title: Myostatin-deficient mice exhibit reduced insulin resistance through activating the AMP-activated protein kinase signalling pathway.
abstract: OBJECTIVE
  Myostatin-null mice (Mstn(-/-)) have reduced body fat and increased tolerance to glucose. To date the molecular mechanisms through which myostatin regulates body fat content and insulin sensitivity are not known. Therefore, the aim of the current study was to identify signalling pathways through which myostatin regulates insulin sensitivity.
  
  
  METHODS
  Wild-type (WT) mice and Mstn(-/-) mice were fed either a control chow diet or a high fat diet (HFD) for 12 weeks. Glucose tolerance testing and insulin stimulated glucose uptake by M. extensor digitorum longus (EDL) were used as variables to determine insulin sensitivity. Quantitative PCR, Western blotting and enzyme assays were used to monitor AMP-activated protein kinase (AMPK) levels and activity.
  
  
  RESULTS
  Mstn(-/-) mice exhibited reduced fat accumulation and peripheral insulin resistance when compared with WT mice, even when they were fed an HFD. Furthermore, treatment with a myostatin antagonist also increased insulin sensitivity during HFD. Consistent with increased insulin sensitivity, we also detected elevated levels of GLUT4, AKT, p-AKT and insulin receptor substrate-1 in Mstn(-/-) muscles. Molecular analysis showed that there is increased expression and activity of AMPK in Mstn(-/-) muscles. Furthermore, we also observed an increase in the AMPK downstream target genes, Sirt1 and Pgc-1α (also known as Ppargc1a), in skeletal muscle of Mstn(-/-) mice.
  
  
  CONCLUSIONS
  We conclude that myostatin inactivation leads to increased AMPK levels and activity resulting in increased insulin sensitivity of skeletal muscle. We propose that, by regulating AMPK in skeletal muscle and adipose tissues, myostatin plays a major role in regulating insulin signalling.
authors.affiliation: Development and Metabolism Program, Singapore Institute for Clinical Sciences, Singapore, Republic of Singapore.
authors.forename: C
authors.initials: C
authors.lastname: Zhang
authors.forename: C
authors.initials: C
authors.lastname: McFarlane
authors.forename: S
authors.initials: S
authors.lastname: Lokireddy
authors.forename: S
authors.initials: S
authors.lastname: Bonala
authors.forename: X
authors.initials: X
authors.lastname: Ge
authors.forename: S
authors.initials: S
authors.lastname: Masuda
authors.forename: P D
authors.initials: PD
authors.lastname: Gluckman
authors.forename: M
authors.initials: M
authors.lastname: Sharma
authors.forename: R
authors.initials: R
authors.lastname: Kambadur
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000502:physiology*; D000818:Animals; D004041:Dietary Fats / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D051275:Glucose Transporter Type 4 / Q000378:metabolism; D007333:Insulin Resistance / Q000502:physiology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D023421:Models, Animal; D018482:Muscle, Skeletal / Q000378:metabolism; D055435:Myostatin / Q000172:deficiency* / Q000235:genetics; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D004041:Dietary Fats; D051275:Glucose Transporter Type 4; D055435:Myostatin; C495693:Slc2a4 protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D055372:AMP-Activated Protein Kinases; D005947:Glucose