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  • Pitavastatin a hydroxy methyl glutaryl coenzyme A HmG

    2018-10-20

    Pitavastatin, a 3-hydroxy-3-methyl-glutaryl-coenzyme A (HmG-CoA) reductase inhibitor, was cytotoxic only to undifferentiated NPCs, whereas another HmG-CoA reductase inhibitor, cilastatin, had no effect. Similarly, 5-FU was substantially more toxic to undifferentiated cultures and resulted in nearly complete killing while minimally impacting differentiating cultures. Both drugs were also found to inhibit the proliferation of NPC cultures, which suggests that the mechanism of toxicity was predominantly anti-proliferative (in agreement with their known mechanisms of toxicity) because they did not decrease the viability of slowly proliferating differentiating NPCs (Chan et al., 2003; Diasio and Harris, 1989). The observation that pitavastatin inhibited proliferation and that cilastatin did not is consistent with the finding of Chan et al. (2003) that statins have highly variable anti-proliferative effects on various cell lines and cancers. DOX and CA are well-known chemotherapeutics with anti-proliferative and cytotoxic activity (Gewirtz, 1999; Momparler, 1982). For undifferentiated NPCs, DOX gave lower NPC viability (lower IC50), and to a lesser extent so did CA (p < 0.10), in comparison with differentiating NPCs. Because ∼3% of differentiating NPCs actively proliferated, the effects of DOX and CA suggest that cytotoxicity was the predominant mechanism of killing differentiating NPCs. This result also suggests that undifferentiated NPCs may be more sensitive to these compounds as a result of both anti-proliferative and cytotoxic mechanisms being effective against the undifferentiated, highly proliferative cell state.
    Experimental Procedures
    Author Contributions
    Acknowledgments The authors are grateful for the technical assistance of Drs Sergey Pryschep and Brigitte Arduini. This work was supported by NIH (ES020903) and NYSTEM (C026717).
    Introduction Adult order Cy5.5 NHS ester is a postmitotic organ that coordinates movement and constantly grows and adapts by remodeling its structure and metabolism. After insult or injury, adult skeletal muscle enables repair and regeneration of existing fibers and formation of new fibers through a population of stem cells that reside underneath the basal lamina called satellite cells (SCs) (Scharner and Zammit, 2011). The SCs reside in a specialized niche and change their quiescent complexion after injury, whereby SCs activate, proliferate, differentiate into myoblasts, and fuse to form myofibers (Bentzinger et al., 2013; Kuang et al., 2008). Each step is affected by various environmental signals and communication with infiltrating and resident cells (Aurora and Olson, 2014; Burzyn et al., 2013; Heredia et al., 2013). Multiple repair and regeneration subprocesses accomplished by SCs (and other cell types) after muscle injury are orchestrated by distinct epigenetic (Asp et al., 2011; Brancaccio and Palacios, 2015), transcriptional (Braun and Gautel, 2011; Buckingham and Rigby, 2014) and post-transcriptional events. However, the integrative dynamics of transcriptional networks and regulatory epigenetic switches at genome-wide levels have only been partly characterized in vivo (Liu et al., 2013; Giordani and Puri, 2013) and, as such, our understanding of the molecular processes involved in muscle regeneration have been limited. Herein, the in vivo evolution of coding and noncoding expression and three different chromatin modifications (H3K4me3, H3K4me1, and H3K27ac) were profiled across nine time points (t = 3 hr to 672 hr) from an injured and uninjured contralateral tibialis anterior (TA) muscle. The generated genomic maps were then contrasted against myogenic transcription factors (MyoD and MyoG) genomic binding data (Cao et al., 2010; The Mouse ENCODE Consortium, 2014) to determine shared and distinguishing signatures at cis-regulatory elements during different stages after injury. The dynamic levels of numerous coding and noncoding transcripts, chromatin state transitions, and differential binding at transcription factor (TF) motifs were integrated and assessed to construct a comprehensive view of the key transcriptional and chromatin factors that influence and modulate in vivo muscle repair and regeneration dynamics.