Ketogenic Diet Ameliorates Dysferlinopathy Phenotype in DYSF-/- Mice by Promoting Mitochondrial Function
Mitochondria play a central role in the generation of energy in the form of ATP and regulated metal ion homeostasis, programmed cell death, and the synthesis of building blocks for the generation of amino acids, lipids, and nucleotides. In muscle, mitochondria play a fundamental role in maintaining bioenergetic homeostasis. Mitochondrial dysfunction has been associated with several muscle disorders. We determined oxygen consumption using SeahorseÒ technology in cell lines carrying pathogenic DYSF mutations, as well as primary cultures from a dysferlinopathy mouse model using glucose or galactose as the main carbon substrate. Mitochondrial function was reduced in dysferlin-deficient cells cultured in glucose but was greatly improved by galactose. Further experiment showed that DYSF-/- cells consume more glucose that normal cells, which probably induces mitochondrial inhibition. We hypothesize that high glucose levels inhibit mitochondrial function, accelerating the pathology of dysferlinopathy. Thus, a change in the cells’ energy source and a re-activation of the mitochondria may improve muscle function. This project studies the effect of a ketogenic diet (KD), which consists of a high-fat, low-carbohydrate diet that induces ketone body (acetoacetate and β-hydroxybutyrate) production in the liver through fat metabolism with the goal of mimicking a starvation state without depriving the body of necessary calories to sustain growth and development. The approach being followed in this project is to study the effects of glucose, β-hydroxybutyrate, and acetoacetate on dysferlin-deficient myoblast cell lines and primary cells from patient biopsies. Also, to test the effects of KD on mitochondrial function and in vivo motor function of dysferlin-deficient mice.