title: Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle.
abstract: Understanding the molecular networks controlling ectopic lipid deposition and insulin responsiveness in skeletal muscle is essential for developing new strategies to treat type 2 diabetes. We recently identified serine/threonine protein kinase 25 (STK25) as a critical regulator of liver steatosis, hepatic lipid metabolism and whole body glucose and insulin homeostasis. Here, we assessed the role of STK25 in control of ectopic fat storage and insulin responsiveness in skeletal muscle.
  
  
  
  Skeletal muscle morphology was studied by histological examination, exercise performance and insulin sensitivity were assessed by treadmill running and euglycaemic-hyperinsulinaemic clamp, respectively, and muscle lipid metabolism was analysed by ex vivo assays in Stk25 transgenic and wild-type mice fed a high-fat diet. Lipid accumulation and mitochondrial function were also studied in rodent myoblasts overexpressing STK25. Global quantitative phosphoproteomics was performed in skeletal muscle of Stk25 transgenic and wild-type mice fed a high-fat diet to identify potential downstream mediators of STK25 action.
  
  
  
  We found that overexpression of STK25 in transgenic mice fed a high-fat diet increases intramyocellular lipid accumulation, impairs skeletal muscle mitochondrial function and sarcomeric ultrastructure, and induces perimysial and endomysial fibrosis, thereby reducing endurance exercise capacity and muscle insulin sensitivity. Furthermore, we observed enhanced lipid accumulation and impaired mitochondrial function in rodent myoblasts overexpressing STK25, demonstrating an autonomous action for STK25 within cells. Global phosphoproteomic analysis revealed alterations in the total abundance and phosphorylation status of different target proteins located predominantly to mitochondria and sarcomeric contractile elements in Stk25 transgenic vs wild-type muscle, respectively, providing a possible molecular mechanism for the observed phenotype.
  
  
  
  STK25 emerges as a new regulator of the complex interplay between lipid storage, mitochondrial energetics and insulin action in skeletal muscle, highlighting the potential of STK25 antagonists for type 2 diabetes treatment.
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden.
authors.forename: Urszula
authors.initials: U
authors.lastname: Chursa
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden.
authors.forename: Esther
authors.initials: E
authors.lastname: Nuñez-Durán
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden.
authors.forename: Emmelie
authors.initials: E
authors.lastname: Cansby
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden.
authors.forename: Manoj
authors.initials: M
authors.lastname: Amrutkar
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden.
authors.forename: Silva
authors.initials: S
authors.lastname: Sütt
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Marcus
authors.initials: M
authors.lastname: Ståhlman
authors.affiliation: Proteomics Core Facility, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Britt-Marie
authors.initials: BM
authors.lastname: Olsson
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.
authors.forename: Jan
authors.initials: J
authors.lastname: Borén
authors.affiliation: Department of Physiology, Institute of Neuroscience and Physiology, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Maria E
authors.initials: ME
authors.lastname: Johansson
authors.affiliation: Wallenberg Laboratory, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Gothenburg, Sweden.|Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark.
authors.forename: Fredrik
authors.initials: F
authors.lastname: Bäckhed
authors.affiliation: Institute of Biomedicine, Electron Microscopy Unit, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Bengt R
authors.initials: BR
authors.lastname: Johansson
authors.affiliation: Proteomics Core Facility, University of Gothenburg, Gothenburg, Sweden.
authors.forename: Carina
authors.initials: C
authors.lastname: Sihlbom
authors.affiliation: Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine, University of Gothenburg, Sahlgrenska University Hospital, Blå stråket 5, SE-41345, Gothenburg, Sweden. Margit.Mahlapuu@gu.se.
authors.forename: Margit
authors.initials: M
authors.lastname: Mahlapuu
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002853:Chromatography, Liquid; D059305:Diet, High-Fat; D007333:Insulin Resistance / Q000235:genetics / Q000502:physiology*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D050356:Lipid Metabolism / Q000235:genetics / Q000502:physiology*; D013058:Mass Spectrometry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018482:Muscle, Skeletal / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics / Q000378:metabolism*; D040901:Proteomics; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D000099317:Hippo Kinases
chemical_list: D047908:Intracellular Signaling Peptides and Proteins; D017346:Protein Serine-Threonine Kinases; C530661:Stk25 protein, mouse; D000099317:Hippo Kinases
keywords: Ectopic lipid storage; Insulin resistance; Mitochondrial dysfunction; Skeletal muscle