Osteocytic Connexin43 Channels Regulate Bone-Muscle Crosstalk.

Guobin Li,Lan Zhang,Francisca M Acosta,Jean X Jiang,Peng Shang,Kaiting Ning,Huiyun Xu,Baoqiang Yang

doi:10.3390/cells10020237

Abstract

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.

Highlights

There is an intimate relationship between bone and skeletal muscle from development, through growth, and into aging [1,2]
The results showed that the phosphorylation levels of S6K1 (p-S6K1) and 4EBP1 (p-4E-BP1), two surrogate markers of mTOR activation, were significantly decreased in GS muscles of ∆130–136 mice compared with that of WT littermates, while there was no difference between R76W and WT (p < 0.05; Figure 1f,g)
These data suggest that the osteocyte Cx43 HCs are involved in the maintenance of muscle mass primarily in fast-twitch muscles, by affecting muscle protein synthesis and degradation

Summary

Introduction

There is an intimate relationship between bone and skeletal muscle from development, through growth, and into aging [1,2]. Bone cells are known to produce factors, for example, osteocalcin [8], prostaglandin E2 (PGE2) [9], Wnt3a [10], and sclerostin [11], which influence the function of skeletal muscle. These findings suggest that bone–muscle biochemical crosstalk is essential for the optimal performance of the two tissues. Given the high degree of vascularity of bone and the intimate connection between bone and vascular supply, it is suggested that osteocyte-specific factors could directly enter the bloodstream and target distant organs and tissues, including skeletal muscle

Methods

Results

Discussion

Conclusion