Endocrine Abstracts

Receptor-activator of nuclear factor kB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are the key regulators of osteoclast differentiation and bone remodelling. Although there is a strong association between osteoporosis and skeletal muscle atrophy, the functional relevance of a particular biological pathway that regulates synchronously bone and skeletal muscle physiopathology remain elusive. We thus hypothesized that RANK/RANKL/OPG, which is a key pathway for bone regulation, is involved in Duchenne muscular dystrophy (DMD) physiopathology. Our results show that muscle-specific RANK deletion (mdx-RANK^mko) in dystrophin deficient mdx mice improves specific force (54% gain of force) of EDL muscles with no protective effect against eccentric contraction-induced muscle dysfunction. In contrast, full-length OPG-Fc injections restore dystrophic EDL muscle force (162% gain in force), protect against eccentric contraction-induced muscle dysfunction ex vivo and significantly improve functional performance on downhill treadmill test and post-exercise mobility. Since OPG serves as a decoy receptor for RANKL and TRAIL, mdx mice were injected with anti-RANKL and anti-TRAIL antibodies to decipher the dual function of OPG. Injections of anti-RANKL and/or anti-TRAIL increase significantly dystrophic EDL muscle force (45 and 17% gains of force, respectively). In agreement, truncated OPG-Fc that contains only the RANKL domains produces similar gains, in terms of force production, than anti-RANKL treatments. To corroborate that full-length OPG-Fc also acts independently of RANK/RANKL pathway, dystrophin/RANK double-deficient mice were treated with full-length OPG-Fc for 10 days. Dystrophic EDL muscles exhibited a significant gain of force relative to untreated dystrophin/RANK double-deficient mice, indicating that the effect of full-length OPG-Fc is in part independent of the RANKL/RANK interaction. In addition, one key determinant of muscle contractility and performance is the Ca²⁺ pump called sarco/endoplasmic reticulum Ca²⁺ ATPase (SERCA). SERCA captures Ca²⁺ from the cytosol into the lumen of the sarcoplasmic reticulum, making Ca²⁺ available for the next contraction. SERCA activity is significantly depressed in dysfunctional and dystrophic muscles and full-length OPG-Fc treatment restored completely SERCA activity and markedly increased SERCA-2a expression. These findings demonstrate the superiority of full-length OPG-Fc treatment relative to truncated OPG-Fc, anti-RANKL, anti-TRAIL or muscle RANK deletion in improving dystrophic muscle function, integrity and protection against eccentric contractions. In conclusion, full-length OPG-Fc may be instrumental in the development of new treatments for muscular dystrophy in which a single therapeutic approach may be foreseeable to maintain both bone and skeletal muscle functions.