title: Altered miR-29 Expression in Type 2 Diabetes Influences Glucose and Lipid Metabolism in Skeletal Muscle.
abstract: MicroRNAs have emerged as important regulators of glucose and lipid metabolism in several tissues; however, their role in skeletal muscle remains poorly characterized. We determined the effects of the miR-29 family on glucose metabolism, lipid metabolism, and insulin responsiveness in skeletal muscle. We provide evidence that miR-29a and miR-29c are increased in skeletal muscle from patients with type 2 diabetes and are decreased following endurance training in healthy young men and in rats. In primary human skeletal muscle cells, inhibition and overexpression strategies demonstrate that miR-29a and miR-29c regulate glucose uptake and insulin-stimulated glucose metabolism. We identified that miR-29 overexpression attenuates insulin signaling and expression of insulin receptor substrate 1 and phosphoinositide 3-kinase. Moreover, miR-29 overexpression reduces hexokinase 2 expression and activity. Conversely, overexpression of miR-29 by electroporation of mouse tibialis anterior muscle decreased glucose uptake and glycogen content in vivo, concomitant with decreased abundance of GLUT4. We also provide evidence that fatty acid oxidation is negatively regulated by miR-29 overexpression, potentially through the regulation of peroxisome proliferator-activated receptor γ coactivator-1α expression. Collectively, we reveal that miR-29 acts as an important regulator of insulin-stimulated glucose metabolism and lipid oxidation, with relevance to human physiology and type 2 diabetes.
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Julie
authors.initials: J
authors.lastname: Massart
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Rasmus J O
authors.initials: RJO
authors.lastname: Sjögren
authors.affiliation: Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Leonidas S
authors.initials: LS
authors.lastname: Lundell
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Mudry
authors.affiliation: Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Niclas
authors.initials: N
authors.lastname: Franck
authors.affiliation: School of Health and Human Performance, Dublin City University, Dublin, Ireland.|3U Diabetes Consortium, National Institute for Cellular Biotechnology, Dublin City University, Dublin, Ireland.
authors.forename: Donal J
authors.initials: DJ
authors.lastname: O'Gorman
authors.affiliation: School of Health and Human Performance, Dublin City University, Dublin, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Egan
authors.affiliation: Department of Molecular Medicine and Surgery, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.|Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Juleen R
authors.identifier: 0000-0001-6891-7497
authors.initials: JR
authors.lastname: Zierath
authors.affiliation: Department of Physiology and Pharmacology, Section for Integrative Physiology, Karolinska Institutet, Stockholm, Sweden anna.krook@ki.se.
authors.forename: Anna
authors.identifier: 0000-0002-0891-0258
authors.initials: A
authors.lastname: Krook
mesh_terms: D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics* / Q000378:metabolism; D015444:Exercise; D005227:Fatty Acids / Q000378:metabolism; D005260:Female; D020869:Gene Expression Profiling; D005947:Glucose / Q000378:metabolism*; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000235:genetics / Q000378:metabolism; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics*; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000378:metabolism*; D010084:Oxidation-Reduction; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha / Q000378:metabolism; D058539:Phosphatidylinositol 3-Kinase / Q000235:genetics / Q000378:metabolism; D010805:Physical Conditioning, Animal; D010807:Physical Endurance; D051381:Rats; D017208:Rats, Wistar; D060888:Real-Time Polymerase Chain Reaction
chemical_list: D005227:Fatty Acids; D051275:Glucose Transporter Type 4; D055504:Insulin Receptor Substrate Proteins; C526366:MIRN29 microRNA, rat; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D000071248:Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; C495693:Slc2a4 protein, mouse; D058539:Phosphatidylinositol 3-Kinase; D005947:Glucose