Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice
- PMID: 22012983
- DOI: 10.1093/hmg/ddr482
Effect of bezafibrate treatment on late-onset mitochondrial myopathy in mice
Abstract
Mitochondrial dysfunction is an important cause of metabolic disorders of children and adults, with no effective therapy options. Recently, induction of mitochondrial biogenesis, by transgenic overexpression of PGC1-alpha [peroxisome proliferator-activated receptor (PPAR)-gamma coactivator 1-alpha], was reported to delay progression of early-onset cytochrome-c-oxidase (COX) deficiency in skeletal muscle of two mouse models: a muscle-specific knock-out of COX10 (COX10-mKO) and a constitutive knock-out of Surf1 (Surf1-KO). A pan-PPAR agonist, bezafibrate, could similarly delay myopathy progression in COX10-mKOs, but not in SURF1-KOs. We asked whether bezafibrate affected disease progression in late-onset adult-type mitochondrial myopathy mice. These 'Deletor mice' express a dominant patient mutation in Twinkle-helicase, leading to accumulation of multiple mtDNA deletions and subsequent progressive respiratory chain (RC) deficiency with COX-negative muscle fibers at 12 months of age. The primary and secondary molecular findings in Deletor mice mimic closely those in patients with Twinkle myopathy. We applied 0.5% bezafibrate diet to Deletors for 22 weeks, starting at disease manifestation, mimicking patient treatment after diagnosis. Bezafibrate delayed significantly the accumulation of COX-negative fibers and multiple mtDNA deletions. However, mitochondrial biogenesis was not induced: mitochondrial DNA copy number, transcript and RC protein amounts decreased in both Deletors and wild-type mice. Furthermore, bezafibrate induced severe lipid oxidation effects, with hepatomegaly and loss of adipose tissue, the mechanism involving lipid mobilization by high hepatic expression of FGF21 cytokine. However, as bezafibrate has been tolerated well by humans, the beneficial muscle findings in Deletor mice support consideration of bezafibrate trials on adult patients with mitochondrial myopathy.
Similar articles
-
Ketogenic diet slows down mitochondrial myopathy progression in mice.Hum Mol Genet. 2010 May 15;19(10):1974-84. doi: 10.1093/hmg/ddq076. Epub 2010 Feb 17. Hum Mol Genet. 2010. PMID: 20167576
-
Mitochondrial myopathy induces a starvation-like response.Hum Mol Genet. 2010 Oct 15;19(20):3948-58. doi: 10.1093/hmg/ddq310. Epub 2010 Jul 23. Hum Mol Genet. 2010. PMID: 20656789
-
Activation of the PPAR/PGC-1alpha pathway prevents a bioenergetic deficit and effectively improves a mitochondrial myopathy phenotype.Cell Metab. 2008 Sep;8(3):249-56. doi: 10.1016/j.cmet.2008.07.006. Cell Metab. 2008. Retraction in: Cell Metab. 2016 Dec 13;24(6):889. doi: 10.1016/j.cmet.2016.11.006. PMID: 18762025 Free PMC article. Retracted.
-
Dual and pan-peroxisome proliferator-activated receptors (PPAR) co-agonism: the bezafibrate lessons.Cardiovasc Diabetol. 2005 Sep 16;4:14. doi: 10.1186/1475-2840-4-14. Cardiovasc Diabetol. 2005. PMID: 16168052 Free PMC article. Review.
-
Elucidating the Beneficial Role of PPAR Agonists in Cardiac Diseases.Int J Mol Sci. 2018 Nov 4;19(11):3464. doi: 10.3390/ijms19113464. Int J Mol Sci. 2018. PMID: 30400386 Free PMC article. Review.
Cited by
-
Mitochondrial dysfunction: mechanisms and advances in therapy.Signal Transduct Target Ther. 2024 May 15;9(1):124. doi: 10.1038/s41392-024-01839-8. Signal Transduct Target Ther. 2024. PMID: 38744846 Free PMC article. Review.
-
Lipodystrophy in methylmalonic acidemia associated with elevated FGF21 and abnormal methylmalonylation.JCI Insight. 2024 Feb 22;9(4):e174097. doi: 10.1172/jci.insight.174097. JCI Insight. 2024. PMID: 38271099 Free PMC article.
-
Interactions of mitochondrial and skeletal muscle biology in mitochondrial myopathy.Biochem J. 2023 Nov 15;480(21):1767-1789. doi: 10.1042/BCJ20220233. Biochem J. 2023. PMID: 37965929 Free PMC article. Review.
-
Methylmalonic Acid Impairs Cell Respiration and Glutamate Uptake in C6 Rat Glioma Cells: Implications for Methylmalonic Acidemia.Cell Mol Neurobiol. 2023 Apr;43(3):1163-1180. doi: 10.1007/s10571-022-01236-1. Epub 2022 Jun 8. Cell Mol Neurobiol. 2023. PMID: 35674974
-
Bezafibrate Rescues Mitochondrial Encephalopathy in Mice via Induction of Daily Torpor and Hypometabolic State.Neurotherapeutics. 2022 Apr;19(3):994-1006. doi: 10.1007/s13311-022-01216-9. Epub 2022 Mar 25. Neurotherapeutics. 2022. PMID: 35334081 Free PMC article.
Publication types
MeSH terms
Substances
LinkOut - more resources
Full Text Sources
Other Literature Sources
Molecular Biology Databases
Research Materials