07 | Role of GDF5 on macrophage polarization in the maintenance of muscle mass and function and during aging

Maxime Gelin¹, E. Hemery¹, F. Truffault¹, G. Juban², C. Perrotta³, F. Pietri-Rouxel¹, M. Traoré¹, S. Falcone¹ | ¹Centre de Recherche en Myologie – U974 INSERM, Sorbonne Université, Institut de Myologie, Paris, France; ²Institut NeuroMyoGène, Physiopathologie et Génétique du Neurone et du Muscle Université Claude Bernard Lyon 1, CNRS U5261, Inserm U1315, University Lyon, Lyon, France; ³Department of Biomedical and Clinical Sciences Università degli Studi di Milano, Milan, Italy. | M. Traoré and S. Falcone contributed equally to this work and corresponding authors. s.falcone@institut-myologie.org; m.traore@institut-myologie.org.

Sarcopenia is a progressive age-related disease causing loss of strength, quality and mass of muscle and leading to frailty, disability and mortality. Importantly, alteration of pro/antiinflammatory pathways related to macrophages (φs) has been shown as critical in the progression of this disease. In a therapeutic perspective, growth and differentiation factor 5/bone morphogenetic protein 14 (GDF5/BMP14), is of great interest because of its broad functions in neuromuscular system and several physiological processes. BMPs were described to regulate immune response cells and φs, however, the impact of GDF5 on their modulation in skeletal muscle physiology has never been investigated. Our recent work demonstrated that GDF5 overexpression prevents age-related muscle wasting by different mechanisms. In addition, it leads to a rejuvenating transcriptomic signature and reverts the expression of several φ-related genes altered by aging, in mice. To expand this knowledge, we are deeply deciphering the effect of GDF5-based treatments on φs regulation, in vitro and in vivo. Here, we show that this factor directly promotes the polarization of naïve primary mouse φs into anti-inflammatory/pro-regenerative φs, in vitro. In addition, we are evaluating its role in muscle repair after inflammation-associated injury, in vivo. Overall, this study will lead to an extensive characterization of the effect of GDF5 on macrophages and inflammation potentially contributing in maintaining skeletal muscle mass and function. The obtained results will improve the knowledge of physiological processes involved in muscle repair and will shed light on novel therapeutic perspectives for neuromuscular diseases.