TLR13 contributes to skeletal muscle atrophy by increasing insulin resistance in chronic kidney disease

Abstract

Objectives Insulin resistance in chronic kidney disease (CKD) stimulates muscle wasting, but the molecular processes behind the resistance are undetermined. However, inflammation in skeletal muscle is implicated in the pathogenesis of insulin resistance and cachexia. Toll‐like receptors (TLRs) are known to regulate local innate immune responses, and microarray data have shown that Tlr13 is upregulated in the muscles of mice with CKD, but the relevance is unknown. Materials and Methods We performed in vitro experiments in C2C12 myotubes and constructed a CKD murine model using subtotal nephrectomy to conduct experiments in vivo. Results Tlr13 expression was stimulated in C2C12 myotubes treated with uremic serum. The expression of Tlr13 was also upregulated in the tibialis anterior muscles of mice with CKD. Tlr13 knockdown with siRNAs in skeletal muscle cells decreased insulin resistance despite the inclusion of uremic serum. This led to increased levels of p‐AKT and suppression of protein degradation. Using immunofluorescence staining and coimmunoprecipitation assay, we found that TLR13 recruits IRF3, which activates Irf3 expression, resulting in decreased AKT activity. Moreover, insulin resistance and proteolysis are re‐induced by Irf3 overexpression under Tlr13 deletion. Conclusions Our results indicate that TLR13 is involved in CKD‐mediated insulin resistance in muscle. In catabolic conditions where insulin signaling is impaired, targeting TLR13 may improve insulin sensitivity and prevent muscle atrophy.

Adiponectin receptors activation performs dual effects on regulating myogenesis and adipogenesis of young and aged muscle satellite cells

“…In this study, we found that the different manifestations of MUSC differentiation in young and aged states had little to do with the AMPK and PPAR‐α signalling pathways; in contrast, the Wnt and PI3K signalling pathways play an important role in adiponectin signalling pathways and are both involved in modulating muscle and adipose metabolism 40,41 . The activated PI3K signalling pathway can attenuate lipid accumulation, rescues myotube formation and ameliorate skeletal muscle atrophy 42–45 . Wnt signalling participates in the regulation of satellite cell differentiation and self‐renewal, and this pathway is poorly activated in mature skeletal muscles 46 .…”

“… 40 , 41 The activated PI3K signalling pathway can attenuate lipid accumulation, rescues myotube formation and ameliorate skeletal muscle atrophy. 42 , 43 , 44 , 45 Wnt signalling participates in the regulation of satellite cell differentiation and self‐renewal, and this pathway is poorly activated in mature skeletal muscles. 46 Activated β‐catenin signalling can increase myogenin expression to stimulate myoblast differentiation and inhibit adipogenic differentiation.…”

Inflammation: Roles in Skeletal Muscle Atrophy

“…Skeletal muscle atrophy is a common and serious complication of CKD. Generally, muscle atrophy caused by CKD is attributed to excessive activation of proteolysis pathways [ 133 ]. Potential causes of muscle atrophy in CKD include metabolic acidosis, inflammation, and insulin resistance [ 134 , 135 , 136 ].…”

“…Potential causes of muscle atrophy in CKD include metabolic acidosis, inflammation, and insulin resistance [ 134 , 135 , 136 ]. Evidence has suggested that pro-inflammatory factors IL-6, TNF-α, and TLRs can accelerate proteolysis and insulin resistance in CKD [ 133 ]. Overexpression of TLR2 and TLR4 can upregulate IL-6, facilitating muscle atrophy [ 137 ].…”

“…A microarray analysis indicated that TLR13 was upregulated in a mouse model of CKD, possibly leading to the overactivation of the immune system along with insulin resistance. It was also found that TLR13 can interact with interferon regulatory factor 3 (IRF3), resulting in a decrease in Akt phosphorylation, while knockdown of IRF3 prevents TLR13-induced insulin resistance and increases p-Akt [ 133 ]. A previous study found that IGF-1 levels seem to be independent of renal function, but IGF-1 binding protein-3 levels increase with the decrease in the glomerular filtration rate, which may lead to a reduced affinity of IGF-1 for IGF-1R in skeletal muscle [ 138 ].…”