FIGURE 1.

Pathways regulated by oxidative stress induced by iron overload in muscle cells and leading to muscle atrophy, changes in endocrine functions, and contributing to neurodegeneration. FOXO3a transcription factor upregulates two main protein degradation pathways, ubiquitin-proteasome and autophagy-lysosome, both involved in muscle atrophy (see details in the text). Iron-mediated ROS elevation inhibits activity of FOXO3a negative regulator, Akt, and stimulates its positive regulator, AMPK. TRAF6 ubiquitin ligase is also involved in stimulation of muscle atrophy mediated by FOXO3a as well as inflammatory response and might be activated by ROS. Ferrous iron-induced ROS have been shown to activate TRAF6 in hepatic macrophages. ROS also induce production of myostatin which leads to muscle atrophy. On the other hand, exercise downregulates myostatin while such myokines as apelin or IL15 are increased and stimulate Akt in skeletal muscle and neuronal tissue thus protect against muscle and neurons atrophy. Loss of muscle mass thus, reduction in their endocrine functions may accelerate neurodegeneration and degeneration of motor neurons promotes muscle atrophy.