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ResearchIn-Press PreviewMetabolismMuscle biology Open Access | 10.1172/jci.insight.196134

Omega-3 fatty acid supplementation improves skeletal muscle mitochondrial function in a model of Barth syndrome

Katharina B. Kuentzel,1 Ana Vranešević,1 Samuel A.J. Trammell,1 Fabian Finger,2 Jesper F. Havelund,3 Yvette L. Schooneveldt,1 Ivan Bradić,3 Nicoline R. Andersen,1 Anna S. Hassing,1 Katja T. Michler,1 Martin R. Larsen,3 Zachary Gerhart-Hines,2 Steven M. Claypool,4 Jonas T. Treebak,2 Andreas M. Fritzen,1 Matthew P. Gillum,1 Steen Larsen,1 Nils Færgeman,3 and Trisha J. Grevengoed1

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Michler, K. in: PubMed | Google Scholar

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Claypool, S. in: PubMed | Google Scholar

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

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1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Fritzen, A. in: PubMed | Google Scholar

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Gillum, M. in: PubMed | Google Scholar

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Larsen, S. in: PubMed | Google Scholar

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Færgeman, N. in: PubMed | Google Scholar |

1Department of Biomedical Sciences, University of Copenhagen, Copenhagen, Denmark

2Novo Nordisk Foundation Center for Metabolic Research, University of Copenhagen, Copenhagen, Denmark

3Department of Biochemistry and Molecular Biology, University of Southern Denmark, Odense, Denmark

4Department of Physiology, Johns Hopkins School of Medicine, Baltimore, United States of America

Find articles by Grevengoed, T. in: PubMed | Google Scholar |

Published June 9, 2026 - More info

JCI Insight. https://doi.org/10.1172/jci.insight.196134.
Copyright © 2026, Kuentzel et al. This work is licensed under the Creative Commons Attribution 4.0 International License. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.
Published June 9, 2026 - Version history
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Abstract

The composition of mitochondrial membrane lipids is crucial to cellular respiration, as seen in Barth syndrome (BTHS), a rare disease affecting skeletal muscle, heart, and neutrophils. In BTHS, mutations in the tafazzin (TAZ) gene reduce remodeling of the mitochondrial phospholipid, cardiolipin, causing mitochondrial dysfunction in skeletal muscle and heart. Here, we investigated effects of altering polyunsaturated fatty acid content in cardiolipin using preclinical models of BTHS. In vitro, the absence of TAZ did not impair omega-3 fatty acid incorporation into cardiolipin and resulted in increased turnover of these acyl chains. To examine this in a functional model, we generated a muscle-specific knockout mouse of TAZ (TAZ MKO), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO with fish-oil-derived omega-3 fatty acids prevented lean mass loss, improved mitochondrial respiration, altered mitochondrial structure, and revealed moderate improvements in the stress response. Surprisingly, no diet-induced changes to cardiolipin species were observed in the TAZ MKO, but other phospholipids were altered by both genotype and diet, revealing complex regulation and potential compensation. Overall, this work provides evidence that omega-3 fatty acid supplementation is beneficial in muscle lacking TAZ to improve quality of life when added to current BTHS treatments.

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  • Version 1 (June 9, 2026): In-Press Preview
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