Autophagy vitalizes the pathogenicity of pathogenic fungi
Xiao-Hong Liu, Hui-Min Gao, Fei Xu, Jian-Ping Lu, Rodney J. Devenish and Fu-Cheng Lin
Pages 1415 - 1425
http://dx.doi.org/10.4161/auto.21274
Plant pathogenic fungi utilize a series of complex infection structures, in particular the appressorium, to gain entry to and colonize plant tissue. As a consequence of the accumulation of huge quantities of glycerol in the cell the appressorium generates immense intracellular turgor pressure allowing the penetration peg of the appressorium to penetrate the leaf cuticle. Autophagic processes are ubiquitous in eukaryotic cells and facilitate the bulk degradation of macromolecules and organelles. The study of autophagic processes has been extended from the model yeast Saccharomyces cerevisiae to pathogenic fungi such as the rice blast fungus Magnaporthe oryzae. Significantly, null mutants for the expression of M. oryzae autophagy gene homologs lose their pathogenicity for infection of host plants. Clarification of the functions and network of interactions between the proteins expressed by M. oryzae autophagy genes will lead to a better understanding of the role of autophagy in fungal pathogenesis and help in the development of new strategies for disease control.
- autophagy-related (ATG) genes
The C. elegans ATG101 homolog EPG-9 directly interacts with EPG-1/Atg13 and is essential for autophagy
Qianqian Liang, Peiguo Yang, E Tian, Jinghua Han and Hong Zhang
Pages 1426 - 1433
http://dx.doi.org/10.4161/auto.21163
Autophagy is an evolutionarily conserved catabolic process that involves the engulfment of cytoplasmic contents in a closed double-membrane structure, called the autophagosome, and their subsequent delivery to the vacuole/lysosomes for degradation. Genetic screens in Saccharomyces cerevisiae have identified more than 30 autophagy-related (Atg) genes that are essential for autophagosome formation. Here we isolated a novel autophagy gene, epg-9, whose loss of function causes defective autophagic degradation of a variety of protein aggregates during C. elegans embryogenesis. Mutations in epg-9 also reduce survival of animals under food depletion conditions. epg-9 mutants exhibit autophagy phenotypes characteristic of those associated with loss of function of unc-51/Atg1 and epg-1/Atg13. epg-9 encodes a protein with significant homology to mammalian ATG101. EPG-9 directly interacts with EPG-1/Atg13. Our study indicates that EPG-9 forms a complex with EPG-1 in the aggrephagy pathway in C. elegans.
Porcine reproductive and respiratory syndrome virus induces autophagy to promote virus replication
Ming-Xia Sun, Li Huang, Rui Wang, Ya-Ling Yu, Chen Li, Peng-Peng Li, Xiao-Chun Hu, Hong-Ping Hao, Hassan A. Ishag and Xiang Mao
Pages 1434 - 1447
http://dx.doi.org/10.4161/auto.21159
An increasing number of studies demonstrate that autophagy, an intrinsic mechanism that can degrade cytoplasmic components, is involved in the infection processes of a variety of pathogens. It can be hijacked by various viruses to facilitate their replication. In this study, we found that PRRSV infection significantly increases the number of double- or single-membrane vesicles in the cytoplasm of host cells in ultrastructural analysis. Our results showed the LC3-I was converted into LC3-II after virus infection, suggesting the autophagy machinery was activated. We further used pharmacological agents and shRNAs to confirm that autophagy promoted the replication of PRRSV in host cells. Confocal microscopy analysis showed that PRRSV inhibited the fusion between autophagosomes and lysosomes, suggesting that PRRSV induced incomplete autophagy. This suppression caused the accumulation of autophagosomes which may serve as replication site to enhance PRRSV replication. It has been shown that NSP2 and NSP3 of arterivirus are two components of virus replication complex. We also found in our studies that NSP2 colocalized with LC3 in MARC-145 cells by performing confocal microscopy analysis and continuous density gradient centrifugation. Our studies presented here indicated that autophagy was activated during PRRSV infection and enhanced PRRSV replication in host cells by preventing autophagosome and lysosome fusion.
