title: Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patients with Type 2 diabetes.
abstract: Type 2 diabetes (T2D) is characterized by insulin resistance, mitochondrial dysregulation and, in some studies, exercise resistance in skeletal muscle. Regulation of autophagy and mitochondrial dynamics during exercise and recovery is important for skeletal muscle homoeostasis, and these responses may be altered in T2D. We examined the effect of acute exercise on markers of autophagy and mitochondrial fusion and fission in skeletal muscle biopsies from patients with T2D (n=13) and weight-matched controls (n=14) before, immediately after and 3 h after an acute bout of exercise. Although mRNA levels of most markers of autophagy [PIK3C, MAP1LC3B, sequestosome 1 (SQSTM1), BCL-2/adenovirus E1B 19-kDa-interacting protein 3 (BNIP3), BNIP3-like (BNIP3L)] and mitochondrial dynamics [optic atrophy 1 (OPA1), fission protein 1 (FIS1)] remained unchanged, some either increased during and after exercise (GABARAPL1), decreased in the recovery period [BECN1, autophagy-related (ATG) 7, DNM1L] or both [mitofusin (MFN) 2, mitochondrial E3 ubiquitin ligase 1 (MUL1)]. Protein levels of ATG7, p62/SQSTM1, forkhead box O3A (FOXO3A) and MFN2 (only controls) as well as dynamin-related protein 1 (DRP1) Ser616phosphorylation increased in response to exercise and/or recovery, whereas microtubule-associated protein 1 light chain 3B (LC3B)-II content was reduced immediately after exercise. Exercise increased the activating Ser555phosphorylation and reduced the inhibitory Ser757phosphorylation of Unc-51-like kinase-1 (ULK1). The LC3B-II content and phosphorylation of ULK1 and DRP1 returned towards pre-exercise levels in the recovery period. Insulin sensitivity was reduced in T2D, but with no differences in the autophagic response to exercise. Our results demonstrate that initiation of autophagy and mitochondrial fission is activated by exercise in human skeletal muscle, and that these responses are intact in T2D. The exercise-induced decrease in LC3B-II could be due to increased autophagic turnover.
authors.affiliation: Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.|The Section of Molecular Diabetes & Metabolism, Department of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Rikke
authors.initials: R
authors.lastname: Kruse
authors.affiliation: The Section of Molecular Diabetes & Metabolism, Department of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Andreas J T
authors.initials: AJ
authors.lastname: Pedersen
authors.affiliation: Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.|The Section of Molecular Diabetes & Metabolism, Department of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Jonas M
authors.initials: JM
authors.lastname: Kristensen
authors.affiliation: Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark.|The Section of Molecular Diabetes & Metabolism, Department of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Stine J
authors.initials: SJ
authors.lastname: Petersson
authors.affiliation: Section of Molecular Physiology, the August Krogh Centre, Department of Nutrition, Exercise and Sports, Faculty of Science, Copenhagen University, DK-2100 Copenhagen, Denmark.
authors.forename: Jørgen F P
authors.initials: JF
authors.lastname: Wojtaszewski
authors.affiliation: Department of Endocrinology, Odense University Hospital, DK-5000 Odense, Denmark kurt.hoejlund@rsyd.dk.|The Section of Molecular Diabetes & Metabolism, Department of Clinical Research and Institute of Molecular Medicine, University of Southern Denmark, DK-5000 Odense, Denmark.
authors.forename: Kurt
authors.initials: K
authors.lastname: Højlund
mesh_terms: D001343:Autophagy; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000628:therapy*; D034281:Dynamins; D005081:Exercise Therapy; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D008928:Mitochondria / Q000378:metabolism; D063154:Mitochondrial Dynamics; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism; D018482:Muscle, Skeletal / Q000378:metabolism / Q000503:physiopathology*
chemical_list: C476525:FIS1 protein, human; D008565:Membrane Proteins; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C415198:OPA1 protein, human; C110768:DNM1L protein, human; D034281:Dynamins
keywords: Type 2 diabetes; autophagy; exercise; insulin resistance; mitochondrial dynamics