Published February 15, 2023 - More info
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.
Nicolas Bonnet, Lucie Bourgoin, Emmanuel Biver, Eleni Douni, Serge Ferrari
Original citation: J Clin Invest. 2019;129(8):3214–3223. https://doi.org/10.1172/JCI125915
Citation for this corrigendum: J Clin Invest. 2023;133(4):169317. https://doi.org/10.1172/JCI169317
The authors recently became aware that an incorrect image was shown in Figure 6F for the Pparb–/– Opg-Fc sample. The correct figure is shown below.
Bone, muscle, and glucose phenotype of Pparb–/– mice treated by OPG-Fc. (A and B) Skeletal muscle volume of the limb and fat infiltration in muscle evaluated by in vivo microCT. (C) Maximal speed evaluated on treadmill normalized by gastrocnemius mass. (D) Limb force evaluated by handgrip normalized by gastrocnemius mass (n = 8 per group). (E) Body temperature evaluated by infrared camera (n = 8 per group). (F) Muscle fiber type, number, and area. Note the type I fibers in blue dark and type II fibers in light blue. Original magnification is ×10. (G) ITT AUC (n = 8 per group). (H) GTT. (I) Relative protein expression in the gastrocnemius. Hatch marks correspond to mice that have received an acute injection of insulin. (J) Relative mRNA expression of insulin signaling in soleus. (K) Relative mRNA expression of Nfkb signaling in soleus (n = 6 per group). Statistical differences were assessed by 1-way ANOVA. †P < 0.05, ‡P < 0.01 significant difference versus WT. Bars show mean ± SEM.
The authors regret the error.
See the related article at RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass.