Laboratory 'Movement, Sport and Health Sciences'-EA7470, University of Rennes/ENS Rennes, Bruz, France.
Exercise and Nutrition Research Program, Mary MacKillop Institute for Health Research, Australian Catholic University, Melbourne, Vic., Australia.
J Cachexia Sarcopenia Muscle. 2022 Apr;13(2):1250-1261. doi: 10.1002/jcsm.12897. Epub 2022 Feb 3.
Iron excess has been proposed as an essential factor in skeletal muscle wasting. Studies have reported correlations between muscle iron accumulation and atrophy, either through ageing or by using experimental models of secondary iron overload. However, iron treatments performed in most of these studies induced an extra-pathophysiological iron overload, more representative of intoxication or poisoning. The main objective of this study was to determine the impact of iron excess closer to pathophysiological conditions on structural and metabolic adaptations (i) in differentiated myotubes and (ii) in skeletal muscle exhibiting oxidative (i.e. the soleus) or glycolytic (i.e. the gastrocnemius) metabolic phenotypes.
The impact of iron excess was assessed in both in vitro and in vivo models. Murine differentiated myotubes were exposed to ferric ammonium citrate (FAC) (i.e. 10 and 50 μM) for the in vitro component. The in vivo model was achieved by a single iron dextran subcutaneous injection (1 g/kg) in mice. Four months after the injection, soleus and gastrocnemius muscles were harvested for analysis.
In vitro, iron exposure caused dose-dependent increases of iron storage protein ferritin (P < 0.01) and dose-dependent decreases of mRNA TfR1 levels (P < 0.001), which support cellular adaptations to iron excess. Extra-physiological iron treatment (50 μM FAC) promoted myotube atrophy (P = 0.018), whereas myotube size remained unchanged under pathophysiological treatment (10 μM FAC). FAC treatments, whatever the doses tested, did not affect the expression of proteolytic markers (i.e. NF-κB, MurF1, and ubiquitinated proteins). In vivo, basal iron content and mRNA TfR1 levels were significantly higher in the soleus compared with the gastrocnemius (+130% and +127%; P < 0.001, respectively), supporting higher iron needs in oxidative skeletal muscle. Iron supplementation induced muscle iron accumulation in the soleus and gastrocnemius muscles (+79%, P < 0.001 and +34%, P = 0.002, respectively), but ferritin protein expression only increased in the gastrocnemius (+36%, P = 0.06). Despite iron accumulation, muscle weight, fibre diameter, and myosin heavy chain distribution remained unchanged in either skeletal muscle.
Together, these data support that under pathophysiological conditions, skeletal muscle can protect itself from the related deleterious effects of excess iron.
铁过剩被认为是骨骼肌萎缩的一个基本因素。研究表明，肌肉铁积累与萎缩之间存在相关性，无论是通过衰老还是通过使用继发性铁过载的实验模型。然而，在这些研究中进行的大多数铁处理会引起更具病理生理学意义的铁过载，更能代表中毒或中毒。本研究的主要目的是确定更接近病理生理条件的铁过剩对结构和代谢适应性的影响（i）在分化的肌管中，（ii）在表现出氧化代谢表型（即比目鱼肌）或糖酵解代谢表型的骨骼肌中。
在体外和体内模型中评估了铁过剩的影响。体外成分中，用柠檬酸铁铵（FAC）（即 10 和 50μM）处理小鼠分化的肌管。体内模型通过在小鼠中单次皮下注射铁葡聚糖（1g/kg）来实现。注射后 4 个月，收获比目鱼肌和腓肠肌进行分析。
在体外，铁暴露导致铁储存蛋白铁蛋白的剂量依赖性增加（P<0.01）和 TfR1 水平的剂量依赖性降低（P<0.001），这支持了细胞对铁过剩的适应。异常铁处理（50μM FAC）促进肌管萎缩（P=0.018），而在病理生理处理（10μM FAC）下肌管大小保持不变。无论测试的剂量如何，FAC 处理均不影响蛋白水解标记物（即 NF-κB、MurF1 和泛素化蛋白）的表达。在体内，与腓肠肌相比，比目鱼肌的基础铁含量和 TfR1 mRNA 水平显著升高（分别增加 130%和 127%；P<0.001），这支持了氧化骨骼肌中更高的铁需求。铁补充剂诱导比目鱼肌和腓肠肌的肌肉铁积累（增加 79%，P<0.001 和增加 34%，P=0.002），但仅在腓肠肌中铁蛋白蛋白表达增加（增加 36%，P=0.06）。尽管有铁积累，但在任何一种骨骼肌中，肌肉重量、纤维直径和肌球蛋白重链分布均保持不变。
总之，这些数据表明，在病理生理条件下，骨骼肌可以保护自身免受过量铁相关的有害影响。
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