Artículo de revista
Mechanical disturbance of osteoclasts induces atp release that leads to protein synthesis in skeletal muscle through an akt-mtor signaling pathway
Fecha
2022Registro en:
Int. J. Mol. Sci. 2022, 23, 9444
10.3390/ijms23169444
Autor
Morales Jiménez, Camilo
Balanta Melo, Julián Andrés
Arias Calderón, Manuel Andrés
Hernández Moya, Nadia Marcela
Gómez Valenzuela, Fernán Daniel
Escobar Álvarez, Alejandro Felipe
Jaimovich Pérez, Enrique Zacarías
Buvinic Radic, Sonja Milena
Institución
Resumen
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® 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 P2X7 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.