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SIRT1 overexpression in skeletal muscle in vivo induces increased insulin sensitivity and enhanced complex I but not complex II–V functions in individual subsarcolemmal and intermyofibrillar mitochondria

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Abstract

SIRT1 is known to improve insulin resistance (IR), but whether this effect is direct or not is still unclear, and this question has not been addressed in vivo in the skeletal muscle. Therefore, we sought to test if acute overexpression of SIRT1 in skeletal muscle of high-fat diet (HFD) rats in vivo would affect subsarcolemmal (SS) and intermyofibrillar (IMF) mitochondrial complexes I–V activities and antioxidant enzymes thereby improving insulin action. In vivo electrotransfer was used to overexpress SIRT1 in the skeletal muscle of rats fed HFD for 12 weeks. Skeletal muscle insulin sensitivity and downstream effects of SIRT1 on AMPK, SIRT3, and mitochondrial biogenesis were studied. Citrate synthase (CS), complexes I–V, oxidative stress, and antioxidant levels were assessed in SS and IMF mitochondria. HFD rats showed skeletal muscle IR as well as decreased SIRT1 and SIRT3 expressions, mitochondrial DNA (mtDNA), and mitochondrial biogenesis (p < 0.05). SS and IMF mitochondria displayed lower CS, complexes I–V, and antioxidant enzyme activities (p < 0.05). By contrast, moderate (~2.5 folds) SIRT1 overexpression attenuated HFD-induced skeletal muscle IR. This improvement was associated with increased AMPK, PGC-1α, SIRT3, and mtDNA expressions as well as SS and IMF mitochondrial CS and complexes I–V activities. Importantly, SIRT1 overexpression largely restored antioxidant enzyme activities and enhanced complex I but not complexes II–V functions in individual SS and IMF mitochondria. This study suggests that SIRT1 overexpression improved IR at least partly by targeting complex I functions of SS and IMF mitochondria through the activation of SIRT1 and SIRT3.

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Abbreviations

HFD:

High-fat diet

IR:

Insulin resistance

PGC-lα:

Peroxisome proliferator-activated receptor-γ coactivator-1α

ROS:

Reactive oxygen species

SS:

Subsarcolemmal

IMF:

Intermyofibrillar

TA:

Tibialis anterior

SOL:

Soleus

GM:

Gastrocnemius

2-DG:

2-deoxy-d-glucose

GIR:

Glucose infusion rate

FFA:

Free fatty acid

TG:

Triglyceride

CS:

Citrate synthase

DCPIP:

Dichlorophenolindo-phenol

mtDNA:

Mitochondrial DNA

NRF-1:

Nuclear respiratory factor 1

mtTFA:

Mitochondrial transcription factor A

SOD:

Superoxide dismutase

FBG:

Fasting blood glucose

FINS:

Fasting insulin

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Acknowledgments

This work was supported by the National Natural Science Foundation of China grants 81300656 and 81300685.

Author contributions

All authors participated in the design, interpretation of the studies and analysis of the data, and review of the manuscript; H-HZ, P-JD, X-JM, P-YZ, and M-WS conducted the experiments; G-JQ and H-HZ wrote the manuscript.

Conflict of interest

The authors declare that they have no conflict of interest regarding this manuscript.

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Authors and Affiliations

  1. Department of Endocrinology, The First Affiliated Hospital of Zhengzhou University, 40 Daxue Road, 450052, Zhengzhou, China

    Hao-Hao Zhang, Gui-Jun Qin, Xia-Lian Li, Ying-Hui Zhang, Pei-Jie Du, Peng-Yu Zhang & Yan-Yan Zhao

  2. Department of Pediatrics, First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, China

    Jing Wu

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  1. Hao-Hao Zhang
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Correspondence to Gui-Jun Qin.

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Zhang, HH., Qin, GJ., Li, XL. et al. SIRT1 overexpression in skeletal muscle in vivo induces increased insulin sensitivity and enhanced complex I but not complex II–V functions in individual subsarcolemmal and intermyofibrillar mitochondria. J Physiol Biochem 71, 177–190 (2015). https://doi.org/10.1007/s13105-015-0396-x

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  • DOI: https://doi.org/10.1007/s13105-015-0396-x

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