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  • AMG-517 synthesis MAPKs are a family of


    MAPKs are a family of phosphorylating enzymes that orchestrate various cellular response in proliferation, apoptosis, inflammation, stress response, and energy metabolism [11]. There are at least four major members including extracellular signal-regulated kinase 1 and 2 (ERK1/2), p38 mitogen-activated protein kinase (p38 MAPK) and c-Jun N-terminal kinases (JNKs) [12]. ERK is mostly activated by mitogenic growth factors; in contrast, JNK and p38 are activated in response to stress stimulation and inflammatory cytokines [13]. It has been implicated that MAPKs regulate myocyte growth, proliferation and fiber type through transcriptional regulation [14]. Activation of MAPKs play critical roles in muscle atrophy [15]. Elevated level of phosphorylated p38 and ERK are observed in muscle biopsy from chronic obstructive pulmonary disease patients [16]. Genetic ablation of JNK3 ameliorates the progression of spinal muscular dystrophy [17]. Under uremia conditions, extensive ROS influx causes enhanced activity of ERKs, JNKs, and p38 MAPKs in a number of different cell types [18]. However, the putative mechanism remains unclear that how specific MAPK molecules participate in IS-mediated uremic sarcopenia. Literature reviews have indicated two fundamental protein degradation mechanisms in muscle atrophy, the ubiquitin-proteasome and the autophagy-lysosome systems [19,20]. Autophagy is necessary for quality control of intracellular protein and enhanced in muscle cells during catabolic conditions [21]. One of the most typical proteins is microtubule-associated protein 1A/1B-light chain 3 (LC3) that functions as the indicator of autophagy process [22]. The increased ratio of LC3-II to LC3-I found in CKD muscle is not fully elucidated [23]. Evidences implicates autophagy as response for removal of ROS-damaged proteins in uremic status [24]. It is currently ambiguous whether antioxidant will rescue IS-mediated myocyte autophagy. On the other hand, there are two muscle specific enzymes, muscle RING finger 1 (MuRF1) and muscle atrophy F-box (MAFbx)/atrogin1, in the group of E3 ubiquitin ligases [25]. MuRF1 mediates the breakdown of various structural proteins, such as AMG-517 synthesis [19], myosin binding protein C and myosin light chains (MLC) [26]. For MAFbx/atrogin1, studies reveal its capability to ubiquitinate sarcomeric proteins [27] and transcriptional factors of muscle protein synthesis, like MyoD [28] and eIF3-f [29]. In CKD muscle, elevated expressions of MuRF1 and MAFbx/atrogin1 are noticed and defined as the process of muscle proteolysis. Additional investigations will be needed to discover the contribution of peculiar MAPK module that switch on muscle wasting signaling. In C2C12 myotube model, we explored IS effect on MAPKs activation and degradation-related proteins (LC3, MAFbx, MuRF1), then define the interplay between MAFbx and specific MAPK molecules via ROS production.
    Materials and methods
    Discussion Applying uremic milieu C2C12 myotube model, we demonstrated that the interplay among p-ERK1/2, p-JNK and ROS engaged skeletal muscle atrophy. The concentrations of IS in this study was determined by previous serum analysis on CKD patients [32,33]. There was no significant cellular death in IS dose up to 1.2 mM. In contrast, the decrease of myocyte mean size was observed in 0.4 mM IS stimulation. Reviews regarding muscle atrophy had pointed out the contribution and coexistence of myocyte apoptosis [34]. However, this theory may be sometimes unjustified, for example, caspase-3 mediated actin degradation as the initial response to catabolic conditions, rather than apoptosis [35]. As a result, this observation has prompted us that myotube atrophy might be prior to cellular apoptosis in IS dose-accumulated myopathy. Tracing atrophy-related proteins might provide more sensitive approach in detecting uremic sarcopenia. During acute kidney injury (AKI) and CKD, IS has been reported to substantially retained in blood circulation and various tissues [36,37]. It remains ambiguous that AKI and CKD might share common mediators of IS-induced muscle toxicity. In current study, increased ERK, JNK, and p38 phosphorylation were identified in C2C12 myotubes after IS exposure for both 1 h and 24 h. Sustained activation of MAPKs cascade are evidenced in renal biopsied from chronic uremia and correlated with fibrosis changes [38,39]. In acute renal failure, MAPK phosphorylation may be interpreted as protective role against ROS in renal proximal tubular cells [40]. In comparison, the precise role of muscle MAPKs in uremia remains poorly defined, especially AKI-relevant muscle weakness. Our findings of consistent MAPKs upregulation might therefore provide an intriguing point of uremic muscle wasting under acute and chronic conditions.