IRON REGULATION IN SKELETAL MUSCLE DIFFERS DEPENDING ON MUSCLE WASTING AND IRON OVERLOAD CONDITIONS

Maëlys AUFFRET1, Luz ORFILA1, Mathieu HOREAU1,2, Martine ROPERT2, Damien FREYSSENET3, Olivier LORÉAL2, Amélie RÉBILLARD1, Frédéric DERBRÉ1

1Laboratory “Movement Sport and Health Sciences” (M2S), EA7470, University Rennes 2, Rennes, France
2INSERM, University of Rennes, INRAE, AEM2 platform, Nutrition Metabolisms and Cancer (NuMeCan) institute, Rennes, France
3Inter-University Laboratory of Human Movement Biology EA 7424, Univ Lyon, University Jean Monnet Saint-Etienne, Saint-Priest-en-Jarez, France

Iron metabolism is crucial in various physiological processes, especially for maintaining muscle function. Previous studies have reported relationships between muscle wasting and iron overload, but the underlying mechanisms in these physiopathological conditions are incompletely characterised. The aim of this study was to characterize in vivo the impact of muscle wasting and secondary iron overload on iron regulatory proteins in skeletal muscle. For this purpose, we used murine models supplemented with iron-dextran (1g/kg), or exhibiting muscle atrophy induced by cancer cachexia (ApcMin/+) or simulated microgravity (hindlimb unloading). Histological and biomolecular analyses were performed on glycolytic skeletal muscle (i.e. quadriceps or gastrocnemius).

Despite intramuscular iron overload, iron-dextran mice do not exhibit muscle mass loss and do not seem to actively facilitate iron efflux, as indicated by the lack of changes of ferroportin and FLVCR1 proteins. Regarding atrophy models, muscle weight loss in unloaded animals is associated with iron accumulation in gastrocnemius, while muscle wasting do not induce iron excess in quadriceps in ApcMin/+mice. However, in both cases, the atrophied skeletal muscles seem to favor iron sequestration by limiting export through ferroportin. Whatever the experimental model, neither myoglobin nor FLVCR1 are modulated in skeletal muscle, suggesting that heme iron might not be specifically regulated under muscle wasting or iron overload conditions. Muscle iron metabolism appears to respond differently depending on the cause of muscle iron overload (i.e. systemic iron overload, disuse or inflammatory origin of atrophy). These results suggest a complex interplay between atrophy pathways and iron homeostasis with skeletal muscle tissue.