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A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology

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Abstract

Diabetic cardiomyopathy describes heart disease in patients with diabetes who have no other cardiac conditions but have a higher risk of developing heart failure. Specific therapies to treat the diabetic heart are limited. A key mechanism involved in the progression of diabetic cardiomyopathy is dysregulation of cardiac energy metabolism. The aim of this study was to determine if increasing the expression of medium-chain acyl-coenzyme A dehydrogenase (MCAD; encoded by Acadm), a key regulator of fatty acid oxidation, could improve the function of the diabetic heart. Male mice were administered streptozotocin to induce diabetes, which led to diastolic dysfunction 8 weeks post-injection. Mice then received cardiac-selective adeno-associated viral vectors encoding MCAD (rAAV6:MCAD) or control AAV and were followed for 8 weeks. In the non-diabetic heart, rAAV6:MCAD increased MCAD expression (mRNA and protein) and increased Acadl and Acadvl, but an increase in MCAD enzyme activity was not detectable. rAAV6:MCAD delivery in the diabetic heart increased MCAD mRNA expression but did not significantly increase protein, activity, or improve diabetes-induced cardiac pathology or molecular metabolic and lipid markers. The uptake of AAV viral vectors was reduced in the diabetic versus non-diabetic heart, which may have implications for the translation of AAV therapies into the clinic.

Key messages

  • The effects of increasing MCAD in the diabetic heart are unknown.

  • Delivery of rAAV6:MCAD increased MCAD mRNA and protein, but not enzyme activity, in the non-diabetic heart.

  • Independent of MCAD enzyme activity, rAAV6:MCAD increased Acadl and Acadvl in the non-diabetic heart.

  • Increasing MCAD cardiac gene expression alone was not sufficient to protect against diabetes-induced cardiac pathology.

  • AAV transduction efficiency was reduced in the diabetic heart, which has clinical implications.

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Data availability

Data generated or analyzed during this study are included in this published article (and its supplementary information files).

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Acknowledgements

We wish to thank Ms Stephanie Jansen (Alfred Research Alliance Animal Facility) for performing the AAV tail vein injections, Ms Amy Hsu (Baker Heart and Diabetes Institute) for technical assistance, and Dr Hongwei Qian (University of Melbourne) for producing the AAV vectors.

Funding

This work was supported by a grant to B.C.B and K.L.W from the Diabetes Australia Research Program (Y19G-BERB), Women in Science Grants from the Baker Heart and Diabetes Institute (to B.C.B), and the Victorian Government’s Operational Infrastructure Support Program. B.C.B is supported by a Baker Fellowship (Baker Heart and Diabetes Institute, Australia). K.L.W is supported by a Future Leader Fellowship from the National Heart Foundation of Australia (award ID 102539). N.M.S. is supported by a Research Training Program scholarship from Monash University. B.G.D, P.G, L.M.D.D, and J.R.M are supported by funding from the National Health and Medical Research Council of Australia.

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Authors and Affiliations

  1. Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, 3010, Australia

    Kate L. Weeks, Antonia J. A. Raaijmakers, Adam J. Trewin, Paul Gregorevic & Lea M. D. Delbridge

  2. Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, 3010, Australia

    Kate L. Weeks, Helen Kiriazis, Brian G. Drew & Julie R. McMullen

  3. Department of Diabetes, Central Clinical School, Monash University, Clayton, VIC, 3800, Australia

    Kate L. Weeks, Nicola M. Sergienko, Brian G. Drew, Julie R. McMullen & Bianca C. Bernardo

  4. Baker Heart and Diabetes Institute, PO Box 6492, Melbourne, VIC, 3004, Australia

    Helen Kiriazis, Emma I. Masterman, Nicola M. Sergienko, Claudia A. Harmawan, Gunes S. Yildiz, Yingying Liu, Brian G. Drew, Julie R. McMullen & Bianca C. Bernardo

  5. Institute for Physical Activity and Nutrition (IPAN), School of Exercise and Nutrition Sciences, Deakin University, Burwood, VIC, 3125, Australia

    Glenn D. Wadley

  6. Centre for Muscle Research, University of Melbourne, Parkville, VIC, 3010, Australia

    Paul Gregorevic

  7. Department of Biochemistry and Molecular Biology, Monash University, Melbourne, VIC, 3800, Australia

    Paul Gregorevic

  8. Department of Neurology, University of Washington School of Medicine, Seattle, WA, 98195, USA

    Paul Gregorevic

  9. Department of Physiology, Anatomy and Microbiology, La Trobe University, Melbourne, VIC, 3086, Australia

    Julie R. McMullen

  10. Department of Paediatrics, University of Melbourne, Parkville, VIC, 3010, Australia

    Bianca C. Bernardo

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  1. Kate L. Weeks
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Contributions

Conceptualization: B.C.B, K.L.W; methodology: B.C.B, K.L.W; investigation: B.C.B, K.L.W, H.K, G.D.W, E.I.M, N.M.S, A.J.A.R, C.A.H, A.J.T, G.S.Y, Y.L; formal analysis: B.C.B, K.L.W, H.K, G.D.W, E.I.M, N.M.S, A.J.A.R, A.J.T; writing—original draft preparation: K.L.W, B.C.B; writing—review and editing: K.L.W, H.K, G.D.W, A.J.T, P.G, L.M.D.D, J.R.M, B.C.B; funding acquisition: B.C.B, K.L.W; resources: G.D.W, B.G.D, P.G, L.M.D.D, J.R.M; supervision: B.C.B, K.L.W, J.R.M. project administration: B.C.B. All authors read and approved the final manuscript.

Corresponding author

Correspondence to Bianca C. Bernardo.

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Ethics approval

This study does not involve human subjects. All experiments using animals were conducted in accordance with the Australian Code for the Care and Use of Animals for Scientific Purposes (National Health & Medical Research Council of Australia, 8th Edition, 2013). All animal procedures and care were approved by the Alfred Research Alliance Animal Ethics Committee (Animal Ethics Committee Approved Project Number E/1867/2018/B).

Competing interests

The authors have no relevant financial or non-financial interests to disclose.

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Kate L. Weeks, Julie R. McMullen, and Bianca C. Bernardo are equal senior authors

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Weeks, K.L., Kiriazis, H., Wadley, G.D. et al. A gene therapy targeting medium-chain acyl-CoA dehydrogenase (MCAD) did not protect against diabetes-induced cardiac pathology. J Mol Med 102, 95–111 (2024). https://doi.org/10.1007/s00109-023-02397-2

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