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.