Iron Chelation Prevents Age-Related Skeletal Muscle Sarcopenia in Klotho Gene Mutant Mice, a Genetic Model of Aging

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.