Muscle RANK is a key regulator of Ca²⁺ storage, SERCA activity, and function of fast-twitch skeletal muscles

Abstract

Receptor-activator of nuclear factor-κB (RANK), its ligand RANKL, and the soluble decoy receptor osteoprotegerin are the key regulators of osteoclast differentiation and bone remodeling. Here we show that RANK is also expressed in fully differentiated myotubes and skeletal muscle. Muscle RANK deletion has inotropic effects in denervated, but not in sham, extensor digitorum longus (EDL) muscles preventing the loss of maximum specific force while promoting muscle atrophy, fatigability, and increased proportion of fast-twitch fibers. In denervated EDL muscles, RANK deletion markedly increased stromal interaction molecule 1 content, a Ca(2+)sensor, and altered activity of the sarco(endo)plasmic reticulum Ca(2+)-ATPase (SERCA) modulating Ca(2+)storage. Muscle RANK deletion had no significant effects on the sham or denervated slow-twitch soleus muscles. These data identify a novel role for RANK as a key regulator of Ca(2+)storage and SERCA activity, ultimately affecting denervated skeletal muscle function.

RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass

“…To better understand the influence of RANKL-RANK signaling on muscle cell metabolism, we investigated insulin signaling in C2C12-differentiated myotubes expressing both RANK and RANKL (15,30). In these cells RANKL increased, whereas OPG decreased, the level of IRS1 Ser318 phosphorylation, which is known to downregulate insulin receptor activity, Gastrocnemius and soleus weights were higher under Dmab versus vehicle (increased by 9.3% and 12%, respectively, P < 0.05; Figure 5H).…”

“…RANK is also expressed in skeletal muscle and activation of the NF-κB pathway mainly inhibits myogenic differentiation, which leads to skeletal muscle dysfunction and loss (12,13). In turn, OPG-Fc has been shown to reduce inflammation, restore the integrity, and improve the function of dystrophic muscles in a mouse model of Duchenne's muscular dystrophy (mdx mice) (14,15). In this model, RANK/RANKL/OPG controls calcium mobilization and the apoptotic and inflammatory processes (14,15).…”

“…In turn, OPG-Fc has been shown to reduce inflammation, restore the integrity, and improve the function of dystrophic muscles in a mouse model of Duchenne's muscular dystrophy (mdx mice) (14,15). In this model, RANK/RANKL/OPG controls calcium mobilization and the apoptotic and inflammatory processes (14,15).…”

A Pooled Analysis of Fall Incidence From Placebo-Controlled Trials of Denosumab

“…For example, a systemic injection of osteoprotegerin (OPG), a soluble decoy receptor of RANKL, has been shown to restore muscle force and improve muscle histology in dystrophic mdx mice, which have the same dystrophin mutation as human patients . The same research group found that muscle RANK is a key regulator for calcium ion storage and sarco/endoplasmic reticulum Ca 2 +ATPase (SERCA) activity and function of fast‐twitch skeletal muscles . That pathways in addition to RANKL/RANK may play an important role in muscular dystrophy was recently suggested by the observation that full‐length OPG‐Fc was superior to anti‐RANKL in alleviating muscular dystrophy in the mouse model …”

RANKL biology: bone metabolism, the immune system, and beyond

“…RANK is also known to be expressed in skeletal muscle. The activation of RANKL/RANK signaling in skeletal muscle leads to the inhibition of myogenic differentiation through the activation of NF-κB, which results in skeletal muscle dysfunction and loss [97]. In fact, administration of the recombinant OPG protein improved muscle strength in a mouse model of Duchenne's muscular dystrophy and denervation-induced muscle atrophy.…”