SIRT3 overexpression in rat muscle does not ameliorate peripheral insulin resistance

Author:

Osborne Brenna123ORCID,Wright Lauren E1,Brandon Amanda E14,Stuart Ella1,Small Lewin1,Hoeks Joris5ORCID,Schrauwen Patrick5,Sinclair David A6,Montgomery Magdalene K17,Cooney Gregory J14,Turner Nigel128ORCID

Affiliation:

1. Diabetes and Metabolism Division, Garvan Institute of Medical Research, Darlinghurst, New South Wales, Australia

2. Department of Pharmacology, School of Biomedical Sciences, UNSW Sydney, New South Wales, Australia

3. Department of Cellular and Molecular Medicine, Center for Healthy Aging, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark

4. Charles Perkins Centre, University of Sydney, New South Wales, Australia

5. NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, the Netherlands

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

7. Department of Anatomy & Physiology, School of Biomedical Sciences, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Victoria, Australia

8. Cellular Bioenergetics Laboratory, Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia

Abstract

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.

Publisher

Bioscientifica

Subject

Endocrinology,Endocrinology, Diabetes and Metabolism

Reference54 articles.

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