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Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk

Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, ost...

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Autores principales: Li, Guobin, Zhang, Lan, Ning, Kaiting, Yang, Baoqiang, Acosta, Francisca M., Shang, Peng, Jiang, Jean X., Xu, Huiyun
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911162/
https://www.ncbi.nlm.nih.gov/pubmed/33530465
http://dx.doi.org/10.3390/cells10020237
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author Li, Guobin
Zhang, Lan
Ning, Kaiting
Yang, Baoqiang
Acosta, Francisca M.
Shang, Peng
Jiang, Jean X.
Xu, Huiyun
author_facet Li, Guobin
Zhang, Lan
Ning, Kaiting
Yang, Baoqiang
Acosta, Francisca M.
Shang, Peng
Jiang, Jean X.
Xu, Huiyun
author_sort Li, Guobin
collection PubMed
description Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences.
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spelling pubmed-79111622021-02-28 Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk Li, Guobin Zhang, Lan Ning, Kaiting Yang, Baoqiang Acosta, Francisca M. Shang, Peng Jiang, Jean X. Xu, Huiyun Cells Article Bone–muscle crosstalk plays an important role in skeletal biomechanical function, the progression of numerous pathological conditions, and the modulation of local and distant cellular environments. Previous work has revealed that the deletion of connexin (Cx) 43 in osteoblasts, and consequently, osteocytes, indirectly compromises skeletal muscle formation and function. However, the respective roles of Cx43-formed gap junction channels (GJs) and hemichannels (HCs) in the bone–muscle crosstalk are poorly understood. To this end, we used two Cx43 osteocyte-specific transgenic mouse models expressing dominant negative mutants, Δ130–136 (GJs and HCs functions are inhibited), and R76W (only GJs function is blocked), to determine the effect of these two types of Cx43 channels on neighboring skeletal muscle. Blockage of osteocyte Cx43 GJs and HCs in Δ130–136 mice decreased fast-twitch muscle mass with reduced muscle protein synthesis and increased muscle protein degradation. Both R76W and Δ130–136 mice exhibited decreased muscle contractile force accompanied by a fast-to-slow fiber transition in typically fast-twitch muscles. In vitro results further showed that myotube formation of C2C12 myoblasts was inhibited after treatment with the primary osteocyte conditioned media (PO CM) from R76W and Δ130–136 mice. Additionally, prostaglandin E2 (PGE2) level was significantly reduced in both the circulation and PO CM of the transgenic mice. Interestingly, the injection of PGE2 to the transgenic mice rescued fast-twitch muscle mass and function; however, this had little effect on protein synthesis and degradation. These findings indicate a channel-specific response: inhibition of osteocytic Cx43 HCs decreases fast-twitch skeletal muscle mass alongside reduced protein synthesis and increased protein degradation. In contrast, blockage of Cx43 GJs results in decreased fast-twitch skeletal muscle contractile force and myogenesis, with PGE2 partially accounting for the measured differences. MDPI 2021-01-26 /pmc/articles/PMC7911162/ /pubmed/33530465 http://dx.doi.org/10.3390/cells10020237 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Li, Guobin
Zhang, Lan
Ning, Kaiting
Yang, Baoqiang
Acosta, Francisca M.
Shang, Peng
Jiang, Jean X.
Xu, Huiyun
Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title_full Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title_fullStr Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title_full_unstemmed Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title_short Osteocytic Connexin43 Channels Regulate Bone–Muscle Crosstalk
title_sort osteocytic connexin43 channels regulate bone–muscle crosstalk
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7911162/
https://www.ncbi.nlm.nih.gov/pubmed/33530465
http://dx.doi.org/10.3390/cells10020237
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