Ferroptosis in a sarcopenia model of senescence accelerated mouse prone 8 (SAMP8)

Abstract

As a systemic syndrome characterized by age-associated degenerative skeletal muscle atrophy, sarcopenia leads to a risk of adverse outcomes in the elderly. Age-related iron accumulation is found in the muscles of sarcopenia animal models and patients, but the role of iron in sarcopenia remains poorly understood. It has been recently found that iron overload in several diseases is involved in ferroptosis, an iron- dependent form of programmed cell death. However, whether this excess iron can result in ferroptosis in muscles is still unclear. In our present study, we found that ferric citrate induced ferroptosis in C2C12 cells, as well as impaired their differentiation from myoblasts to myotubes. Due to the decreased muscle mass and fiber size, 40-week-old senescence accelerated mouse prone 8 (SAMP8) mice were used as a sarcopenia model, in whose muscles the iron content and markers of ferroptosis were found to increase, compared to 8-week- old SAMP8 controls. Moreover, our results showed that iron overload upregulated the expression of P53, which subsequently repressed the protein level of Slc7a11 (solute carrier family 7, member 11), a known ferroptosis-related gene. The downregulation of Slc7a11 then induced the ferroptosis of muscle cells through the accumulation of lipid peroxidation products, which may be one of the causes of sarcopenia. The findings in this study indicate that iron plays a key role in triggering P53- Slc7a11-mediated ferroptosis in muscles, and suggest that targeting iron accumulation and ferroptosis might be a therapeutic strategy for treating sarcopenia.

Oxidative and glycolytic skeletal muscles deploy protective mechanisms to avoid atrophy under pathophysiological iron overload

“…The aim of the present study was to investigate whether iron overload reflecting pathophysiological conditions impacts skeletal muscle structure, cellular mechanisms regulating iron metabolism, or muscle atrophy. In response to iron overload close to clinically relevant levels, our data contrast with previous studies, 23 , 24 , 32 , 33 as excess iron did not induce muscle atrophy. Indeed, FAC‐treated myotubes and iron dextran supplementation in mice induced iron accumulation in cells and skeletal muscle, but neither muscle atrophy nor activation of key signalling pathways involved in proteolysis.…”

“…In accordance with these findings and our in vitro results, no reduction in muscle weight and fibre size compared with control animals was observed in iron‐treated mice. Such data contrast with previous studies reporting that iron overload promotes skeletal muscle atrophy in mice 23,24,32 . However, experimental protocols used in those studies induced a systemic and muscle iron overload largely beyond the classical findings observed in pathophysiological conditions.…”

“…Such data contrast with previous studies reporting that iron overload promotes skeletal muscle atrophy in mice. 23 , 24 , 32 However, experimental protocols used in those studies induced a systemic and muscle iron overload largely beyond the classical findings observed in pathophysiological conditions. Here, we used an experimental murine model iron overload, 26 , 27 which involved injecting a unique dose of iron dextran to animals (1 g/kg), corresponding to an absolute dose of iron range from 25 to 35 mg. Four months after the injection, we reported a clinical picture of a high iron overload with blood parameters similar to those observed in humans.…”

Ferroptosis Induction in Multiple Myeloma Cells Triggers DNA Methylation and Histone Modification Changes Associated with Cellular Senescence

“…In agreement with our observations, studies in neuronal and retina epithelial cells have revealed that ferroptotic compounds are able to promote cellular senescence [96][97][98]. Whether cellular senescence promotes sensitization [97,99] or resistance [100] to ferroptosis is currently still under debate. The ferroptosis-driven epigenetic changes characterized in this study seem to suggest that RSL3-mediated oxidative stress orchestrates DNA damage and genomic instability, which induces premature cell senescence and prompts activation of DNA repair genes such as NR4A2.…”

Association Between Serum Iron Status and Muscle Mass in Adults: Results From NHANES 2015–2018

“…There is growing evidence that elevated reactive oxygen species (ROS) and increased local oxidative stress caused by excess iron may play an important role. In one hand, ROS can cause lipids, proteins, mitochondria, and nucleic acids damage, finally resulting in cellular dysfunction and ferroptosis ( 14 , 24 , 31 ). On the other hand, oxidative stress may lead to muscle tissue damage by increasing expression of inflammatory cytokines, such as interleukin-1 (IL-1), tumor necrosis factor-α (TNF-α), and IL-6 ( 32 ).…”