Duchenne muscular dystrophy (DMD) is the most severe form of muscular dystrophy which leads to progressive muscle degeneration and inflammation. The receptor activator of nuclear factor NF-κB ligand (RANKL) and its receptor (RANK), which are expressed in bone and skeletal and cardiac muscles, form a signaling network upstream from nuclear factor-kappa B (NF-κB). We thus hypothesized that prolonged silencing RANKL/RANK signaling would significantly improve DMD. We showed that RANK and RANKL protein levels were increased in the microenvironment of myofibers of 5-month-old utrophin haploinsufficient mdx (mdx/utrn+/−) mice and that a 4 mg/kg dose of anti-RANKL antibody every 3 d for 28 days is optimal and more effective than 1 mg/kg every 3 d for improving the ex vivo maximum specific force (sP0) of dystrophic EDL muscles from mdx/utrn+/− mice. This functional improvement was associated with a reduction in muscle edema, damage, and fibrosis and a marked reduction in serum CK levels. The anti-RANKL treatment inhibited the NF-κB pathway, increased the proportion of anti-inflammatory and non-cytotoxic M2 macrophages, and reduced the number of centrally-nucleated myofibers and the frequency of small myofibers, suggesting that anti-RANKL inhibits the cycle of degeneration/regeneration in dystrophic mice. A three-point bending test showed that a 28-d anti-RANKL treatment increases the mechanical properties of bone in mdx/utrn+/− dystrophic mice. In conclusion, the anti-RANKL treatment protected against skeletal muscle dysfunctions while enhancing bone mechanical properties, filling two needs with one deed in the context of muscular dystrophy.

Although their physiology and functions are very different, bones, skeletal and smooth muscles, as well as the heart have the same embryonic origin. Skeletal muscles and bones interact with each other to enable breathing, kinesis, and the maintenance of posture. Often, muscle and bone tissues degenerate synchronously under various conditions such as cancers, space travel, aging, prolonged bed rest, and neuromuscular diseases. In addition, bone tissue, skeletal and smooth muscles, and the heart share common signaling pathways. The RANK/RANKL/OPG pathway, which is essential for bone homeostasis, is also implicated in various physiological processes such as sarcopenia, atherosclerosis, and cardiovascular diseases. Several studies have reported bone-skeletal muscle crosstalk through the RANK/RANKL/OPG pathway. This review will summarize the current evidence indicating that the RANK/RANKL/OPG pathway is involved in muscle function. First, we will briefly discuss the role this pathway plays in bone homeostasis. Then, we will present results from various sources indicating that it plays a physiopathological role in skeletal, smooth muscle, and cardiac functions. Understanding how the RANK/RANKL/OPG pathway interferes in several physiological disorders may lead to new therapeutic approaches aimed at protecting bones and other tissues with a single treatment.

Bone and muscle are tightly coupled and form a functional unit under normal conditions. The receptor-activator of nuclear factor κB/receptor-activator of nuclear factor κB ligand/osteoprotegerin (RANK/RANKL/OPG) triad plays a crucial role in bone remodeling. RANKL inhibition by OPG prevents osteoporosis. In contrast, the absence of OPG results in elevated serum RANKL and early onset osteoporosis. However, the impacts of OPG deletion on muscle structure and function are unknown. Our results showed that 1-, 3- and 5-month-old Opg−/− mice have reduced tibial and femoral bone biomechanical properties and higher levels of circulating RANKL. OPG-deficient mice displayed reduced locomotor activity and signs of muscle weakness at 5 months of age. Furthermore, OPG deficiency did not affect the skeletal muscles in 1- and 3-month-old mice. However, it impaired fast-twitch EDL but not slow-twitch Sol muscles in 5-month-old Opg−/− mice. Moreover, 5-month-old Opg−/− mice exhibited selective atrophy of fast-twitch-type IIb myofibers, with increased expression of atrophic proteins such as NF-kB, atrogin-1 and MuRF-1. We used an in vitro model to show that RANKL-stimulated C2C12 myotubes significantly increased the expression of NF-kB, atrogin-1 and MuRF-1. A 2-month anti-RANKL treatment starting at 3 months of age in Opg−/− mice improved voluntary activity, the ex vivo maximum specific force (sP0) of EDL muscles, and whole limb grip force performance and rescued the biomechanical properties of bone. In conclusion, the deletion of OPG and the disruption of the RANKL/OPG balance induced osteoporosis as well as the selective weakness and atrophy of the powerful fast-twitch IIb myofibers, which was partly alleviated by an anti-RANKL treatment.