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Overexpression of protein kinase STK25 in mice exacerbates ectopic lipid accumulation, mitochondrial dysfunction and insulin resistance in skeletal muscle.

Artikel i vetenskaplig tidskrift
Författare Urszula Chursa
Esther Nuñez Durán
Emmelie Cansby
Manoj Amrutkar
Silva Sütt
Marcus Ståhlman
Britt-Marie Olsson
Jan Borén
Maria Johansson
Fredrik Bäckhed
Bengt R Johansson
Carina Sihlbom
Margit Mahlapuu
Publicerad i Diabetologia
Volym 60
Nummer/häfte 3
Sidor 553–567
ISSN 1432-0428
Publiceringsår 2017
Publicerad vid Wallenberglaboratoriet
Institutionen för neurovetenskap och fysiologi, sektionen för fysiologi
Core Facilities, Proteomics
Institutionen för biomedicin
Institutionen för medicin, avdelningen för molekylär och klinisk medicin
Sidor 553–567
Språk en
Länkar dx.doi.org/10.1007/s00125-016-4171-...
www.ncbi.nlm.nih.gov/entrez/query.f...
Ämneskategorier Medicinsk cellbiologi, Fysiologi

Sammanfattning

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.

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