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  • Enhanced oxidative stress has been suggested as the critical

    2020-01-22

    Enhanced oxidative stress has been suggested as the critical mechanisms of IS-produced muscle damage [41,42]. NAC as a direct reactive oxygen species ROS scavenger is frequently discussed in the clinical trials of radiocontrast-induced AKI prevention [43]. Despite some supportive epidemiological data, the evidence of antioxidant supplement is still extremely limited in the field of sarcopenia, particularly CKD-related myopathy [44]. In C2C12 cells, we found that NAC pretreatment effectively reversed IS-mediated smaller myotube diameters. The actions of IS-induced ROS are intimately through peculiar signaling pathways [45]. Accordingly, the capability of NAC treatment on ERK, JNK and p38 phosphorylation induced by IS in C2C12 myotubes were examined. Only ERK1/2 activation was suppressed by NAC accompanied with recovery of IS-mediated myotube atrophy. In murine model for cancer cachexia, elevated ERK1/2 phosphorylation is identified and Selumetinib therapy promoted muscle gain via ERK1/2 inhibition [46]. The functions of p-ERK1/2 in uremic sarcopenia still need further exploration. Concluding the above reviews, prevention of NAC blocked ERK1/2 phosphorylation, implying the potential of p-ERK1/2 inhibitor as a therapeutic target to ameliorate IS-induced ROS damage on skeletal muscle. Excessive autophagosome accumulation aggravated muscle wasting and its activation was highlighted in uremia-related myopathy [47,48]. In C2C12 myotubes, the increase of LC3β protein revealed apparent dosage sensitivity on IS stimulation (0.1–0.4 mM). Emerging evidence has pointed out the importance of basal autophagy in muscle mass OTX-015 and atrophy prevention [49]. Furthermore, autophagy may function as protective response for cell survival under stress [50]. Concluding the above remarks, the dose-dependent upregulation of LC3β could be beneficial or detrimental on C2C12 myotubes. And, the altered LC3β level may be regarded as quick indicator of IS-produced muscle toxicity. Subsequently, we found that NAC could attenuate IS-mediated muscle LC3β upregulation. The similar NAC results has been reported in unfolding protein-induced neurotoxicity [51] and ischemia-reperfusion hepatic injury [52]. Our data supported that LC3β may act as the delicate index for IS-accumulation and encourage the NAC supplement in detoxifying ROS-mediated autophagy. MAFbx (also called atrogin-1) and MuRF1 are two well-characterized E3-ubiquitin-conjugating enzymes in uremia myopathy [53]. One of the targeted substrate for MuRF1 is MLC [54]. Moreover, MLC phosphorylation is increased in IS-treated smooth muscle cell dose dependently suggested the decreased motility [55]. In C2C12 myotubes, MLC protein expression was suppressed by IS treatment, together with p-MLC upregulation. Consistently, under 0.4 mM IS incubation, both mRNA and protein level of MAFbx were increased hinted that the increased activity of ubiquitin system in IS-stimulated C2C12 cells. The application of NAC and p-JNK inhibitor recovered MAFbx protein upregulation induced by IS in cultured myotubes, respectively. In denervated mouse muscle cell, NAC also decreases MAFbx protein level through ROS inhibition [56]. These results provided further evidence for the responsibility of ROS in IS-mediated MAFbx regulation in skeletal muscle. Collectively, IS may exert MAFbx protein regulation via JNK phosphorylation which has therapeutic potential to develop JNK inhibitor in treating uremia sarcopenia.
    Conclusions
    Conflicts of interest
    Acknowledgements This work was supported by Ministry of Science and Technology (MOST107-2320-B-016-011-MY3) in Taiwan. The author, Chih-Ying Changchien, would like to thank Dr. Herng-Sheng Lee and Chi-Kang Chih for the mental support to complete this manuscript.
    Introduction MiRNAs are short (∼22 nucleotide), endogenously expressed non-protein coding RNAs that act as negative regulators of gene expression by inhibiting mRNA translation or promoting mRNA degradation through complementary base-pair binding (M.A. Valencia-Sanchez et al., 2006). The ability to interact with a huge number of target mRNAs leads to the expectation that miRNAs play important roles in coordinating many cellular processes, such as cell differentiation, proliferation, death, metabolism, tumorigenesis and heart disease (Bushati and Cohen, 2007). The diversity and abundance of miRNAs offer an enormous level of combinatorial possibilities to form a complex intertwined regulatory network between miRNAs and their targets (Inui et al., 2010).