Mitochondrial DNA Damage And Impaired Iron Homeostasis In Muscle Aging

Iron dyshomeostasis has been indicated as a major risk factor for the development and progression of several disease conditions. Impairment of iron balance is also an aging feature especially in post-mitotic tissues. In particular, while age-related systemic iron deficiency (anemia) compromise oxygen availability, increased cellular and mitochondrial iron levels have been involved in DNA mutation load. We purified total proteins and DNA from muscle samples of young (Y, n=10) and sedentary older adults, classified as high- (HFE, n=14) and low-functioning (LFE, n=6) based on the Short Physical Performance Battery (SPPB). The effect of aging on key proteins involved in iron homeostasis and qualitative alterations of mtDNA and how these relate to physical performance was evaluated. A decrease in muscle volume, as quantified through 3D-NMR, was found in LFE (38%) and HFE (30%) participants compared to the younger counterpart and positively correlated with physical performance. A lower expression of the iron import protein transferrin receptor (TfR1) but not Zip14 was also found in both groups of elderly participants, regardless of the SPPB score. The analysis of the mutation load of mitochondrial DNA (mtDNA) (e.g., single-strand, double-strand breaks and abasic sites), instead, showed an increase in mtDNA damage in HFE and LFE participants, with no differences between the two groups. This study showed an association between altered mitochondrial homeostasis and levels of intracellular iron in aged human muscles. The accumulation of mtDNA mutations and the decline in iron balance may therefore represent critical steps to muscle aging and possible targets for interventions against muscle wasting.