Physiological role of receptor activator nuclear factor-kB (RANK) in denervation-induced muscle atrophy and dysfunction

Abstract

The bone remodeling and homeostasis are mainly controlled by the receptor-activator of nuclear factor kB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin (OPG) pathway. While there is a strong association between osteoporosis and skeletal muscle dysfunction, the functional relevance of a particular biological pathway that synchronously regulates bone and skeletal muscle physiopathology remains elusive. Our recent article published in the American Journal of Physiology (Cell Physiology) showed that RANK is also expressed in fully differentiated C2C12 myotubes and skeletal muscles. We used the Cre-Lox approach to inactivate muscle RANK (RANKmko) and showed that RANK deletion preserves the force of denervated fast-twitch EDL muscles. However, RANK deletion had no positive impact on slow-twitch Sol muscles. In addition, denervating RANKmko EDL muscles induced an increase in the total calcium concentration ([CaT]), which was associated with a surprising decrease in SERCA activity. Interestingly, the levels of STIM-1, which mediates Ca2+ influx following the depletion of SR Ca2+ stores, were markedly higher in denervated RANKmko EDL muscles. We speculated that extracellular Ca2+ influx mediated by STIM-1 may be important for the increase in [CaT] and the gain of force in denervated RANKmko EDL muscles. Overall, these findings showed for the first time that the RANKL/RANK interaction plays a role in denervation-induced muscle atrophy and dysfunction.

The SarcoEndoplasmic Reticulum Calcium ATPase (SERCA) pump: a potential target for intervention in aging and skeletal muscle pathologies

“…Currently, there are two potential factors that have been studied regarding the influence of denervation on SERCA function, one is through phospholamban (PLN) [ 28 ], and the other is via receptor activator nuclear factor-kB (RANK) [ 14 , 15 ]. As mentioned above, PLN is an inhibitor of SERCA pumps expressing in all muscle types.…”

“…Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin (OPG) are members of the tumor necrosis factor superfamily that regulate bone remodeling [ 29 , 32 ]. The study of the regulating roles of Ca 2+ through the interactions between RANK and RANKL is still a newly emerging area, but its function related to regulating cellular Ca 2+ storage and a series of Ca 2+ pumps in denervated muscles has been measured [ 14 , 15 ]. In a muscle-specific RANK knock out mouse model, they demonstrated that in denervated fast twitch muscles (EDL), the RANK deletion markedly increased the content of STIM 1, a Ca 2+ sensor, the SERCA activity, the SR Ca 2+ storage, and also the corresponding muscular functions, such as force production and muscle fatigability [ 15 ].…”

The Role of Osteokines in Sarcopenia: Therapeutic Directions and Application Prospects

“…This may be explained by the function of denosumab, which prevents binding of the RANK receptor by RANKL, with a resultant reduction in cytokines (e.g., TNF can cause muscle wasting and cellular apoptosis). Prior to this, some researchers confirmed that conditional knockout of RANK in muscle could prevent denervation-induced muscle weakness ( Dufresne et al, 2016a ). Taken together, the RANK/RANKL/OPG system may play an important role in muscle metabolism and the development of sarcopenia.…”