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Scientific article
Open access
English

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

Published inJournal of Clinical Investigation, vol. 129, no. 8, p. 3214-3223
Publication date2019
Abstract

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.

Keywords
  • Bone Biology
  • Bone disease
  • Muscle
  • Muscle Biology
  • Osteoporosis
Funding
  • Swiss National Science Foundation - 3100A0-116633/1
  • Autre - European Foundation for the Study of Diabetes and Foundation for Research in Osteoporosis and Bone Disease (ME10883)
Citation (ISO format)
BONNET, Nicolas et al. RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass. In: Journal of Clinical Investigation, 2019, vol. 129, n° 8, p. 3214–3223. doi: 10.1172/JCI125915
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Article (Published version)
Identifiers
ISSN of the journal0021-9738
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Technical informations

Creation08/30/2019 10:01:00 AM
First validation08/30/2019 10:01:00 AM
Update time03/15/2023 6:06:03 PM
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