SIRT3 overexpression in rat muscle does not ameliorate peripheral insulin resistance

in Journal of Endocrinology
Authors:
Brenna Osborne Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Department of Pharmacology, School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia
Department of Cellular and Molecular Medicine, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

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Lauren E Wright Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

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Amanda E Brandon Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Charles Perkins Centre, University of Sydney, New South Wales, Australia

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Ella Stuart Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

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Lewin Small Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

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Joris Hoeks NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

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Patrick Schrauwen NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

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David A Sinclair Department of Genetics, Paul F. Glenn Center for Biology of Aging Research, Harvard Medical School, Boston, Massachusetts, USA

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Magdalene K Montgomery Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Department of Anatomy & Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia

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Gregory J Cooney Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Charles Perkins Centre, University of Sydney, New South Wales, Australia

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Nigel Turner Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia
Department of Pharmacology, School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia
Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

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Correspondence should be addressed to N Turner: n.turner@victorchang.edu.au
DOI:
https://doi.org/10.1530/JOE-22-0101
Volume/Issue:
Volume 258: Issue 3
Article Type:
Research Article
Article ID:
e220101
Online Publication Date:
01 Aug 2023
Copyright:
© 2023 the author(s) 2023
Restricted access
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Reduced expression of the NAD+-dependent deacetylase, SIRT3, has been associated with insulin resistance and metabolic dysfunction in humans and rodents. In this study, we investigated whether specific overexpression of SIRT3 in vivo in skeletal muscle could prevent high-fat diet (HFD)-induced muscle insulin resistance. To address this, we used a muscle-specific adeno-associated virus (AAV) to overexpress SIRT3 in rat tibialis and extensor digitorum longus (EDL) muscles. Mitochondrial substrate oxidation, substrate switching and oxidative enzyme activity were assessed in skeletal muscles with and without SIRT3 overexpression. Muscle-specific insulin action was also assessed by hyperinsulinaemic–euglycaemic clamps in rats that underwent a 4-week HFD-feeding protocol. Ex vivo functional assays revealed elevated activity of selected SIRT3-target enzymes including hexokinase, isocitrate dehydrogenase and pyruvate dehydrogenase that was associated with an increase in the ability to switch between fatty acid- and glucose-derived substrates in muscles with SIRT3 overexpression. However, during the clamp, muscles from rats fed an HFD with increased SIRT3 expression displayed equally impaired glucose uptake and insulin-stimulated glycogen synthesis as the contralateral control muscle. Intramuscular triglyceride content was similarly increased in the muscle of high-fat-fed rats, regardless of SIRT3 status. Thus, despite SIRT3 knockout (KO) mouse models indicating many beneficial metabolic roles for SIRT3, our findings show that muscle-specific overexpression of SIRT3 has only minor effects on the acute development of skeletal muscle insulin resistance in high-fat-fed rats.

Supplementary Materials

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Copyright:
© 2023 the author(s) 2023
Article ID:
e220101
Article Type:
Research Article
Received Date:
20 Apr 2022
Accepted Date:
19 Jun 2023
Print Publication Date:
01 Sep 2023
Online Publication Date:
01 Aug 2023
Keywords:
SIRT3; sirtuin; skeletal muscle; insulin resistance; mitochondrial function

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