title: Ketogenic diet slows down mitochondrial myopathy progression in mice.
abstract: Mitochondrial dysfunction is a major cause of neurodegenerative and neuromuscular diseases of adult age and of multisystem disorders of childhood. However, no effective treatment exists for these progressive disorders. Cell culture studies suggested that ketogenic diet (KD), with low glucose and high fat content, could select against cells or mitochondria with mutant mitochondrial DNA (mtDNA), but proper patient trials are still lacking. We studied here the transgenic Deletor mouse, a disease model for progressive late-onset mitochondrial myopathy, accumulating mtDNA deletions during aging and manifesting subtle progressive respiratory chain (RC) deficiency. We found that these mice have widespread lipidomic and metabolite changes, including abnormal plasma phospholipid and free amino acid levels and ketone body production. We treated these mice with pre-symptomatic long-term and post-symptomatic shorter term KD. The effects of the diet for disease progression were followed by morphological, metabolomic and lipidomic tools. We show here that the diet decreased the amount of cytochrome c oxidase negative muscle fibers, a key feature in mitochondrial RC deficiencies, and prevented completely the formation of the mitochondrial ultrastructural abnormalities in the muscle. Furthermore, most of the metabolic and lipidomic changes were cured by the diet to wild-type levels. The diet did not, however, significantly affect the mtDNA quality or quantity, but rather induced mitochondrial biogenesis and restored liver lipid levels. Our results show that mitochondrial myopathy induces widespread metabolic changes, and that KD can slow down progression of the disease in mice. These results suggest that KD may be useful for mitochondrial late-onset myopathies.
authors.affiliation: Research Program of Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki 00290, Finland.
authors.forename: Sofia
authors.initials: S
authors.lastname: Ahola-Erkkilä
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Carroll
authors.forename: Katja
authors.initials: K
authors.lastname: Peltola-Mjösund
authors.forename: Valtteri
authors.initials: V
authors.lastname: Tulkki
authors.forename: Ismo
authors.initials: I
authors.lastname: Mattila
authors.forename: Tuulikki
authors.initials: T
authors.lastname: Seppänen-Laakso
authors.forename: Matej
authors.initials: M
authors.lastname: Oresic
authors.forename: Henna
authors.initials: H
authors.lastname: Tyynismaa
authors.forename: Anu
authors.initials: A
authors.lastname: Suomalainen
mesh_terms: D000818:Animals; D004272:DNA, Mitochondrial / Q000235:genetics; D055423:Diet, Ketogenic; D018450:Disease Progression; D003576:Electron Transport Complex IV / Q000378:metabolism; D005260:Female; D018628:Gene Dosage / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000473:pathology; D008297:Male; D055432:Metabolomics; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008928:Mitochondria / Q000201:enzymology / Q000648:ultrastructure; D017240:Mitochondrial Myopathies / Q000517:prevention & control*; D018485:Muscle Fibers, Skeletal / Q000201:enzymology / Q000473:pathology / Q000648:ultrastructure; D009765:Obesity / Q000473:pathology; D010641:Phenotype; D017384:Sequence Deletion / Q000235:genetics
chemical_list: D004272:DNA, Mitochondrial; D003576:Electron Transport Complex IV