Abstract
Skeletal muscle atrophy, referred to as sarcopenia, is often observed in chronic kidney disease (CKD) patients, especially in patients who are undergoing hemodialysis. The purpose of this study was to determine whether uremic toxins are involved in CKD-related skeletal muscle atrophy. Among six protein-bound uremic toxins, indole containing compounds, indoxyl sulfate (IS) significantly inhibited proliferation and myotube formation in C2C12 myoblast cells. IS increased the factors related to skeletal muscle breakdown, such as reactive oxygen species (ROS) and inflammatory cytokines (TNF-α, IL-6 and TGF-β1) in C2C12 cells. IS also enhanced the production of muscle atrophy-related genes, myostatin and atrogin-1. These effects induced by IS were suppressed in the presence of an antioxidant or inhibitors of the organic anion transporter and aryl hydrocarbon receptor. The administered IS was distributed to skeletal muscle and induced superoxide production in half-nephrectomized (1/2 Nx) mice. The chronic administration of IS significantly reduced the body weights accompanied by skeletal muscle weight loss. Similar to the in vitro data, IS induced the expression of myostatin and atrogin-1 in addition to increasing the production of inflammatory cytokines by enhancing oxidative stress in skeletal muscle. These data suggest that IS has the potential to accelerate skeletal muscle atrophy by inducing oxidative stress-mediated myostatin and atrogin-1 expression.
Highlights
Found that inflammatory cytokines such as TNF-α, IL-6 and TGF-β1 levels, which were known to cause skeletal muscle break down, were increased in muscles of chronic kidney disease (CKD) mice, whereas the inhibition of myostatin reduced the levels of these cytokines in the circulation[9]
The findings reported here indicate that indoxyl sulfate (IS) is a potent uremic toxin that accelerates the development of skeletal muscle atrophy associated with CKD by inducing the oxidative stress-mediated expression of myostatin and atrogin-1
We focused on six protein-bound solutes, namely, IS, indole acetic acid (IA), p-cresyl sulfate (PCS), hippuric acid (HA), kynurenic acid (KA) and carboxy-4-methyl-5-propyl-2 -furanpropanoic acid (CMPF) due to their high accumulation under CKD conditions and their detrimental effects
Summary
Found that inflammatory cytokines such as TNF-α, IL-6 and TGF-β1 levels, which were known to cause skeletal muscle break down, were increased in muscles of CKD mice, whereas the inhibition of myostatin reduced the levels of these cytokines in the circulation[9]. Uremic toxins are accumulated in the body under CKD conditions and are considered to exert detrimental actions. Recent accumulating evidence has clarified that protein-bound uremic toxins are related to renal toxicity and CKD complications, including cardiovascular damage caused by enhanced oxidative stress and inflammation[19,20]. We first tested the in vitro effects of six protein-bound uremic toxins on cell proliferation and differentiation (myotube formation), or oxidative stress using a mouse myoblast cell line (C2C12), and its effects on inflammation, myostatin expression, muscle atrophy- or myogenic-related genes expression and Akt phosphorylation in C2C12 cells are evaluated. The findings reported here indicate that IS is a potent uremic toxin that accelerates the development of skeletal muscle atrophy associated with CKD by inducing the oxidative stress-mediated expression of myostatin and atrogin-1
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