Advanced Age Is Associated with Iron Dyshomeostasis and Mitochondrial DNA Damage in Human Skeletal Muscle

Abstract

Whether disruption of iron metabolism is implicated in human muscle aging is presently unclear. We explored the relationship among iron metabolism, muscle mitochondrial homeostasis, inflammation, and physical function in older adults and young controls. Eleven young and 23 older men and women were included. Older adults were classified into high-functioning (HF) and low-functioning (LF) groups according to their Short Physical Performance Battery score. Vastus lateralis muscle biopsies were assayed for total iron content, expression of 8-oxoguanine and DNA glycosylase (OGG1), 3-nitrotyrosine (3-NT) levels, and mitochondrial DNA (mtDNA) content and damage. Circulating ferritin and hepcidin levels were also quantified. Muscle iron levels were greater in the old group. Protein expression of transferrin receptor 1, Zrt-Irt-like protein (ZIP) 8, and ZIP14 were lower in old participants. Circulating levels of ferritin, hepcidin, interleukin 6 (IL6), and C-reactive protein were higher in the old group. Old participants showed lower mtDNA content and greater mtDNA damage. OGG1 protein expression declined with age, whereas 3-NT levels were greater in old participants. Finally, a negative correlation was determined between ZIP14 expression and circulating IL6 levels in LF older adults. None of assayed parameters differed between HF and LF participants. Our findings suggest that muscle iron homeostasis is altered in old age, which might contribute to loss of mtDNA stability. Muscle iron metabolism may therefore represent a target for interventions against muscle aging.

Keywords: ZIP; ferritin; hepcidin; inflammation; iron overload; mitochondrial dysfunction; mtDNA; muscle aging; physical performance; transferrin.

Figure 1

Total content of iron in the vastus lateralis muscle of young and old participants. Bars represent mean values (± standard deviation) in the three experimental groups. Values are expressed in ppm. * p < 0.05 vs. young group (n = 11). HF: high-functioning (n = 16); LF: low-functioning (n = 7).

Figure 2

Protein expression of (A) transferrin receptor 1 (TFR1), (B) Zrt-Irt-like protein (ZIP) 8, and (C) ZIP14 in the vastus lateralis muscle of young and old participants. Bars represent mean values (±standard deviation) in the three experimental groups. Values are expressed in arbitrary units (a.u.). Representative blots are shown. * p < 0.05 vs. young group (n = 11). HF: high-functioning (n = 16); LF: low-functioning (n = 7).

Figure 3

Plasma levels of (A) ferritin and (B) hepcidin in young and old participants. Bars represent mean values (± standard deviation) in the three experimental groups. * p < 0.05 vs. young group (n = 11). HF: high-functioning (n = 16); LF: low-functioning (n = 7).

Figure 4

Plasma levels of (A) interleukin 6 (IL6) and (B) C-reactive protein (CRP) in young and old participants. Bars represent mean values (±standard deviation) in the three experimental groups. * p < 0.05 vs. young group (n = 11). HF: high-functioning (n = 16); LF: low-functioning (n = 7).

Figure 5

(A) mtDNA content and (B) mtDNA damage in the vastus lateralis muscle of young and old participants. Bars represent mean values (± standard deviation) in the three experimental groups. * p < 0.05 vs. young group (n = 11). HF: high-functioning (n = 16); LF: low-functioning (n = 7).

Figure 6

Protein expression of (A) 8-oxoguanine DNA glycosylase (OGG1) and (B) levels of 3-nitrotyrosine (3-NT) in the vastus lateralis muscle of young and old participants. Bars represent mean values (±standard deviation) in the three experimental groups. Representative blots of OGG1 and 3-NT are shown in panel (C) a.u. arbitrary units. * p < 0.05 vs. young group (n = 11). HF: high functioning (n = 16); LF: low functioning (n = 7).