Ketogenic diet slows down mitochondrial myopathy progression in mice

Sofia Ahola-Erkkilä, Christopher Carroll, Katja Peltola-Mjösund, Valtteri Tulkki, Ismo Mattila, Tuulikki Seppänen-Laakso, Matej Oresic, Henna Tyynismaa, Anu Suomalainen (Corresponding Author)

Research output: Contribution to journalArticleScientificpeer-review

102 Citations (Scopus)

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.
Original languageEnglish
Pages (from-to)1974-1984
Number of pages11
JournalHuman Molecular Genetics
Volume19
Issue number10
DOIs
Publication statusPublished - 2010
MoE publication typeA1 Journal article-refereed

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Ketogenic Diet
Mitochondrial Myopathies
Mitochondrial DNA
Diet
Disease Progression
Mitochondrial Diseases
Ketone Bodies
Muscles
Neuromuscular Diseases
Metabolomics
Organelle Biogenesis
Muscular Diseases
Electron Transport Complex IV
Electron Transport
Neurodegenerative Diseases
Transgenic Mice
Phospholipids
Mitochondria
Cell Culture Techniques
Fats

Cite this

Ahola-Erkkilä, S., Carroll, C., Peltola-Mjösund, K., Tulkki, V., Mattila, I., Seppänen-Laakso, T., ... Suomalainen, A. (2010). Ketogenic diet slows down mitochondrial myopathy progression in mice. Human Molecular Genetics, 19(10), 1974-1984. https://doi.org/10.1093/hmg/ddq076
Ahola-Erkkilä, Sofia ; Carroll, Christopher ; Peltola-Mjösund, Katja ; Tulkki, Valtteri ; Mattila, Ismo ; Seppänen-Laakso, Tuulikki ; Oresic, Matej ; Tyynismaa, Henna ; Suomalainen, Anu. / Ketogenic diet slows down mitochondrial myopathy progression in mice. In: Human Molecular Genetics. 2010 ; Vol. 19, No. 10. pp. 1974-1984.
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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.",
author = "Sofia Ahola-Erkkil{\"a} and Christopher Carroll and Katja Peltola-Mj{\"o}sund and Valtteri Tulkki and Ismo Mattila and Tuulikki Sepp{\"a}nen-Laakso and Matej Oresic and Henna Tyynismaa and Anu Suomalainen",
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Ahola-Erkkilä, S, Carroll, C, Peltola-Mjösund, K, Tulkki, V, Mattila, I, Seppänen-Laakso, T, Oresic, M, Tyynismaa, H & Suomalainen, A 2010, 'Ketogenic diet slows down mitochondrial myopathy progression in mice', Human Molecular Genetics, vol. 19, no. 10, pp. 1974-1984. https://doi.org/10.1093/hmg/ddq076

Ketogenic diet slows down mitochondrial myopathy progression in mice. / Ahola-Erkkilä, Sofia; Carroll, Christopher; Peltola-Mjösund, Katja; Tulkki, Valtteri; Mattila, Ismo; Seppänen-Laakso, Tuulikki; Oresic, Matej; Tyynismaa, Henna; Suomalainen, Anu (Corresponding Author).

In: Human Molecular Genetics, Vol. 19, No. 10, 2010, p. 1974-1984.

Research output: Contribution to journalArticleScientificpeer-review

TY - JOUR

T1 - Ketogenic diet slows down mitochondrial myopathy progression in mice

AU - Ahola-Erkkilä, Sofia

AU - Carroll, Christopher

AU - Peltola-Mjösund, Katja

AU - Tulkki, Valtteri

AU - Mattila, Ismo

AU - Seppänen-Laakso, Tuulikki

AU - Oresic, Matej

AU - Tyynismaa, Henna

AU - Suomalainen, Anu

PY - 2010

Y1 - 2010

N2 - 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.

AB - 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.

U2 - 10.1093/hmg/ddq076

DO - 10.1093/hmg/ddq076

M3 - Article

VL - 19

SP - 1974

EP - 1984

JO - Human Molecular Genetics

JF - Human Molecular Genetics

SN - 0964-6906

IS - 10

ER -

Ahola-Erkkilä S, Carroll C, Peltola-Mjösund K, Tulkki V, Mattila I, Seppänen-Laakso T et al. Ketogenic diet slows down mitochondrial myopathy progression in mice. Human Molecular Genetics. 2010;19(10):1974-1984. https://doi.org/10.1093/hmg/ddq076