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

Abstract

Receptor activator of NF-κB ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. A neutralizing Ab against RANKL, denosumab, improves bone strength in osteoporosis. OPG also improves muscle strength in mouse models of Duchenne’s muscular dystrophy (mdx) and denervation-induced atrophy, but its role and mechanisms of action on muscle weakness in other conditions remain to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKLTg+), or lack Pparb and concomitantly develop sarcopenia (Pparb–/–). In women, taking denosumab for more than 3 years improved appendicular lean mass and handgrip strength compared with no treatment, whereas bisphosphonate did not. HuRANKLTg+ mice displayed lower limb force and maximal speed, while their leg muscle mass was diminished, with a lower number of type I and II fibers. Both OPG and denosumab increased limb force proportionally to the increase in muscle mass. They markedly improved muscle insulin sensitivity and glucose uptake, and decreased antimyogenic and inflammatory gene expression in muscle, such as myostatin and protein tyrosine phosphatase receptor-γ. Similarly, in Pparb–/–, OPG increased muscle volume and force while also normalizing insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusion, RANKL deteriorates while its inhibitors improve muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence, denosumab could represent a novel therapeutic approach for sarcopenia.