- porcine reproductive and respiratory syndrome virus
Oxidative stress impairs autophagic flux in prion protein-deficient hippocampal cells
Jae-Min Oh, Eun-Kyoung Choi, Richard I. Carp and Yong-Sun Kim
Pages 1448 - 1461
http://dx.doi.org/10.4161/auto.21164
We previously reported that autophagy is upregulated in Prnp-deficient (Prnp0/0) hippocampal neuronal cells in comparison to cellular prion protein (PrPC)-expressing (Prnp+/+) control cells under conditions of serum deprivation. In this study, we determined whether a protective mechanism of PrPC is associated with autophagy using Prnp0/0 hippocampal neuronal cells under hydrogen peroxide (H2O2)-induced oxidative stress. We found that Prnp0/0 cells were more susceptible to oxidative stress than Prnp+/+ cells in a dose- and time-dependent manner. In addition, we observed enhanced autophagy by immunoblotting, which detected the conversion of microtubule-associated protein 1 light chain 3 β (LC3B)-I to LC3B-II, and we observed increased punctate LC3B immunostaining in H2O2-treated Prnp0/0 cells compared with H2O2-treated control cells. Interestingly, this enhanced autophagy was due to impaired autophagic flux in the H2O2-treated Prnp0/0 cells, while the H2O2-treated Prnp+/+ cells showed enhanced autophagic flux. Furthermore, caspase-dependent and independent apoptosis was observed when both cell lines were exposed to H2O2. Moreover, the inhibition of autophagosome formation by Atg7 siRNA revealed that increased autophagic flux in Prnp+/+ cells contributes to the prosurvival effect of autophagy against H2O2 cytotoxicity. Taken together, our results provide the first experimental evidence that the deficiency of PrPC may impair autophagic flux via H2O2-induced oxidative stress.
ROS-induced mitochondrial depolarization initiates PARK2/PARKIN-dependent mitochondrial degradation by autophagy
Yuqing Wang, Yulia Nartiss, Boris Steipe, G. Angus McQuibban and Peter K. Kim
Pages 1462 - 1476
http://dx.doi.org/10.4161/auto.21211
Reactive oxygen species (ROS) have been implicated as a signal for general autophagy. Both mitochondrial-produced and exogenous ROS induce autophagosome formation. However, it is unclear whether ROS are required for the selective autophagic degradation of mitochondria, a process called mitophagy. Recent work using carbonyl cyanide m-chlorophenylhydrazone (CCCP), a mitochondrial-uncoupling reagent, has been shown to induce mitophagy. However, CCCP treatment may not be biologically relevant since it causes the depolarization of the entire mitochondrial network. Since mitochondria are the main ROS production sites in mammalian cells, we propose that short bursts of ROS produced within mitochondria may be involved in the signaling for mitophagy. To test this hypothesis, we induced an acute burst of ROS within mitochondria using a mitochondrial-targeted photosensitizer, mitochondrial KillerRed (mtKR). Using mtKR, we increased ROS levels in the mitochondrial matrix, which resulted in the loss of membrane potential and the subsequent activation of PARK2-dependent mitophagy. Importantly, we showed that overexpression of the mitochondrial antioxidant protein, superoxide dismutase-2, can squelch mtKR-induced mitophagy, demonstrating that mitochondrial ROS are responsible for mitophagy activation. Using this assay, we examined the impact of mitochondrial morphology on mitophagy. It was shown recently that elongated mitochondria are more resistant to mitophagy through unknown mechanisms. Here, we show that elongated mitochondria are more resistant to ROS-induced damage and mitophagy compared with fragmented mitochondria, suggesting that mitochondrial morphology has an important role in regulating ROS and mitophagy. Together, our results suggest that ROS-induced mitochondrial damage may be an important upstream activator of mitophagy.
- neurodegenerative disorders
Autophagy: Resetting glutamine-dependent metabolism and oxygen consumption
Tsung-Chin Lin, Yun-Ru Chen, Elizabeth Kensicki, Angela Ying-Jian Li, Mei Kong, Yang Li, Robert P. Mohney, Han-Ming Shen, Bangyan Stiles, Noboru Mizushima, Liang-In Lin and David K. Ann
Pages 1477 - 1493
http://dx.doi.org/10.4161/auto.21228
Autophagy is a catabolic process that functions in recycling and degrading cellular proteins, and is also induced as an adaptive response to the increased metabolic demand upon nutrient starvation. However, the prosurvival role of autophagy in response to metabolic stress due to deprivation of glutamine, the most abundant nutrient for mammalian cells, is not well understood. Here, we demonstrated that when extracellular glutamine was withdrawn, autophagy provided cells with sub-mM concentrations of glutamine, which played a critical role in fostering cell metabolism. Moreover, we uncovered a previously unknown connection between metabolic responses to ATG5 deficiency and glutamine deprivation, and revealed that WT and atg5−/− MEFs utilized both common and distinct metabolic pathways over time during glutamine deprivation. Although the early response of WT MEFs to glutamine deficiency was similar in many respects to the baseline metabolism of atg5−/− MEFs, there was a concomitant decrease in the levels of essential amino acids and branched chain amino acid catabolites in WT MEFs after 6 h of glutamine withdrawal that distinguished them from the atg5−/− MEFs. Metabolomic profiling, oxygen consumption and pathway focused quantitative RT-PCR analyses revealed that autophagy and glutamine utilization were reciprocally regulated to couple metabolic and transcriptional reprogramming. These findings provide key insights into the critical prosurvival role of autophagy in maintaining mitochondrial oxidative phosphorylation and cell growth during metabolic stress caused by glutamine deprivation.
