title: Exercise-induced BCL2-regulated autophagy is required for muscle glucose homeostasis.
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.
authors.affiliation: Center for Autophagy Research, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, Texas 75390, USA.
authors.forename: Congcong
authors.initials: C
authors.lastname: He
authors.forename: Michael C
authors.initials: MC
authors.lastname: Bassik
authors.forename: Viviana
authors.initials: V
authors.lastname: Moresi
authors.forename: Kai
authors.initials: K
authors.lastname: Sun
authors.forename: Yongjie
authors.initials: Y
authors.lastname: Wei
authors.forename: Zhongju
authors.initials: Z
authors.lastname: Zou
authors.forename: Zhenyi
authors.initials: Z
authors.lastname: An
authors.forename: Joy
authors.initials: J
authors.lastname: Loh
authors.forename: Jill
authors.initials: J
authors.lastname: Fisher
authors.forename: Qihua
authors.initials: Q
authors.lastname: Sun
authors.forename: Stanley
authors.initials: S
authors.lastname: Korsmeyer
authors.forename: Milton
authors.initials: M
authors.lastname: Packer
authors.forename: Herman I
authors.initials: HI
authors.lastname: May
authors.forename: Joseph A
authors.initials: JA
authors.lastname: Hill
authors.forename: Herbert W
authors.initials: HW
authors.lastname: Virgin
authors.forename: Christopher
authors.initials: C
authors.lastname: Gilpin
authors.forename: Guanghua
authors.initials: G
authors.lastname: Xiao
authors.forename: Rhonda
authors.initials: R
authors.lastname: Bassel-Duby
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Beth
authors.initials: B
authors.lastname: Levine
mesh_terms: D052242:Adiponectin / Q000097:blood; D000818:Animals; D051017:Apoptosis Regulatory Proteins / Q000235:genetics / Q000378:metabolism; D001343:Autophagy / Q000187:drug effects / Q000235:genetics / Q000502:physiology*; D000071186:Beclin-1; D002478:Cells, Cultured; D004041:Dietary Fats / Q000009:adverse effects; D005508:Food Deprivation / Q000502:physiology; D055879:Gene Knock-In Techniques; D005947:Glucose / Q000378:metabolism*; D018149:Glucose Intolerance / Q000139:chemically induced / Q000517:prevention & control; D005951:Glucose Tolerance Test; D006706:Homeostasis / Q000187:drug effects; D020738:Leptin / Q000097:blood; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018482:Muscle, Skeletal / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009154:Mutation; D009206:Myocardium / Q000166:cytology / Q000378:metabolism*; D010766:Phosphorylation / Q000235:genetics; D010805:Physical Conditioning, Animal / Q000502:physiology*; D010807:Physical Endurance / Q000235:genetics / Q000502:physiology; D005082:Physical Exertion / Q000235:genetics / Q000502:physiology; D011485:Protein Binding / Q000235:genetics; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2; D012420:Running / Q000502:physiology
chemical_list: D052242:Adiponectin; D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D004041:Dietary Fats; D020738:Leptin; D011518:Proto-Oncogene Proteins; D019253:Proto-Oncogene Proteins c-bcl-2; C052617:Bcl2 protein, mouse; D005947:Glucose