Bose Chhanda, Megyesi Judit, Karaduta Oleg, Singh Sharda P, Swaminathan Sundararaman, Shah Sudhir V
Central Arkansas Veterans Healthcare System, Little Rock, Arkansas, USA.
University of Arkansas for Medical Sciences, Little Rock, Arkansas, USA.
J Cachexia Sarcopenia Muscle. 2025 Feb;16(1):e13678. doi: 10.1002/jcsm.13678.
A decline in skeletal muscle mass and function known as skeletal muscle sarcopenia is an inevitable consequence of aging. Sarcopenia is a major cause of decreased muscle strength, physical frailty and increased muscle fatigability, contributing significantly to an increased risk of physical disability and functional dependence among the elderly. There remains a significant need for a novel therapy that can improve sarcopenia and related problems in aging. Iron accumulation, especially catalytic iron (labile iron) through increased oxidative stress, could be one of the contributing factors to sarcopenia. Our study aimed to examine the effect of an iron chelator on age-related sarcopenia in mice.
We investigated the effect of iron chelation (deferiprone, DFP) in sarcopenia, using mice with klotho deficiency (kl/kl), an established mouse model for aging. Four weeks old Klotho male mice were treated with 25 mg/kg body weight of iron chelator deferiprone in drinking water for 8-14 weeks (n = 12/group, treated and untreated). At the end of the study, gastrocnemius, quadriceps and bicep muscles were dissected and used for western blot and immunohistochemistry analysis, histopathology and iron staining. Serum total iron, catalytic iron and cytokine ELISAs were performed with established methods.
Treatment with DFP significantly reduced loss of muscle mass in gastrocnemius and quadriceps muscles (p < 0.0001). Total and catalytic iron content of serum and iron in muscles were significantly (both p < 0.0001) lower in the treated animals. The inhibitory factor of myogenesis, the myostatin protein in gastrocnemius muscles (p = 0.019) and serum (p = 0.003) were downregulated after 8 weeks of therapy accompanied by an increased in muscle contractile protein myosin heavy chain (~2.9 folds, p = 0.0004). Treatment decreased inflammation (serum IL6 and TNFα) (p < 0.0001, p = 0.005), respectively, and elevated insulin-like growth factor levels (p = 0.472). This was associated with reduced DNA damage and reduced 8-hydroxy 2 deoxyguanosine in muscle and HO-1 protein (p < 0.001, p = 079), respectively. Significant weight loss (p < 0.001) and decreased water intake (p = 0.012) were observed in untreated mice compared to treatment group. Kaplan-Meier survival curves show the median life span of treated mice was 108 days as compared to 63 days for untreated mice (p = 0.0002).
In summary, our research findings indicate that deferiprone reduced age-related sarcopenia in the muscles of Klotho mice. Our finding suggests chelation of excess iron could be an effective therapy to counter sarcopenia. However, additional studies are needed to evaluate and determine the efficacy in humans.
骨骼肌质量和功能的下降，即骨骼肌少肌症，是衰老不可避免的结果。少肌症是肌肉力量下降、身体虚弱和肌肉易疲劳性增加的主要原因，对老年人身体残疾和功能依赖风险的增加有显著影响。目前仍迫切需要一种新的疗法来改善衰老过程中的少肌症及相关问题。铁蓄积，尤其是通过增加氧化应激导致的催化铁（不稳定铁）蓄积，可能是少肌症的促成因素之一。我们的研究旨在探讨铁螯合剂对小鼠年龄相关性少肌症的影响。
我们使用早衰蛋白缺乏（kl/kl）小鼠，一种已确立的衰老小鼠模型，研究铁螯合（去铁酮，DFP）对少肌症的影响。4周龄的早衰蛋白雄性小鼠在饮用水中接受25mg/kg体重的铁螯合剂去铁酮治疗8 - 14周（每组n = 12只，治疗组和未治疗组）。在研究结束时，解剖腓肠肌、股四头肌和肱二头肌，用于蛋白质免疫印迹和免疫组织化学分析、组织病理学和铁染色。采用既定方法进行血清总铁、催化铁和细胞因子酶联免疫吸附测定。
DFP治疗显著减少了腓肠肌和股四头肌的肌肉质量损失（p < 0.0001）。治疗组动物血清中的总铁和催化铁含量以及肌肉中的铁含量均显著降低（p均< 0.0001）。治疗8周后，腓肠肌中肌肉生成抑制因子、肌肉生长抑制素蛋白（p = 0.019）和血清中该蛋白（p = 0.003）下调，同时肌肉收缩蛋白肌球蛋白重链增加（约2.9倍，p = 0.0004）。治疗分别降低了炎症反应（血清IL - 6和TNFα）（p < 0.0001，p = 0.005），并提高了胰岛素样生长因子水平（p = 0.472）。这与肌肉中DNA损伤减少、8 - 羟基 - 2 - 脱氧鸟苷减少以及HO - 1蛋白减少（p < 0.001，p = 0.079）相关。与治疗组相比，未治疗小鼠体重显著下降（p < 0.001）且饮水量减少（p = 0.012）。Kaplan - Meier生存曲线显示，治疗组小鼠的中位寿命为108天，而未治疗组小鼠为63天（p = 0.0002）。
总之，我们的研究结果表明，去铁酮可减轻早衰蛋白小鼠肌肉中的年龄相关性少肌症。我们的发现表明，螯合过量的铁可能是对抗少肌症的有效疗法。然而，需要进一步的研究来评估并确定其在人类中的疗效。
