Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance
- Darren C Henstridge*,1,
- Clinton R Bruce*,1,2,
- Brian G Drew3,
- Kálmán Tory4,
- Attila Kolonics4,
- Emma Estevez1,
- Jason Chung1,
- Nadine Watson1,
- Timothy Gardner1,
- Robert S Lee-Young1,
- Timothy Connor5,
- Matthew J Watt2,
- Kevin Carpenter6,
- Mark Hargreaves7,
- Sean L McGee5,
- Andrea L Hevener3 and
- Mark A Febbraio1,4,†
- 1Cellular & Molecular Metabolism Laboratory, Baker IDI Heart & Diabetes Institute, 75 Commercial Road, Melbourne, VIC, 3004 Australia,
- 2Department of Physiology, Monash University, Clayton VIC 3800 Australia,
- 3David Geffen School of Medicine, Division of Endocrinology, Diabetes and Hypertension, University of California, Los Angeles, CA, USA,
- 4N-Gene Research Laboratories Ltd., 1137 Budapest, Szent-Istvan Krt. 18, Hungary,
- 5Metabolic Research Unit, School of Medicine, Deakin University, Geelong, VIC, Australia,
- 6Department of Biochemical Genetics, The Children’s Hospital at Westmead and the Disciplines of Genetic Medicine & Paediatrics and Child Health, University of Sydney, NSW, Australia,
- 7Department of Physiology, The University of Melbourne, Parkville, VIC, Australia.
- †Address for correspondence: Mark A. Febbraio, Email:
Induction of heat shock protein 72 (HSP72) protects against obesity-induced insulin resistance, but the underlying mechanisms are unknown. Here we show that HSP72 plays a pivotal role in increasing skeletal muscle mitochondrial number and oxidative metabolism. Mice overexpressing HSP72 in skeletal muscle (HSP72Tg) and control wildtype (WT) mice were fed either a chow or high fat diet (HFD). Despite a similar energy intake when comparing HSP72Tg with WT mice, the HFD increased body weight, intramuscular lipid accumulation (triacylglecerol (TAG), diacylglecerol (DAG) but not ceramide) and insulin resistance in WT mice alone. Whole body oxygen consumption, fatty acid oxidation and endurance running capacity were markedly increased in HSP72Tg mice. Moreover, HSP72Tg mice exhibited an increase in mitochondrial number. In addition, the HSP72 co-inducer BGP-15, currently in human clinical trials for type 2 diabetes, also increased mitochondrial number and insulin sensitivity in a rat model of type 2 diabetes. Together, these data identify a novel role for activation of HSP72 in skeletal muscle. Thus, the increased oxidative metabolism associated with activation of HSP72 has potential clinical implications, not only for type 2 diabetes, but for other disorders where mitochondrial function is compromised.
- Received June 19, 2013.
- Accepted January 9, 2014.
- © 2014 by the American Diabetes Association.
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