Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway
Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeleta...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | International Journal of Molecular Sciences |
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| Online Access: | https://www.mdpi.com/1422-0067/23/16/9444 |
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| author | Camilo Morales-Jiménez Julián Balanta-Melo Manuel Arias-Calderón Nadia Hernández Fernán Gómez-Valenzuela Alejandro Escobar Enrique Jaimovich Sonja Buvinic |
| author_facet | Camilo Morales-Jiménez Julián Balanta-Melo Manuel Arias-Calderón Nadia Hernández Fernán Gómez-Valenzuela Alejandro Escobar Enrique Jaimovich Sonja Buvinic |
| author_sort | Camilo Morales-Jiménez |
| collection | DOAJ |
| description | Muscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell<sup>®</sup> chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X<sub>7</sub> receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies. |
| first_indexed | 2024-03-09T04:19:09Z |
| format | Article |
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| institution | Directory Open Access Journal |
| issn | 1661-6596 1422-0067 |
| language | English |
| last_indexed | 2024-03-09T04:19:09Z |
| publishDate | 2022-08-01 |
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| series | International Journal of Molecular Sciences |
| spelling | doaj.art-8c4d6bbe5eda40a497cc4d940bd589882023-12-03T13:50:15ZengMDPI AGInternational Journal of Molecular Sciences1661-65961422-00672022-08-012316944410.3390/ijms23169444Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling PathwayCamilo Morales-Jiménez0Julián Balanta-Melo1Manuel Arias-Calderón2Nadia Hernández3Fernán Gómez-Valenzuela4Alejandro Escobar5Enrique Jaimovich6Sonja Buvinic7Institute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileInstitute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago 8380453, ChileInstitute for Research in Dental Sciences, Faculty of Dentistry, Universidad de Chile, Santiago 8380544, ChileMuscle and bone are tightly integrated through mechanical and biochemical signals. Osteoclasts are cells mostly related to pathological bone loss; however, they also start physiological bone remodeling. Therefore, osteoclast signals released during bone remodeling could improve both bone and skeletal muscle mass. Extracellular ATP is an autocrine/paracrine signaling molecule released by bone and muscle cells. Then, in the present work, it was hypothesized that ATP is a paracrine mediator released by osteoclasts and leads to skeletal muscle protein synthesis. RAW264.7-derived osteoclasts were co-cultured in Transwell<sup>®</sup> chambers with flexor digitorum brevis (FDB) muscle isolated from adult BalbC mice. The osteoclasts at the upper chamber were mechanically stimulated by controlled culture medium perturbation, resulting in a two-fold increase in protein synthesis in FDB muscle at the lower chamber. Osteoclasts released ATP to the extracellular medium in response to mechanical stimulation, proportional to the magnitude of the stimulus and partly dependent on the P2X<sub>7</sub> receptor. On the other hand, exogenous ATP promoted Akt phosphorylation (S473) in isolated FDB muscle in a time- and concentration-dependent manner. ATP also induced phosphorylation of proteins downstream Akt: mTOR (S2448), p70S6K (T389) and 4E-BP1 (T37/46). Exogenous ATP increased the protein synthesis rate in FDB muscle 2.2-fold; this effect was blocked by Suramin (general P2X/P2Y antagonist), LY294002 (phosphatidylinositol 3 kinase inhibitor) and Rapamycin (mTOR inhibitor). These blockers, as well as apyrase (ATP metabolizing enzyme), also abolished the induction of FDB protein synthesis evoked by mechanical stimulation of osteoclasts in the co-culture model. Therefore, the present findings suggest that mechanically stimulated osteoclasts release ATP, leading to protein synthesis in isolated FDB muscle, by activating the P2-PI3K-Akt-mTOR pathway. These results open a new area for research and clinical interest in bone-to-muscle crosstalk in adaptive processes related to muscle use/disuse or in musculoskeletal pathologies.https://www.mdpi.com/1422-0067/23/16/9444bone-muscle interactionsmuscle physiologybone remodelingosteoclastspurinergic signalingextracellular ATP |
| spellingShingle | Camilo Morales-Jiménez Julián Balanta-Melo Manuel Arias-Calderón Nadia Hernández Fernán Gómez-Valenzuela Alejandro Escobar Enrique Jaimovich Sonja Buvinic Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway International Journal of Molecular Sciences bone-muscle interactions muscle physiology bone remodeling osteoclasts purinergic signaling extracellular ATP |
| title | Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway |
| title_full | Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway |
| title_fullStr | Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway |
| title_full_unstemmed | Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway |
| title_short | Mechanical Disturbance of Osteoclasts Induces ATP Release That Leads to Protein Synthesis in Skeletal Muscle through an Akt-mTOR Signaling Pathway |
| title_sort | mechanical disturbance of osteoclasts induces atp release that leads to protein synthesis in skeletal muscle through an akt mtor signaling pathway |
| topic | bone-muscle interactions muscle physiology bone remodeling osteoclasts purinergic signaling extracellular ATP |
| url | https://www.mdpi.com/1422-0067/23/16/9444 |
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