RANKL inhibition improves muscle strength and insulin sensitivity and restores bone mass
Open accessAbstract
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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Osteokines are novel exercise-inducible soluble factors secreted by osteocytes, osteoblasts, and osteoclasts that play an important role in the body's response to exercise, mainly including RANKL, sclerostin, osteocalcin, FGF23, Wnt3a, TGF-β, IGF-1, and PGE2.
“Osteokines, novel exercise-inducible soluble factors secreted by osteocytes, osteo blasts, and osteoclasts, play an important role in the body’s response to exercise, mainly including RANKL [127], sclerostin [128], osteocalcin [129], fibroblast growth factor 23 (FGF23) [95], Wnt3a [130], TGF-β [131], IGF-1 [132], and prostaglandin E2 (PGE2) [133] (Figure 3).”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [127]
RANKL inhibition improves muscle strength and insulin sensitivity in osteoporotic mice and humans through the RANK/RANKL/OPG signaling pathways, potentially representing a new therapeutic avenue for sarcopenia.
“Research has shown that RANKL inhibition improves muscle strength and insulin sensitivity in osteoporotic mice and humans through the RANK/RANKL/OPG signaling pathways, potentially representing a new therapeutic avenue for sarcopenia [127].”
From Exerkines and Sarcopenia: Unveiling the Mechanism Behind Exercise-Induced Mitochondrial Homeostasis (2025) · cites this paper as [127]
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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
- Venue
- Journal of Clinical Investigation
- Published
- 2019-07-02
- Volume
- 129
- Issue
- 8
- Pages
- 3214-3223
- ISSN
- 0021-9738 (ISSN-L)
- 1558-8238
- 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 › 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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