Impact of exercise on oocyte quality in the POLG mitochondrial DNA mutator mouse.

Mitochondrial DNA (mtDNA) mutator mouse carries a proofreading-deficient mitochondrial DNA polymerase leading to accumulation of mtDNA mutations. This mouse was originally engineered in two independent labs (Trifunovic et al. 2004, Kujoth et al. 2005) and has since been used to study various aspects of mitochondrial dysfunction.

Several studies have tried to find ways to improve the various phenotypes of the mtDNA mutator mouse, which include sarcopenia, hearing loss, osteoporosis, alopecia, weight loss, testicular atrophy, enlarged heart etc. For instance, our group showed recently that increasing mtDNA copy number of mtDNA mutator mice can partially rescue the testicular atrophy phenotype (Jiang et al. 2017)

It was published already seven years ago that exercise might improve the phenotype of the mitochondrial DNA (mtDNA) mutator mouse (Safdar et al. 2011). Like most papers using mtDNA mutator mouse as the model organism, Safdar et al. has the shortcoming that their WT control mice also inherited mtDNA mutations from a heterozygous mtDNA mutator mother, a.k.a. they made a “dirty” breeding (Kauppila et al. 2017). Therefore, this study had no “true” WT mouse model as a control. Also more recently, two papers from these authors have now Editorial Expression of Concerns (JBC study, PNAS study) so let’s see what happens with these findings.

Now a recent paper from a different group suggests that exercising mtDNA mutator mice might affect oocyte quality (Faraci et al. 2018). It was not reported how these mice have been bred, so one should be very cautious when interpreting the results. For instance, it would be important to know how many generations the heterozygous mtDNA mutator females have been bred and whether the WT control mice are a WT littermate from a heterozygote X heterozygote cross.

All in all, exercise has almost no effect on the oocytes of mtDNA mutator mice. For some of the differences seen it is also impossible to tell whether they are caused by changes in oocytes themselves of some systemic changes.

References:

Editorial Expression of Concern: Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A. 2018. PMID: 29891666

Expression of concern for: Exercise increases mitochondrial PGC-1 α content and promotes nuclear-mitochondrial cross-talk to coordinate mitochondrial biogenesis. J Biol Chem. 2018. PMID: 29602880

Faraci C, Annis S, Jin J, Li H, Khrapko K, Woods D. Impact of exercise on oocyte quality in the POLG mitochondrial DNA mutator mouse. Reproduction. 2018. PMID: 29875308

Jiang M, Kauppila TES, Motori E, Li X, Atanassov I, Folz-Donahue K, Bonekamp NA, Albarran-Gutierrez S, Stewart JB, Larsson NG. Increased Total mtDNA Copy Number Cures Male Infertility Despite Unaltered mtDNA Mutation Load. Cell Metab. 2017. PMID: 28768180

Kauppila TES, Kauppila JHK1, Larsson NG. Mammalian Mitochondria and Aging: An Update. Cell Metab. 2017. PMID: 28094012

Kujoth GC, Hiona A, Pugh TD, Someya S, Panzer K, Wohlgemuth SE, Hofer T, Seo AY, Sullivan R, Jobling WA, Morrow JD, Van Remmen H, Sedivy JM, Yamasoba T, Tanokura M, Weindruch R, Leeuwenburgh C, Prolla TA. Mitochondrial DNA mutations, oxidative stress, and apoptosis in mammalian aging. Science. 2005. PMID: 16020738

Safdar A, Bourgeois JM, Ogborn DI, Little JP, Hettinga BP, Akhtar M, Thompson JE, Melov S, Mocellin NJ, Kujoth GC, Prolla TA, Tarnopolsky MA. Endurance exercise rescues progeroid aging and induces systemic mitochondrial rejuvenation in mtDNA mutator mice. Proc Natl Acad Sci U S A. 2011. PMID: 21368114

Trifunovic A, Wredenberg A, Falkenberg M, Spelbrink JN, Rovio AT, Bruder CE, Bohlooly-Y M, Gidlöf S, Oldfors A, Wibom R, Törnell J, Jacobs HT, Larsson NG. Premature ageing in mice expressing defective mitochondrial DNA polymerase. Nature. 2004. PMID: 15164064