Deciphering role of GDF5 on pathophysiology of muscular dystrophy – GETUP

Duchenne muscular dystrophy (DMD) is a myopathy caused by the absence of the protein dystrophin which leads to damage to the integrity of muscle fibers accompanied by cycles of degeneration/regeneration. Initially, regeneration is supported by the proliferation and differentiation of satellite cells (MuSCs). However, their regenerative potential is gradually depleted resulting in muscle dysfunction. Nevertheless, other resident muscle cells (MRCs) have been shown to participate in muscle regeneration.
Members of the Bone Morphogenetic Protein (BMP) family are key players in muscle homeostasis and their signaling modulates MuSCs proliferation/differentiation in regenerating muscle. Notably, the stimulated BMP1 receptor has been shown to induce muscle hypertrophy and we showed that overexpression of BMP14 (also called GDF5) helps preventing age-related loss of muscle mass. Despite evidence that GDF5 is a positive modulator of muscle mass homeostasis and a potential regulator of muscle repair, its potential applications to preserve muscle quality in disease such as DMD has not been explored. Our preliminary results support the hypothesis that GDF5 treatment promotes a hyperplastic effect in DMD muscle through modulation of MRCs.
Our aim is to decipher the role of GDF5 treatment in modulating of MRCs and to evaluate its potential benefits in a severe preclinical model of DMD (Ratdel52) whose pathophysiological context closely mimicks human pathology.
Our results will shed light on the fundamental mechanisms underlying the hyperplastic effect of GDF5, paving the way for combined therapeutic strategies to preserve muscle mass in dystrophic muscle.