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

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 mice with muscle-specific knockout of Taz (TAZ MKO mice), which recapitulated the human phenotype in skeletal muscle. Supplementing the diet of TAZ MKO mice 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 in cardiolipin species were observed in the TAZ MKO mice, 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.