RANKL signaling drives skeletal muscle into the oxidative profile
© The Author(s) 2024. Published by Oxford University Press on behalf of the American Society for Bone and Mineral Research. All rights reserved. For permissions, please email: journals.permissionsoup.com..
The bone-muscle unit refers to the reciprocal regulation between bone and muscle by mechanical interaction and tissue communication via soluble factors. The receptor activator of NF-κB ligand (RANKL) stimulation induces mitochondrial biogenesis and increases the oxidative capacity in osteoclasts and adipocytes. RANKL may bind to the membrane bound receptor activator of NF-κB (RANK) or to osteoprotegerin (OPG), a decoy receptor that inhibits RANK-RANKL activation. RANK is highly expressed in skeletal muscle, but the contribution of RANKL to healthy skeletal muscle fiber remains elusive. Here we show that RANKL stimulation in C2C12-derived myotubes induced activation of mitochondrial biogenesis pathways as detected by RNA-seq and western blot. RANKL expanded the mitochondrial reticulum, as shown by mitochondrial DNA quantification and MitoTracker staining, and boosted the spare respiratory capacity. Using MEK and MAPK inhibitors, we found that RANKL signals via ERK and p38 to induce mitochondrial biogenesis. The soleus from OPG-/- and OPG+/- mice showed higher respiratory rates compared to C57BL6/J wild-type (WT) mice, which correlates with high serum RANKL levels. RANKL infusion using a mini-osmotic pump in WT mice increased the number of mitochondria, boosted the respiratory rate, increased succinate dehydrogenase (SDH) activity in skeletal muscle, and improved the fatigue resistance of gastrocnemius. Therefore, our findings reveal a new role of RANKL as an osteokine-like protein that impacts muscle fiber metabolism.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - year:2024 |
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| Enthalten in: |
Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research - (2024) vom: 15. Apr. |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Cavalcanti de Araújo, Paulo Henrique [VerfasserIn] |
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| Links: |
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| Themen: |
Fiber type switch |
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| Anmerkungen: |
Date Revised 15.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1093/jbmr/zjae058 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| 520 | |a The bone-muscle unit refers to the reciprocal regulation between bone and muscle by mechanical interaction and tissue communication via soluble factors. The receptor activator of NF-κB ligand (RANKL) stimulation induces mitochondrial biogenesis and increases the oxidative capacity in osteoclasts and adipocytes. RANKL may bind to the membrane bound receptor activator of NF-κB (RANK) or to osteoprotegerin (OPG), a decoy receptor that inhibits RANK-RANKL activation. RANK is highly expressed in skeletal muscle, but the contribution of RANKL to healthy skeletal muscle fiber remains elusive. Here we show that RANKL stimulation in C2C12-derived myotubes induced activation of mitochondrial biogenesis pathways as detected by RNA-seq and western blot. RANKL expanded the mitochondrial reticulum, as shown by mitochondrial DNA quantification and MitoTracker staining, and boosted the spare respiratory capacity. Using MEK and MAPK inhibitors, we found that RANKL signals via ERK and p38 to induce mitochondrial biogenesis. The soleus from OPG-/- and OPG+/- mice showed higher respiratory rates compared to C57BL6/J wild-type (WT) mice, which correlates with high serum RANKL levels. RANKL infusion using a mini-osmotic pump in WT mice increased the number of mitochondria, boosted the respiratory rate, increased succinate dehydrogenase (SDH) activity in skeletal muscle, and improved the fatigue resistance of gastrocnemius. Therefore, our findings reveal a new role of RANKL as an osteokine-like protein that impacts muscle fiber metabolism | ||
| 650 | 4 | |a Journal Article | |
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| 650 | 4 | |a RANKL | |
| 650 | 4 | |a fiber type switch | |
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| 650 | 4 | |a skeletal muscle | |
| 700 | 1 | |a Cezine, Maria Eduarda Ramos |e verfasserin |4 aut | |
| 700 | 1 | |a Vulczak, Anderson |e verfasserin |4 aut | |
| 700 | 1 | |a Vieira, Luiz Carlos |e verfasserin |4 aut | |
| 700 | 1 | |a Matsuo, Flávia Sayuri |e verfasserin |4 aut | |
| 700 | 1 | |a Remoto, Júlia Maranghetti |e verfasserin |4 aut | |
| 700 | 1 | |a Santos, Audrei Dos Reis |e verfasserin |4 aut | |
| 700 | 1 | |a Miyabara, Elen Haruka |e verfasserin |4 aut | |
| 700 | 1 | |a Alberici, Luciane Carla |e verfasserin |4 aut | |
| 700 | 1 | |a Osako, Mariana Kiomy |e verfasserin |4 aut | |
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