- transcriptional reprogramming
SNCA (α-synuclein)-induced toxicity in yeast cells is dependent on Sir2-mediated mitophagy
Belém Sampaio-Marques, Carolina Felgueiras, Alexandra Silva, Márcio Rodrigues, Sandra Tenreiro, Vanessa Franssens, Andreas S. Reichert, Tiago F. Outeiro, Joris Winderickx and Paula Ludovico
Pages 1494 - 1509
http://dx.doi.org/10.4161/auto.21275
SNCA (α-synuclein) misfolding and aggregation is strongly associated with both idiopathic and familial forms of Parkinson disease (PD). Evidence suggests that SNCA has an impact on cell clearance routes and protein quality control systems such as the ubiquitin-proteasome system (UPS) and autophagy. Recent advances in the key role of the autosomal recessive PARK2/PARKIN and PINK1 genes in mitophagy, highlighted this process as a prominent new pathogenic mechanism. Nevertheless, the role of autophagy/mitophagy in the pathogenesis of sporadic and autosomal dominant familial forms of PD is still enigmatic. The yeast Saccharomyces cerevisiae is a powerful “empty room” model that has been exploited to clarify different molecular aspects associated with SNCA toxicity, which combines the advantage of being an established system for aging research. The contribution of autophagy/mitophagy for the toxicity induced by the heterologous expression of the human wild-type SNCA gene and the clinical A53T mutant during yeast chronological life span (CLS) was explored. A reduced CLS together with an increase of autophagy and mitophagy activities were observed in cells expressing both forms of SNCA. Impairment of mitophagy by deletion of ATG11 or ATG32 resulted in a CLS extension, further implicating mitophagy in the SNCA toxicity. Deletion of SIR2, essential for SNCA toxicity, abolished autophagy and mitophagy, thereby rescuing cells. These data show that Sir2 functions as a regulator of autophagy, like its mammalian homolog, SIRT1, but also of mitophagy. Our work highlights that increased mitophagy activity, mediated by the regulation of ATG32 by Sir2, is an important phenomenon linked to SNCA-induced toxicity during aging.
Inhibition of autophagy as a therapeutic strategy of iron-induced brain injury after hemorrhage
Chiu-Wei Chen, Tzu-Yin Chen, Ke-Li Tsai, Chih-Lung Lin, Kazunari K. Yokoyama, Wen-Sen Lee, Chuang Chin Chiueh and Chin Hsu
Pages 1510 - 1520
http://dx.doi.org/10.4161/auto.21289
Premenopausal women have better survival than men after intracerebral hemorrhage, which is associated with iron overproduction and autophagy induction. To examine the participation of neuronal autophagy and estrogen receptor α (ERα) in the E2–mediated protection, PC12 neurons treated with Atg7 (autophagy-related protein 7) siRNA, rapamycin (an autophagy inducer), or Erα siRNA were applied. To study whether autophagy involves in β-estradiol 3-benzoate (E2)-mediated neuroprotection against iron-induced striatal injury, castration and E2 capsule implantation were performed at 2 weeks and 24 h, respectively, before ferrous citrate (FC) infusion into the caudate nucleus (CN) of Sprague Dawley male and female rats. Furthermore, the role of neuronal autophagy in the sex difference of FC-induced CN injury was confirmed by using conditional knockout Atg7 in dopamine receptor 2 (DRD2)-containing neurons in mice. The results showed that the suppression of FC-induced autophagy by E2 was abolished by Erα siRNA preincubation. Atg7 silencing simulates and rapamycin diminishes E2-mediated neuroprotection against FC-induced neurotoxicity. In vivo, FC induced a lower degree of autophagy, autophagic cell death, injury severity, histological lesion and behavioral deficit in female rats than in males. E2 implantation decreased the levels of both FC-induced autophagy and injury in ovariectomized rats. Moreover, the sex difference of FC-induced CN injury was diminished in Atg7 knockout mice. Thus, suppression of autophagy by E2 via ERα contributes to less severity of iron-induced brain injury in females than in male. This finding opens up the prospect for a therapeutic strategy targeting autophagic inhibition for patients suffering from intracerebral iron overload.
