title: Aging-related changes in the iron status of skeletal muscle.
abstract: The rise in non-heme iron (NHI) concentration observed in skeletal muscle of aging rodents is thought to contribute to the development of sarcopenia. The source of the NHI has not been identified, nor have the physiological ramifications of elevated iron status in aged muscle been directly examined. Therefore, we assessed plantaris NHI and heme iron (HI) levels in addition to expression of proteins involved in iron uptake (transferrin receptor-1; TfR1), storage (ferritin), export (ferroportin; FPN), and regulation (iron regulatory protein-1 (IRP1) and -2 (IRP2)) of male F344xBN F1 rats (n=10/group) of various ages (8, 18, 28, 32, and 36 months) to further understand iron regulation in aging muscle. In a separate experiment, iron chelator (pyridoxal isonicotinoyl hydrazone; PIH) or vehicle was administered to male F344xBN F1 rats (n=8/group) beginning at 30 months of age to assess the impact on plantaris muscle mass and function at ~36 months of age. Principle findings revealed the increased NHI concentration in old age was consistent with concentrating effects of muscle atrophy and reduction in HI levels, with no change in the total iron content of the muscle. The greatest increase in muscle iron content occurred during the period of animal growth and was associated with downregulation of TfR1 and IRP2 expression. Ferritin upregulation did not occur until senescence and the protein remained undetectable during the period of muscle iron content elevation. Lastly, administration of PIH did not significantly (p>0.05) impact NHI or measures of muscle atrophy or contractile function. In summary, this study confirms that the elevated NHI concentration in old age is largely due to the loss in muscle mass. The increased muscle iron content during aging does not appear to associate with cytosolic ferritin storage, but the functional consequences of elevated iron status in old age remains to be determined.
authors.affiliation: Department of Exercise Science, Syracuse University, 820 Comstock Ave., Room 201 WB, Syracuse, NY 13244, USA. Electronic address: kcderuis@syr.edu.
authors.forename: Keith C
authors.initials: KC
authors.lastname: DeRuisseau
authors.forename: Young-Min
authors.initials: YM
authors.lastname: Park
authors.forename: Lara R
authors.initials: LR
authors.lastname: DeRuisseau
authors.forename: Patrick M
authors.initials: PM
authors.lastname: Cowley
authors.forename: Christopher H
authors.initials: CH
authors.lastname: Fazen
authors.forename: Robert P
authors.initials: RP
authors.lastname: Doyle
mesh_terms: D000375:Aging / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000818:Animals; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D005293:Ferritins / Q000235:genetics / Q000378:metabolism; D015870:Gene Expression; D006418:Heme / Q000378:metabolism; D007501:Iron / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology; D035941:Iron Regulatory Protein 1 / Q000235:genetics / Q000378:metabolism; D035942:Iron Regulatory Protein 2 / Q000235:genetics / Q000378:metabolism; D007538:Isoniazid / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D009119:Muscle Contraction / Q000187:drug effects; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D009133:Muscular Atrophy / Q000378:metabolism / Q000473:pathology; D011730:Pyridoxal / Q000031:analogs & derivatives / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D051381:Rats; D011914:Rats, Inbred BN; D011916:Rats, Inbred F344; D011990:Receptors, Transferrin / Q000235:genetics / Q000378:metabolism; D055948:Sarcopenia / Q000378:metabolism / Q000473:pathology; D000098742:Ferroportin
chemical_list: D027682:Cation Transport Proteins; D007502:Iron Chelating Agents; D012333:RNA, Messenger; D011990:Receptors, Transferrin; C545564:Tfrc protein, rat; D000098742:Ferroportin; D011730:Pyridoxal; D006418:Heme; C021079:pyridoxal isonicotinoyl hydrazone; D005293:Ferritins; D007501:Iron; D035941:Iron Regulatory Protein 1; D035942:Iron Regulatory Protein 2; D007538:Isoniazid
keywords: BM; CON; DMT1; F344xBN F1; FPN; Fischer 344 Brown Norway F1 hybrid rat; HI; IRE; IRP1; IRP2; MM; Muscle aging; Muscle function; NADPH; NHI; OCT; PIH; Pyridoxal isonicotinoyl hydrazone; ROS; Sarcopenia; Skeletal muscle iron regulation; TfR1; VEH; body mass; control; divalent metal transporter-1; ferroportin; heme iron; iron regulatory protein-1; iron regulatory protein-2; iron responsive element; muscle mass; nicotinomide adenine dinucleotide phosphate; non-heme iron; optimal cutting temperature; pyridoxal isonicotinoyl hydrazone; reactive oxygen radical species; transferrin receptor-1; vehicle