Cited by 315Muscle Physiology and DisordersNutrition and Health in AgingBone Metabolism and Diseases

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

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Bonnet, Nicolas, Bourgoin, Lucie, Biver, Emmanuel, Douni, Eleni, Ferrari, Serge·2019·Journal of Clinical Investigation

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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.

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Authors: Bonnet, N., Bourgoin, L., Biver, E., Douni, E., & Ferrari, S.
Affiliations: University Hospital of Geneva (CH)
Agricultural University of Athens (GR)
Corresponding author: Bonnet, Nicolas
ORCID: Bonnet, Nicolas
Biver, Emmanuel
Douni, Eleni
Ferrari, Serge
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2019-07-02
Volume: 129
Issue: 8
Pages: 3214-3223
ISSN: 0021-9738 (ISSN-L)
1558-8238
DOI: 10.1172/jci125915
PMC: PMC6668701
OpenAlex: W2945787015
Cited by: 314
References: 41
Citations by year: 2026: 39 · 2025: 48 · 2024: 42 · 2023: 48 · 2022: 45 · 2021: 46 · 2020: 36 · 2019: 10
FWCI: 11.34
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Journal of Clinical Investigation (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Archive ouverte UNIGE (University of Geneva) (publishedVersion, other-oa)
DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Archive ouverte UNIGE (University of Geneva) (submittedVersion, cc-by)
Funders: Swiss National Science Foundation grant (No 3100A0-116633/1)
European Foundation for the Study of Diabetes (ME1598)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Muscle Physiology and Disorders
Health Sciences › Medicine › Physiology (medical) › Nutrition and Health in Aging
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Bone Metabolism and Diseases
Keywords: RANKL inhibition, denosumab, osteoprotegerin, muscle strength, insulin sensitivity, sarcopenia, osteoporosis, PPARδ, muscle atrophy, muscle fiber composition, myostatin, PTEN, skeletal muscle glucose uptake, muscle inflammation, bisphosphonates, osteoclastogenesis
MeSH terms: Denosumab, Animals, Bone and Bones, Cell Line, Female, Humans, Insulin Resistance, Male, Mice, Transgenic, Organ Size, Osteoporosis, PPAR-beta, Mice, Osteoprotegerin, RANK Ligand, Muscle Strength, Sarcopenia

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

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