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  • In summary this study reveals that the stability

    2024-02-23

    In summary, this study reveals that the stability of rapsyn is critically dependent on HSP90β, highlighting a novel function of HSP90β in NMJ formation and maintenance. It also identifies a mechanism in agrin signaling for AChR clustering, i.e., by upregulating the interaction between HSP90β and rapsyn. Agrin is known to increase rapsyn interaction with AChR, which reaches maximal levels within 40 min of stimulation (Moransard et al., 2003). We show that levels of HSP90β in the surface AChR complex begin to increase ∼1 hr after stimulation and peak around 12 hr (Figure 1C). These observations suggest that the initial targets of agrin/MuSK signaling include the interaction of the AChR and rapsyn, which is followed by the rapsyn-HSP90β association. Recruited HSP90β maintains the stability of rapsyn associated with surface AChRs, contributing to cluster formation and maintenance (Figure 8). Considering that several members of the HSP90 machinery are present at the PSD or aggresomes in neurites (Moon et al., 2001, Romorini et al., 2004, Suzuki et al., 1999, Walikonis et al., 2000), these results may provide insight into CNS synapse formation. In support of the notion, pharmacological inhibitors of HSP90 have been shown to rapidly reduce AMPA receptor currents in hippocampal slices, probably by interfering with constitutive trafficking of AMPA receptors (Gerges et al., 2004).
    Experimental Procedures
    Acknowledgments
    Introduction Loss of functional skeletal muscle tissue due to traumatic injury, extensive surgical tumor excision and muscle atrophy caused by prolonged denervation, produces a physiological deficit for which there is still no effective clinical treatment [1], [2]. Although autologous grafting techniques relocate muscle tissue to the site of the defect, this technique results in donor-site morbidity, causing functional loss and volume deficiency in the donor muscle [3]. Alternatively, the use of tissue engineered muscle consisting of patient's own Bestatin hydrochloride may potentially provide a therapeutic solution to this unmet medical need. As such, extensive investigations have been made to develop clinically applicable engineered muscle tissue that would produce contractile function in vivo[4]. One strategy to create engineered muscle involves the use of stem or progenitor cells that are seeded on a three-dimensional supporting structures (scaffolds) followed by implantation in vivo[5], [6], [7], [8]. The essential components that are required to successfully engineer functional muscle tissue in vivo are adequate muscle tissue organization, vascularization and innervation [9]. To achieve functional muscle tissues, several innovative approaches have been introduced to facilitate organization of muscle fibers and improve contractile function. These include the use of computerized bioreactors that provide cyclic mechanical strains to align and induce unidirectional muscle fiber orientation, development of scaffolds that provide aligned polymer fibers that guide directional orientation of cells, and methods to increase vascularization of implanted muscle constructs [4], [10], [11]. Although these Bestatin hydrochloride advances have provided potential solutions to building vascularized contractile muscle tissue in vivo, the issues related to innervation of constructs in vivo have not been adequately addressed to date. The established contacts of tissue engineered muscle constructs with host nervous tissue are critically important following implantation, as failure of innervation leads to atrophy of muscle tissue and loss of contractile function [12]. When muscle cells/fibers are implanted in the body, host nerves contact with the muscle fibers to form neuromuscular junctions (NMJ). It has been demonstrated that denervated muscle, which is analogous to in vitro engineered muscle constructs, can be reinnervated upon direct transplantation of host nerve [13]. However, the process of innervations into denervated muscle is slow, and substantial time is required before muscle tissue can be functional. Therefore, methods to accelerate innervations are needed.