Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance

Darren C Henstridge, Clinton R Bruce, Brian G Drew, Kalman Tory, Attila Kolonics, Emma Estevez, Jason Chung, Nadine Watson, Timothy Gardner, Robert S Lee-Young, Timothy Connor, Matthew James Watt, Kevin Carpenter, Mark Hargreaves, Sean L McGee, Andrea Hevener, Mark Anthony Febbraio

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Abstract

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.
Original languageEnglish
Pages (from-to)1881 - 1894
Number of pages14
JournalDiabetes
Volume63
Issue number6
DOIs
Publication statusPublished - 2014

Cite this

Henstridge, Darren C ; Bruce, Clinton R ; Drew, Brian G ; Tory, Kalman ; Kolonics, Attila ; Estevez, Emma ; Chung, Jason ; Watson, Nadine ; Gardner, Timothy ; Lee-Young, Robert S ; Connor, Timothy ; Watt, Matthew James ; Carpenter, Kevin ; Hargreaves, Mark ; McGee, Sean L ; Hevener, Andrea ; Febbraio, Mark Anthony. / Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. In: Diabetes. 2014 ; Vol. 63, No. 6. pp. 1881 - 1894.
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abstract = "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.",
author = "Henstridge, {Darren C} and Bruce, {Clinton R} and Drew, {Brian G} and Kalman Tory and Attila Kolonics and Emma Estevez and Jason Chung and Nadine Watson and Timothy Gardner and Lee-Young, {Robert S} and Timothy Connor and Watt, {Matthew James} and Kevin Carpenter and Mark Hargreaves and McGee, {Sean L} and Andrea Hevener and Febbraio, {Mark Anthony}",
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doi = "10.2337/db13-0967",
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Henstridge, DC, Bruce, CR, Drew, BG, Tory, K, Kolonics, A, Estevez, E, Chung, J, Watson, N, Gardner, T, Lee-Young, RS, Connor, T, Watt, MJ, Carpenter, K, Hargreaves, M, McGee, SL, Hevener, A & Febbraio, MA 2014, 'Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance', Diabetes, vol. 63, no. 6, pp. 1881 - 1894. https://doi.org/10.2337/db13-0967

Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance. / Henstridge, Darren C; Bruce, Clinton R; Drew, Brian G; Tory, Kalman; Kolonics, Attila; Estevez, Emma; Chung, Jason; Watson, Nadine; Gardner, Timothy; Lee-Young, Robert S; Connor, Timothy; Watt, Matthew James; Carpenter, Kevin; Hargreaves, Mark; McGee, Sean L; Hevener, Andrea; Febbraio, Mark Anthony.

In: Diabetes, Vol. 63, No. 6, 2014, p. 1881 - 1894.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Activating HSP72 in rodent skeletal muscle increases mitochondrial number and oxidative capacity and decreases insulin resistance

AU - Henstridge, Darren C

AU - Bruce, Clinton R

AU - Drew, Brian G

AU - Tory, Kalman

AU - Kolonics, Attila

AU - Estevez, Emma

AU - Chung, Jason

AU - Watson, Nadine

AU - Gardner, Timothy

AU - Lee-Young, Robert S

AU - Connor, Timothy

AU - Watt, Matthew James

AU - Carpenter, Kevin

AU - Hargreaves, Mark

AU - McGee, Sean L

AU - Hevener, Andrea

AU - Febbraio, Mark Anthony

PY - 2014

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N2 - 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.

AB - 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.

UR - http://www.ncbi.nlm.nih.gov/pubmed/24430435

U2 - 10.2337/db13-0967

DO - 10.2337/db13-0967

M3 - Article

VL - 63

SP - 1881

EP - 1894

JO - Diabetes

JF - Diabetes

SN - 0012-1797

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ER -