Department of Agricultural, Food and Nutritional Sciences, University of Alberta, Edmonton, Alberta, Canada.
Department of Medicine, Division of Geriatrics, UCLA, Los Angeles, CA, USA.
Mech Ageing Dev. 2019 Sep;182:111126. doi: 10.1016/j.mad.2019.111126. Epub 2019 Aug 2.
The age-induced, exponential accumulation of mitochondrial DNA (mtDNA) deletion mutations contributes to muscle fiber loss. The causes of these mutations are not known. Systemic inflammation is associated with decreased muscle mass in older adults and is implicated in the formation of sporadic mtDNA deletions. Macrophage migration inhibitory factor knockout (MIF-KO) mice are long-lived with decreased inflammation. We hypothesized that aged MIF-KO mice would have lower mtDNA deletion frequencies and fewer electron transport chain (ETC) deficient fibers. We measured mtDNA copy number and mutation frequency as well as the number and length of ETC deficient fibers in 22-month old MIF-KO and F2 hybrid control mice. We also measured mtDNA copy number and deletion frequency in female UM-HET3 mice, a strain whose lifespan matches the MIF-KO mice. We did not observe a significant effect of MIF ablation on muscle mtDNA deletion frequency. There was a significantly lower mtDNA copy number in the MIF-KO mice and the lifespan-matched UM-HET3 mice compared to the F2 hybrids, suggesting the importance of genetic background in mtDNA copy number control. Our data do not support a definitive role for MIF in age-induced mtDNA deletions.
线粒体 DNA（mtDNA）缺失突变的年龄相关性指数积累导致肌肉纤维丧失。这些突变的原因尚不清楚。全身性炎症与老年人肌肉量减少有关，并与散发性 mtDNA 缺失的形成有关。巨噬细胞移动抑制因子敲除（MIF-KO）小鼠寿命长，炎症减少。我们假设老年 MIF-KO 小鼠的 mtDNA 缺失频率更低，电子传递链（ETC）缺陷纤维更少。我们测量了 22 个月大的 MIF-KO 和 F2 杂交对照小鼠的 mtDNA 拷贝数和突变频率，以及 ETC 缺陷纤维的数量和长度。我们还测量了女性 UM-HET3 小鼠的 mtDNA 拷贝数和缺失频率，该品系的寿命与 MIF-KO 小鼠相匹配。我们没有观察到 MIF 缺失对肌肉 mtDNA 缺失频率有显著影响。与 F2 杂交相比，MIF-KO 小鼠和寿命匹配的 UM-HET3 小鼠的 mtDNA 拷贝数明显较低，这表明遗传背景在 mtDNA 拷贝数控制中非常重要。我们的数据不支持 MIF 在年龄诱导的 mtDNA 缺失中的明确作用。