- iron-induced brain injury
Curbing autophagy and histone deacetylases to kill cancer cells
Noor Gammoh, Paul A. Marks and Xuejun Jiang
Pages 1521 - 1522
http://dx.doi.org/10.4161/auto.21151
Cells respond to cytotoxicity by activating a variety of signal transduction pathways. One pathway frequently upregulated during cytotoxic response is macroautophagy (hereafter referred to as autophagy). Previously, we demonstrated that pan-histone deacetylase (HDAC) inhibitors, such as the anticancer agent suberoylanilide hydroxamic acid (SAHA, Vorinostat), can induce autophagy. In this study, we show that HDAC inhibition triggers autophagy by suppressing MTOR and activating the autophagic kinase ULK1. Furthermore, autophagy inhibition can sensitize cells to both apoptotic and nonapoptotic cell death induced by SAHA, suggesting the therapeutic potential of autophagy targeting in combination with SAHA therapy. This study also raised a series of questions: What is the role of HDACs in regulating autophagy? Do individual HDACs have distinct functions in autophagy? How do HDACs regulate the nutrient-sensing kinase MTOR? Since SAHA-induced nonapoptotic cell death is not driven by autophagy, what then is the mechanism underlying the apoptosis-independent death? Tackling these questions should lead to a better understanding of autophagy and HDAC biology and contribute to the development of novel therapeutic strategies.
Autophagy induction by vitamin D inhibits both Mycobacterium tuberculosis and human immunodeficiency virus type 1
Grant R. Campbell and Stephen A. Spector
Pages 1523 - 1525
http://dx.doi.org/10.4161/auto.21154
Low vitamin D levels in human immunodeficiency virus type-1 (HIV) infected persons are associated with more rapid disease progression and increased risk for Mycobacterium tuberculosis infection. We report that physiological concentrations of 1α,25-dihydroxycholecalciferol (1,25D3), the active form of vitamin D, inhibits M. tuberculosis and HIV replication in co-infected macrophages through human cathelicidin microbial peptide-dependent autophagy that requires phagosomal maturation. These findings provide a biological explanation for the importance of vitamin D sufficiency in HIV and M. tuberculosis-infected persons, and provide new insights into novel approaches to prevent and treat HIV infection and related opportunistic infections.
- Mycobacterium tuberculosis
ER stress and autophagy contribute to CsA-induced death of malignant glioma cells
Iwona Anna Ciechomska and Bozena Kaminska
Pages 1526 - 1528
http://dx.doi.org/10.4161/auto.21155
Cyclosporine A (CsA), which revolutionized transplantology due to its ability to block the activation of lymphocytes and other immune system cells, triggers autophagy in malignant glioma cell lines via stimulation of endoplasmic reticulum (ER) stress. We also found that autophagy serves as a protective mechanism against CsA toxicity.
How does acetylation regulate autophagy?
Cong Yi and Li Yu
Pages 1529 - 1530
http://dx.doi.org/10.4161/auto.21156
Mounting evidence suggests that acetylation plays an important role in various biological processes including transcriptional regulation, DNA damage repair, cell cycle progression, aging, and glycolysis. It is increasingly recognized that acetylation also regulates autophagy; for example, increasing the cellular acetylation level by treating cells with histone deacetylase (HDAC) inhibitors such as TSA can promote autophagy, and knockdown of the histone acetyltransferase KAT2B/p300 induces autophagy in nutrient-rich conditions. Our goal is to dissect the molecular mechanisms underlying the seemingly complicated role of acetylation in autophagy. We used Saccharomyces cerevisiae as a model organism because it can be genetically manipulated in a relatively easy and reliable way, allowing us to test the function of acetylases, deacetylases and acetylation sites on autophagy regulation in a “clean” system.
