Scriptaid enhances skeletal muscle insulin action and cardiac function in obese mice.
To determine the effect of Scriptaid, a compound that can replicate aspects of the exercise adaptive response through disruption of the class IIa histone deacetylase (HDAC) corepressor complex, on muscle insulin action in obesity.



Diet-induced obese mice were administered Scriptaid (1 mg/kg) via daily intraperitoneal injection for 4 weeks. Whole-body and skeletal muscle metabolic phenotyping of mice was performed, in addition to echocardiography, to assess cardiac morphology and function.



Scriptaid treatment had no effect on body weight or composition, but did increase energy expenditure, supported by increased lipid oxidation, while food intake was also increased. Scriptaid enhanced the expression of oxidative genes and proteins, increased fatty acid oxidation and reduced triglycerides and diacylglycerides in skeletal muscle. Furthermore, ex vivo insulin-stimulated glucose uptake by skeletal muscle was enhanced. Surprisingly, heart weight was reduced in Scriptaid-treated mice and was associated with enhanced expression of genes involved in oxidative metabolism in the heart. Scriptaid also improved indices of both diastolic and systolic cardiac function.



These data show that pharmacological targeting of the class IIa HDAC corepressor complex with Scriptaid could be used to enhance muscle insulin action and cardiac function in obesity.
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Vidhi
V
Gaur
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Timothy
T
Connor
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Kylie
K
Venardos
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Darren C
DC
Henstridge
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Sheree D
SD
Martin
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Courtney
C
Swinton
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Shona
S
Morrison
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Kathryn
0000-0003-1412-6715
K
Aston-Mourney
Department of Physiology, The University of Melbourne, Parkville, Australia.
Stefan M
SM
Gehrig
Department of Physiology, The University of Melbourne, Parkville, Australia.
Roelof
R
van Ewijk
Department of Physiology, The University of Melbourne, Parkville, Australia.
Gordon S
GS
Lynch
Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.|Division of Diabetes and Metabolism, Garvan Institute of Medical Research, Darlinghurst, Australia.
Mark A
MA
Febbraio
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Canada.
Gregory R
GR
Steinberg
Department of Physiology, The University of Melbourne, Parkville, Australia.
Mark
M
Hargreaves
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.
Ken R
KR
Walder
Metabolic Research Unit, School of Medicine, Deakin University, Geelong, Australia.|Metabolism and Inflammation Program, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
Sean L
0000-0001-6953-106X
SL
McGee
D000818:Animals; D019440:Anti-Obesity Agents / Q000009:adverse effects / Q000627:therapeutic use; D002316:Cardiotonic Agents / Q000009:adverse effects / Q000627:therapeutic use*; D059305:Diet, High-Fat / Q000009:adverse effects; D004452:Echocardiography; D015150:Echocardiography, Doppler; D004734:Energy Metabolism / Q000187:drug effects*; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects; D006321:Heart / Q000000981:diagnostic imaging / Q000187:drug effects* / Q000503:physiopathology; D056464:Histone Deacetylase 2 / Q000037:antagonists & inhibitors / Q000378:metabolism; D056572:Histone Deacetylase Inhibitors / Q000009:adverse effects / Q000627:therapeutic use*; D006898:Hydroxylamines / Q000009:adverse effects / Q000627:therapeutic use*; D007333:Insulin Resistance; D008297:Male; D008810:Mice, Inbred C57BL; D018482:Muscle, Skeletal / Q000187:drug effects* / Q000378:metabolism; D009206:Myocardium / Q000473:pathology; D009765:Obesity / Q000188:drug therapy* / Q000209:etiology / Q000473:pathology / Q000503:physiopathology; D009929:Organ Size; D011804:Quinolines / Q000009:adverse effects / Q000627:therapeutic use*
D019440:Anti-Obesity Agents; D002316:Cardiotonic Agents; D056572:Histone Deacetylase Inhibitors; D006898:Hydroxylamines; D011804:Quinolines; C410733:scriptaid; C533424:Hdac2 protein, mouse; D056464:Histone Deacetylase 2
animal pharmacology