Centre for Muscle Research, Department of Anatomy and Physiology, The University of Melbourne, Parkville, Victoria, Australia.
Melbourne Dementia Research Centre, The Florey Institute of Neuroscience and Mental Health, The University of Melbourne, Parkville, Victoria, Australia.
J Cachexia Sarcopenia Muscle. 2021 Apr;12(2):476-492. doi: 10.1002/jcsm.12685. Epub 2021 Mar 4.
Oxidative stress is implicated in the insidious loss of muscle mass and strength that occurs with age. However, few studies have investigated the role of iron, which is elevated during ageing, in age-related muscle wasting and blunted repair after injury. We hypothesized that iron accumulation leads to membrane lipid peroxidation, muscle wasting, increased susceptibility to injury, and impaired muscle regeneration.
To examine the role of iron in age-related muscle atrophy, we compared the skeletal muscles of 3-month-old with 22- to 24-month-old 129SvEv FVBM mice. We assessed iron distribution and total elemental iron using laser ablation inductively coupled plasma mass spectrometry and Perls' stain on skeletal muscle cross-sections. In addition, old mice underwent ischaemia-reperfusion (IR) injury (90 min ischaemia), and muscle regeneration was assessed 14 days after injury. Immunoblotting was used to determine lipid peroxidation (4HNE) and iron-related proteins. To determine whether muscle iron content can be altered, old mice were treated with deferiprone (DFP) in the drinking water, and we assessed its effects on muscle regeneration after injury.
We observed a significant increase in total elemental iron (+43%, P < 0.05) and lipid peroxidation (4HNE: +76%, P < 0.05) in tibialis anterior muscles of old mice. Iron was further increased after injury (adult: +81%, old: +135%, P < 0.05) and associated with increased lipid peroxidation (+41%, P < 0.05). Administration of DFP did not impact iron or measures of lipid peroxidation in skeletal muscle or modulate muscle mass. Increased muscle iron concentration and lipid peroxidation were associated with less efficient regeneration, evident from the smaller fibres in cross-sections of tibialis anterior muscles (-24%, P < 0.05) and an increased percentage of fibres with centralized nuclei (+4124%, P < 0.05) in muscles of old compared with adult mice. Administration of DFP lowered iron after IR injury (PRE: -32%, P < 0.05 and POST: -41%, P < 0.05), but did not translate to structural improvements.
Muscles from old mice have increased iron levels, which are associated with increased lipid peroxidation, increased susceptibility to IR injury, and impaired muscle regeneration. Our results suggest that iron is involved in effective muscle regeneration, highlighting the importance of iron homeostasis in muscle atrophy and muscle repair.
氧化应激与衰老相关的肌肉质量和力量逐渐丧失有关。然而，很少有研究调查铁在年龄相关性肌肉减少症和损伤后修复迟钝中的作用，铁在衰老过程中会升高。我们假设铁积累导致膜脂质过氧化、肌肉减少、增加受伤易感性和肌肉再生受损。
为了研究铁在年龄相关性肌肉萎缩中的作用，我们比较了 3 月龄和 22-24 月龄 129SvEv FVBM 小鼠的骨骼肌。我们使用激光烧蚀电感耦合等离子体质谱和骨骼肌切片上的 Perls 染色来评估铁的分布和总元素铁。此外，老年小鼠进行缺血再灌注（IR）损伤（缺血 90 分钟），并在损伤后 14 天评估肌肉再生。免疫印迹用于测定脂质过氧化（4HNE）和铁相关蛋白。为了确定肌肉铁含量是否可以改变，老年小鼠用去铁酮（DFP）在饮水中治疗，并评估其对损伤后肌肉再生的影响。
我们观察到老年小鼠胫骨前肌中铁的总元素（+43%，P<0.05）和脂质过氧化（4HNE：+76%，P<0.05）显著增加。损伤后铁进一步增加（成人：+81%，老年：+135%，P<0.05），并伴有脂质过氧化增加（+41%，P<0.05）。DFP 的给药不影响骨骼肌中的铁或脂质过氧化的测量值，也不调节肌肉质量。增加的肌肉铁浓度和脂质过氧化与更有效的再生有关，这从胫骨前肌横切面上的纤维变小（-24%，P<0.05）和纤维中中心核的百分比增加（+4124%，P<0.05）明显看出，与成年小鼠相比，老年小鼠的肌肉中。DFP 给药后 IR 损伤后的铁含量降低（PRE：-32%，P<0.05 和 POST：-41%，P<0.05），但结构改善没有转化。
老年小鼠的肌肉铁水平升高，与脂质过氧化增加、IR 损伤易感性增加和肌肉再生受损有关。我们的结果表明，铁参与有效的肌肉再生，突出了铁平衡在肌肉萎缩和肌肉修复中的重要性。
