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


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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    • "The gene profiles emphasize the physiological functions of skeletal muscles in response to exercise [18] [19] [20] [21]. Importantly, exercise-induced autophagy is required to maintain skeletal muscle mass and contribute to improving glucose metabolism [22] [23] [24] [25]. However, aberrant autophagy flux is detrimental for muscle health and leads to muscle atrophy and degeneration, while sufficient autophagy flux helps maintain healthy myofibers [26]. "
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    ABSTRACT: Purpose: We examined whether resistance exercise training restores impaired autophagy functions caused by Chloroquine (CQ)-induced Sporadic Inclusion Body Myositis (sIBM) in rat skeletal muscle. Methods: Male wistar rats were randomly assigned into three groups: Sham (n = 6), CQ (n = 6), and CQ + Exercise (CE, n = 6). To create a rat model of sIBM, rats in the CQ and CE group were intraperitoneally injected with CQ 5 days a week for 16 weeks. Rats in the CE group performed resistance exercise training 3 times a week for 8 weeks in conjunction with CQ starting from week 9 to week 16. During the training period, maximal carrying load, body weight, muscle weight, and relative muscle weight were measured. Autophagy responses were examined by measuring specific markers. Results: While maximal carrying capacity for resistance exercise training was dramatically increased in the CE group, no significant changes occurred in the skeletal muscle weight as well as in the relative muscle weight of CE compared to the other groups. CQ treatment caused significant increases in the levels of Beclin-1 and p62, and decreases in the levels of LAMP-2 proteins. Interestingly, no significant differences in the LC3-II/I ratio or the LC3-II protein levels were observed. Although CQ-treatment groups suppressed the levels of the potent autophagy inducer, BNIP3, p62 levels were decreased in only the CE group. Conclusion: Our findings demonstrate that sIBM induced by CQ treatment results in muscle degeneration via impaired autophagy and that resistance exercise training improves movable loading activity. Finally, regular exercise training may provide protection against sIBM by enhancing the autophagy flux through p62 protein.
    11/2015; 19(3):225-34. DOI:10.5717/jenb.2015.15090710
    • "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
    • "The number of LC3-positive puncta was quantified by fluorescence microscopy as described (Qu et al. 2003). Briefly, five randomly chosen images (using a 209 objective) per plantaris muscle section were examined by an observer blinded to intervention allocation and the number of LC3-positive puncta per 2500 lm 2 was then calculated as described (He et al. 2012). The percentage of Sirt3-positive muscle fibre in pixel was determined by the area of Sirt3-positively stained muscle fibre divided by the total area of the muscle fibre. "
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    ABSTRACT: Autophagy has been shown to be responsive to physical exercise. However, the effects of prolonged habitual exercise on autophagy in cardiac muscle remain unknown. The present study aimed to examine whether long-term habitual exercise alters the basal autophagic signalling in cardiac muscle. Female Sprague-Dawley rats aged 2 months were randomly assigned to control and exercise groups. Animals in exercise group were kept in cages with free access exercise wheels to perform habitual exercise for 5 months. Animals in the control group were placed in cages without exercise wheels. Ventricular muscle tissues were harvested for analysis after 5 months. Phosphorylation statuses of upstream autophagic regulatory proteins and protein expressions of downstream autophagic facts remained unchanged in the cardiac muscle of exercise animals when compared to control animals. Intriguingly, the protein abundance of microtubule-associated protein-1 light chain -3 II (LC3-II), heat shock protein 72 (HSP72) and peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) were significantly increased in cardiac muscle of exercise rats relative to control rats. 5 months of habitual exercise causes the adaptive increase in LC3-II reserve without altering autophagic flux, which probably contributes to the elevation of cellular autophagic capacity and efficiency of cardiac muscle. © Georg Thieme Verlag KG Stuttgart · New York.
    International Journal of Sports Medicine 03/2015; 36(07). DOI:10.1055/s-0034-1398494 · 2.07 Impact Factor
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