Blockade of receptor activator of nuclear factor‐κB signaling greatly improves SERCA activity and contractility in atrophic and dystrophic skeletal muscles (731.7)

Receptor‐activator of nuclear factor‐κB (RANK), its ligand RANKL and the soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor (TNF) superfamily that control osteoclast differentiation, bone remodelling and osteoporosis. Since bone and skeletal muscle physiopathology occurs synchronously, we tested whether RANK/RANKL pathway is involved in muscle dysfunction following different muscle wasting conditions. Contractile properties of EDL muscles were obtained following 14d of denervation in mice specifically deficient in RANK skeletal muscle or in dystrophic mdx mice treated daily for 10d with OPG [0.3mg/kg], the natural inhibitor of RANKL. The activity and expression of sarco/endoplasmic reticulum Ca2+ ATPase (SERCA) were determined in denervated or dystrophic muscles. RANK muscle deletion did not prevent atrophy but greatly reduced the losses of force production and SERCA activity in denervated EDL muscles. Force production of EDL muscles also increased by 140% in OPG‐treated relative to PBS‐treated mdx mice while the treatment with OPG prevented the loss of the fast twitch SERCA1 protein content in dystrophic mice. Together, these data indicate that the deletion or blockage of RANK/RANKL pathway has inotropic effects and increases SERCA activity and expression in fast‐twitch skeletal muscles opening promising new avenues for several muscle diseases.