RANKL Inhibition Reduces Cardiac Hypertrophy in Mice and Possibly in Children with Duchenne Muscular Dystrophy.

Cardiomyopathy has become one of the leading causes of death in patients with Duchenne muscular dystrophy (DMD). We recently reported that the inhibition of the interaction between the receptor activator of nuclear factor κB ligand (RANKL) and receptor activator of nuclear factor κB (RANK) significantly improves muscle and bone functions in dystrophin-deficient mice. RANKL and RANK are also expressed in cardiac muscle.

The inflammatory response, a mixed blessing for muscle homeostasis and plasticity.

Skeletal muscle makes up almost half the body weight of heathy individuals and is involved in several vital functions, including breathing, thermogenesis, metabolism, and locomotion. Skeletal muscle exhibits enormous plasticity with its capacity to adapt to stimuli such as changes in mechanical loading, nutritional interventions, or environmental factors (oxidative stress, inflammation, and endocrine changes). Satellite cells and timely recruited inflammatory cells are key actors in muscle homeostasis, injury, and repair processes.

The Roles of RANK/RANKL/OPG in Cardiac, Skeletal, and Smooth Muscles in Health and Disease.

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.

Testing the efficacy of a human full-length OPG-Fc analog in a severe model of cardiotoxin-induced skeletal muscle injury and repair.

Although receptor-activator of nuclear factor κB (RANK), its ligand RANKL, and osteoprotegerin (OPG), which are members of the tumor necrosis factor (TNF) superfamily, were first discovered in bone cells, they are also expressed in other cells, including skeletal muscle. We previously showed that the RANK/RANKL/OPG pathway is involved in the physiopathology of Duchenne muscular dystrophy and that a mouse full-length OPG-Fc (mFL-OPG-Fc) treatment is superior to muscle-specific RANK deletion in protecting dystrophic muscles. Although mFL-OPG-Fc has a beneficial effect in the context of muscular dystrophy, the function of human FL-OPG-Fc (hFL-OPG-Fc) during muscle repair is not yet known.

Muscle weakness and selective muscle atrophy in osteoprotegerin-deficient mice.

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.

An anti-RANKL treatment reduces muscle inflammation and dysfunction and strengthens bone in dystrophic mice.

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.