Age-specific stimulation of erythropoiesis resulting from defective heme synthesis-export axis in skeletal-muscle

Interorgan and intratissue communication is fundamental to maintain homeostasis under healthy and pathologic conditions. In this framework, increasing evidence highlights the previously unrecognized endocrine role of skeletal muscle, and the possibility for muscle to communicate with distant tissues in response to different stimuli and requirements. In the attempt to investigate how altered muscle homeostasis can be sensed by the organism and how signals coming from muscles can induce a specific response in peripheral tissues, we exploited a muscle specific Flvcr1a-null mouse, characterized by defective heme synthesis, low myoglobin and a consequent local hypoxia in skeletal muscle. The data obtained demonstrate that muscle hypoxia is perceived by the body, which responds by increasing erythropoiesis. The enhanced erythropoiesis is associated with reduced hepatic expression of hepcidin, the hormone responsible for iron mobilization to sustain red blood cells production, and to increased renal production of erythropoietin. Interestingly, in skeletal muscles we also found an increased expression of myonectin, a myokine recently showed to be induced under hypoxic condition and a mediator of hepcidin suppression. Overall, our data indicate that the effects of disrupted heme synthesis in skeletal muscle are sensed by peripheral tissues and support the existence of a possible direct muscle-kidney crosstalk, able to inform the kidney regarding the condition of muscle local hypoxia and to induce an erythropoietic response in order to support oxygen delivery to muscles.