TY - JOUR

T1 - Intact initiation of autophagy and mitochondrial fission by acute exercise in skeletal muscle of patientswith type 2 diabetes

AU - Kruse Sørensen, Rikke

AU - Pedersen, Andreas James Thestrup

AU - Kristensen, Jonas Møller

AU - Petersson, Stine Juhl

AU - Wojtaszewski, Jørgen

AU - Højlund, Kurt

N1 - CURIS 2017 NEXS 016

PY - 2017

Y1 - 2017

N2 - AIMS: 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 homeostasis, and these responses may be altered in T2D.MATERIALS AND METHODS: 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 3h after an acute bout of exercise.RESULTS: While mRNA levels of most markers of autophagy ( PIK3C, MAP1LC3B, SQSTM1, BNIP3, BNIP3L ) and mitochondrial dynamics ( OPA1, FIS1 ) remained unchanged, some either increased during and after exercise (GABARAPL1 ), decreased in the recovery period ( BECN1, ATG7, DNM1L ), or both ( MFN2, MUL1 ). Protein levels of ATG7, p62/SQSTM1, FOXO3A, and MFN2 (only controls) as well as the DRP1 Ser616 phosphorylation increased in response to exercise and/or recovery, while LC3B-II content was reduced immediately after exercise. Exercise increased the activating Ser555 phosphorylation and reduced the inhibitory Ser757 phosphorylation of ULK1. The LC3B-II content and phosphorylations of ULK1 and DRP1 returned toward pre-exercise levels in the recovery period. Insulin sensitivity was reduced in T2D, but with no differences in the autophagic response to exercise.CONCLUSIONS: 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.

AB - AIMS: 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 homeostasis, and these responses may be altered in T2D.MATERIALS AND METHODS: 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 3h after an acute bout of exercise.RESULTS: While mRNA levels of most markers of autophagy ( PIK3C, MAP1LC3B, SQSTM1, BNIP3, BNIP3L ) and mitochondrial dynamics ( OPA1, FIS1 ) remained unchanged, some either increased during and after exercise (GABARAPL1 ), decreased in the recovery period ( BECN1, ATG7, DNM1L ), or both ( MFN2, MUL1 ). Protein levels of ATG7, p62/SQSTM1, FOXO3A, and MFN2 (only controls) as well as the DRP1 Ser616 phosphorylation increased in response to exercise and/or recovery, while LC3B-II content was reduced immediately after exercise. Exercise increased the activating Ser555 phosphorylation and reduced the inhibitory Ser757 phosphorylation of ULK1. The LC3B-II content and phosphorylations of ULK1 and DRP1 returned toward pre-exercise levels in the recovery period. Insulin sensitivity was reduced in T2D, but with no differences in the autophagic response to exercise.CONCLUSIONS: 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.

KW - Faculty of Science

KW - Autophagy

KW - Exercise

KW - Insulin resistance

KW - Mitochondrial dynamics

KW - Type 2 diabetes

U2 - 10.1042/CS20160736

DO - 10.1042/CS20160736

M3 - Journal article

C2 - 27837193

VL - 131

SP - 37

EP - 47

JO - Clinical Science

JF - Clinical Science

SN - 0143-5221

IS - 1

ER -