation, and this phenomenon was dose- and time-dependent. The events were secondary to the activation of the mammalian-target of rapamycin (mTOR)-pathway induced by leptin, as testified by its reversion induced by mTOR inhibition with rapamycin. At molecular level these phenomena associated with Bcl-2 up-regulation and its interaction with Beclin-1, whose complex exerts a negative effect on autophagy. Materials/Methods The impact of leptin on autophagy of Tconv cells was determined at biochemical level by western blotting and by flow cytometry; the interaction between BCL-2 and Beclin-1 by co-immunoprecipitation assays. Conclusions Our results, suggest that in unconditioned, freshly-isolated human Tconv cells, autophagy and proliferation are controlled by leptin during TCR-engagement, and that both phenomena occur alternatively indicating a balance between these processes during immune activation.
    Metabolism 10/2014; 63(10). DOI:10.1016/j.metabol.2014.06.010 · 3.89 Impact Factor
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