Mitochondrial division prevents neurodegeneration
Zhongyan Zhang, Yusuke Kageyama and Hiromi Sesaki
Pages 1531 - 1533
http://dx.doi.org/10.4161/auto.21213
Mitochondrial division is mediated by the conserved dynamin-related GTPase DNM1L/DRP1. DNM1L assembles onto the surface of mitochondria and constricts this tubular organelle. Alterations in mitochondrial division are linked to many neurodegenerative diseases. However, the in vivo function of mitochondrial division is poorly understood. In our recent paper, we studied the physiological role of mitochondrial division in postmitotic neurons using the cre-loxP system. We found that the loss of DNM1L resulted in increased oxidative damage in mitochondria, impaired respiration and neurodegeneration in postmitotic neurons. Suggesting a decrease in mitochondrial turnover, mitophagy-related proteins such as LC3, SQSTM1/p62 and ubiqutin accumulated in division-defective mitochondria. These findings suggest that mitochondrial division functions as an important quality control mechanism that suppresses oxidative damage and neurodegeneration in vivo
Unconventional roles of nonlipidated LC3 in ERAD tuning and coronavirus infection
Riccardo Bernasconi, Julia Noack and Maurizio Molinari
Pages 1534 - 1536
http://dx.doi.org/10.4161/auto.21229
Secretory and membrane proteins attain their native structure in the endoplasmic reticulum (ER). Folding-defective polypeptides are selected for degradation by processes collectively defined as ER-associated degradation (ERAD). Enhanced ERAD activity may interfere with protein biogenesis by inappropriately targeting not-yet-native protein folding intermediates for disposal. The regulation of ERAD is therefore crucial to maintain cellular proteostasis. At steady-state, select ERAD regulators are constitutively removed from the ER in a series of processes collectively defined as ERAD tuning. This sets the ERAD activity at levels that do not interfere with completion of ongoing folding programs. Our latest work highlights a crucial, autophagy-independent role of nonlipidated LC3 (LC3-I) as part of a membrane-bound receptor that insures the vesicle-mediated clearance of at least two ERAD regulators from the ER, EDEM1 and OS9. This pathway is hijacked by coronaviruses (CoV), and silencing of LC3 substantially inhibits viral replication.
The MAPK1/3 pathway is essential for the deregulation of autophagy observed in G2019S LRRK2 mutant fibroblasts
José M. Bravo-San Pedro, Rubén Gómez-Sánchez, Mireia Niso-Santano, Elisa Pizarro-Estrella, Ana Aiastui-Pujana, Ana Gorostidi, Vicente Climent, Rakel López de Maturana, Rosario Sanchez-Pernaute, Adolfo López de Munain, José M. Fuentes and Rosa A. González-Polo
Pages 1537 - 1539
http://dx.doi.org/10.4161/auto.21270
The link between the deregulation of autophagy and cell death processes can be essential in the development of several neurodegenerative diseases, such as Parkinson disease (PD). However, the molecular mechanism of deregulation of this degradative process in PD patients is unknown. The leucine-rich repeat kinase 2 (LRRK2) gene is related to PD and its implication in autophagy regulation has been described. Our recent work shows that the presence of the G2019S LRRK2 mutation, one of the most prevalent in LRRK2, is accompanied by a deregulation of autophagy basal levels dependent on the MAPK1/3 (ERK2/1) pathway.
Macroautophagy can press a brake on presynaptic neurotransmission
Ciara A. Torres and David Sulzer
Pages 1540 - 1541
http://dx.doi.org/10.4161/auto.21330
The mechanistic target of rapamycin (MTOR) has been implicated in regulating synaptic plasticity and neurodegeneration, but MTOR’s role in modulating presynaptic function through autophagy is unexplored. We studied presynaptic function in ventral dopamine neurons, a system from which neurotransmitter release can be measured directly by cyclic voltammetry. We generated mutant mice that were specifically deficient for macroautophagy in dopaminergic neurons by deleting the Atg7 gene in cells that express the dopamine uptake transporter. Dopamine axonal profiles in the mutant dorsal striatum were ~one third larger in the mutant mice, released ~50% more stimulus-evoked dopamine release, and exhibited more rapid presynaptic recovery than controls. Rapamycin reduced dopamine neuron axon profile size by ~30% in control mice, but had no effect on macroautophagy deficient axons. Acute rapamycin decreased dopaminergic synaptic vesicle density by ~25% and inhibited evoked dopamine release by ~25% in control mice, but not in the Atg7 deficient mutants. Thus, both basal and induced macroautophagy can provide a brake on presynaptic activity in vivo, perhaps by regulating the turnover of synaptic vesicles, and further regulates terminal volume and the kinetics of transmitter release.
