Ferroptosis and Its Potential Role in the Physiopathology of Skeletal Muscle Atrophy

Abstract

Skeletal muscle atrophy is a major health concern, severely affecting the patient's mobility and life quality. In the pathological process of skeletal muscle atrophy, with the progressive decline in muscle quality, strength, and function, the incidence of falling, fracture, and death is greatly increased. Unfortunately, there are no effective treatments for this devastating disease. Thus, it is imperative to investigate the exact pathological molecular mechanisms underlying the development of skeletal muscle atrophy and to identify new therapeutic targets. Decreased muscle mass, strength, and muscle fiber cross-sectional area are typical pathological features and manifestations of skeletal muscle atrophy. Ferroptosis, an emerging type of programmed cell death, is characterized by iron-dependent oxidative damage, lipid peroxidation, and reactive oxygen species accumulation. Notably, the understanding of its role in skeletal muscle atrophy is emerging. Ferroptosis has been found to play an important role in the intricate interplay between the pathological mechanisms of skeletal muscle atrophy and its progression caused by multiple factors. This provides new opportunities and challenges in the treatment of skeletal muscle atrophy. Therefore, we systematically elucidated the ferroptosis mechanism and its progress in skeletal muscle atrophy, aiming to provide a comprehensive insight into the intricate relationship between ferroptosis and skeletal muscle atrophy from the perspectives of iron metabolism and lipid peroxidation and to provide new insights for targeting the pathways related to ferroptosis and the treatment of skeletal muscle atrophy.

Keywords: Xc-GSH-GPX4 pathway; ferroptosis; iron metabolism; lipid peroxidation; skeletal muscle atrophy.

Figure 1

Regulatory pathways of protein synthesis and degradation. IGF/PI3K/AKT regulates protein homeostasis. IGF/PI3K/AKT/GSK3β and IGF/PI3K/AKT/m-TOR promote protein synthesis. IGF/PI3K/AKT/FOXO suppresses protein degradation. The calcium-dependent calpain system, cysteine–aspartate protease system, mandolin–proteasome pathway, ubiquitin–proteasome system (UPS), and the autophagy–lysosome pathway (ALP) promoting protein degradation.

Figure 2

Ferroptosis has been implicated in various systemic diseases.

Figure 3

Signaling pathways that contribute to ferroptosis. (1) Transferrin (TF) binds to the transferrin receptor (TfR) to mediate Fe³⁺ entry into cells. The Fe³⁺ is reduced to Fe²⁺ by the ferriductase STEAP3, and the free Fe²⁺ is transported out of the endosome via the divalent metal transporter 1 (DMT1). Increased free Fe²⁺ in cells promotes the production of hydroxyl radicals (·OH) and ROS via the Fenton reaction, triggering ferroptosis. (2) Activating the system Xc-GSH-GPX4 pathway inhibits ferroptosis. (3) ACSL4 and LPCAT3 facilitate the conversion of PUFA to PUFA-CoAs, increasing cellular sensitivity to ferroptosis. (4) LOX (such as ALOX15) drives ferroptosis by promoting the peroxidation of PUFA. (5) Erastin inhibits the system Xc-GSH-GPX4, leading to the accumulation of lipid peroxidation and triggering ferroptosis. (6) Erastin inhibits the Keap/Nrf2/Ho-1 pathway, resulting in increased free Fe²⁺. (7) Erastin directly interacts with VDAC2/3 and induces mitochondrial dysfunction, triggering ferroptosis.