Journal Article

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

Bourgoin, Lucie, Ferrari, Serge, Douni, Eleni, Bonnet, Nicolas, Biver, Emmanuel

2019

Overview

Receptor activator of Nfkb ligand (RANKL) activates, while osteoprotegerin (OPG) inhibits, osteoclastogenesis. In turn 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-induce atrophy, but its role and mechanisms of action on muscle weakness in other conditions remains to be investigated. We investigated the effects of RANKL inhibitors on muscle in osteoporotic women and mice that either overexpress RANKL (HuRANKL-Tg+), or lack Pparb and concomitantly develop sarcopenia (Pparb-/-). In women, denosumab over 3 years improved appendicular lean mass and handgrip strength compared to no treatment, whereas bisphosphonate did not. HuRANKL-Tg+ 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 decrease anti-myogenic 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 their insulin signaling and higher expression of inflammatory genes in skeletal muscle. In conclusions, RANKL deteriorates, while its inhibitor improves, muscle strength and insulin sensitivity in osteoporotic mice and humans. Hence denosumab could represent a novel therapeutic approach for sarcopenia.

• Publisher: American Society for Clinical Investigation
• Subject: Alendronate / Animal models / Animals / Atrophy / Biomedical research / Bone and Bones - metabolism / Bone and Bones - pathology / Bone density / Bone mass / Bone strength / Cell Line / Comparative analysis / Denervation / Denosumab / Denosumab - pharmacology / Diabetes / Duchenne's muscular dystrophy / Female / Fractures / Gene expression / Genes / Glucose / Glucose metabolism / Homeostasis / Humans / Inflammation / Insulin / Insulin Resistance / Ligands / Male / Mice / Mice, Transgenic / Monoclonal antibodies / Muscle Strength / Muscle weakness / Muscular dystrophy / Musculoskeletal system / Myostatin / NF-κB protein / Novels / Organ Size - drug effects / Organ Size - genetics / Osteoclastogenesis / Osteoporosis / Osteoporosis - drug therapy / Osteoporosis - genetics / Osteoporosis - metabolism / Osteoporosis - pathology / Osteoprotegerin / Osteoprotegerin - genetics / Osteoprotegerin - metabolism / Phenols (Class of compounds) / Phosphatase / Phosphatases / PPAR-beta - genetics / PPAR-beta - metabolism / Protein-tyrosine-phosphatase / Proteins / RANK Ligand - antagonists & inhibitors / RANK Ligand - genetics / RANK Ligand - metabolism / Rodents / Sarcopenia / Sarcopenia - drug therapy / Sarcopenia - genetics / Sarcopenia - metabolism / Sarcopenia - pathology / Skeletal muscle / TRANCE protein / Tyrosine / Zoledronate