Normalization of sphingomyelin levels by 2-hydroxyoleic acid induces autophagic cell death of SF767 cancer cells
Silvia Terés, Victoria Lladó, Mónica Higuera, Gwendolyn Barceló-Coblijn, M. Laura Martin, Maria Antònia Noguera-Salvà, Amaia Marcilla-Etxenike, José Manuel García-Verdugo, Mario Soriano-Navarro, Carlos Saus, Ulises Gómez-Pinedo, Xavier Busquets and Pablo V. Escribá
Pages 1542 - 1544
http://dx.doi.org/10.4161/auto.21341
The very high mortality rate of gliomas reflects the unmet therapeutic need associated with this type of brain tumor. We have discovered that the plasma membrane fulfills a critical role in the propagation of tumorigenic signals, whereby changes in membrane lipid content can either activate or silence relevant pathways. We have designed a synthetic fatty acid, 2-hydroxyoleic acid (2OHOA), that specifically activates sphingomyelin synthase (SGMS), thereby modifying the lipid content of cancer cell membranes and restoring lipid levels to those found in normal cells. In reverting, the structure of the membrane by activating SGMS, 2OHOA inhibits the RAS-MAPK pathway, which in turn fails to activate the CCND (Cyclin D)-CDK4/CDK6 and PI3K-AKT1 pathways. The overall result in SF767 cancer cells, a line that is resistant to apoptosis, is the sequential induction of cell cycle arrest, cell differentiation and autophagy. Such effects are not observed in normal cells (MRC-5) and thus, this specific activation of programmed cell death infers greater efficacy and lower toxicity to 2OHOA than that associated with temozolomide (TMZ), the reference drug for the treatment of glioma.
- lipid bilayer and proliferation
WIP-ing out atherosclerosis with autophagy
Anna Brichkina and Dmitry V. Bulavin
Pages 1545 - 1547
http://dx.doi.org/10.4161/auto.21402
Atherosclerosis commonly causes coronary and cerebrovascular diseases, which are major morbidities worldwide. Controlling these conditions remains a challenge owing to an incomplete understanding of underlying molecular mechanisms. We have recently shown that PPM1D/WIP1 phosphatase plays a crucial role in regulating atherosclerosis in mice. Deletion of Ppm1d results in the suppression of lipid droplet accumulation in macrophages, which prevents the formation of foam cells, and ultimately the development of atherosclerotic plaques. This process is controlled by the ATM-MTOR pathway and depends on the activation of selective autophagy to regulate cholesterol efflux from macrophage foam cells. Our data suggest that modulating autophagy through the PPM1D-ATM-MTOR pathway may be beneficial at both early and advanced stages of atherosclerosis.
Exercise induces autophagy in peripheral tissues and in the brain
Congcong He, Rhea Sumpter, Jr. and Beth Levine
Pages 1548 - 1551
http://dx.doi.org/10.4161/auto.21327
We recently identified physical exercise as a newly defined inducer of autophagy in vivo. Exercise induced autophagy in multiple organs involved in metabolic regulation, such as muscle, liver, pancreas and adipose tissue. To study the physiological role of exercise-induced autophagy, we generated mice with a knock-in nonphosphorylatable mutation in BCL2 (Thr69Ala, Ser70Ala and Ser84Ala) (BCL2 AAA) that are defective in exercise- and starvation-induced autophagy but not in basal autophagy. We found that BCL2 AAA mice could not run on a treadmill as long as wild-type mice, and did not undergo exercise-mediated increases in skeletal glucose muscle uptake. Unlike wild-type mice, the BCL2 AAA mice failed to reverse high-fat diet-induced glucose intolerance after 8 weeks of exercise training, possibly due to defects in signaling pathways that regulate muscle glucose uptake and metabolism during exercise. Together, these findings suggested a hitherto unknown important role of autophagy in mediating exercise-induced metabolic benefits. In the present addendum, we show that treadmill exercise also induces autophagy in the cerebral cortex of adult mice. This observation raises the intriguing question of whether autophagy may in part mediate the beneficial effects of exercise in neurodegeneration, adult neurogenesis and improved cognitive function.
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