IL-6 and Serum Amyloid A Synergy Mediates Angiotensin II–Induced Muscle Wasting

Abstract

Animal studies suggest that increased levels of circulating angiotensin II (AngII) could contribute to the loss of lean body mass in chronic kidney disease, but the mechanism by which this occurs is unclear. Here, AngII infusion increased circulating IL-6 and its hepatic production in wild-type mice, suggesting that AngII-induced inflammation may trigger muscle loss. AngII infusion also stimulated the suppressor of cytokine signaling (SOCS3) in muscle, which led to loss of insulin receptor substrate 1 (IRS-1), thereby impairing insulin/IGF-1 signaling and enhancing protein degradation. All of these responses to AngII were suppressed in IL-6 -deficient mice. Recombinant human IL-6 (rhIL-6) treatment of cultured myotubes only minimally increased SOCS3, however, suggesting the contribution of other mediators. Because AngII increases hepatic serum amyloid A (SAA) expression in an IL-6 -dependent manner, we treated wild-type mice with rhIL-6 and an SAA1-overexpressing adenovirus; the combination led to a significantly greater increase in SOCS3 and decrease in IRS-1 compared with either rhIL-6 or SAA1 alone. We observed similar effects on SOCS3 and IRS-1 when we treated cultured muscle myotubes with rhIL-6 and SAA1. Taken together, these results suggest an interorgan response to high levels of AngII: Hepatic production of IL-6 and SAA increases, and these mediators act synergistically to impair insulin/IGF-1 signaling, which promotes muscle proteolysis. Targeting the high levels of IL-6 and SAA in catabolic disorders might be a therapeutic approach to prevent muscle wasting.

Angiotensin Type 2 Receptor Signaling in Satellite Cells Potentiates Skeletal Muscle Regeneration

“…mediated by intermediate molecules, including cytokines and glucocorticoids (4,18), which is consistent with the fact that adult muscle fibers express little to no Ang II receptors (18,19). However, we demonstrated recently that Ang II also acts directly on skeletal muscle via its effects on satellite cells (19).…”

“…Ang (1-7), mainly produced from Ang II by ACE2 and signaling through the Mas receptor, has been reported to regulate skeletal muscle insulin sensitivity (34,35), decrease fibrosis, and improve muscle function in a mouse model of muscle dystrophy (36). It has been shown by us (2-9) and by others (10 -12) (4,18), which is consistent with the fact that adult muscle fibers express little to no Ang II receptors (18,19). However, recently, we discovered that satellite cells express the AT1R and that Ang II acts via these receptors to prevent satellite cell proliferation and suppress muscle regeneration (19).…”

Role of Integrin-β3 Protein in Macrophage Polarization and Regeneration of Injured Muscle

“…RT-PCR-RT-PCR was performed as described (15,16); the relative gene expression was calculated from cycle threshold values using 18 S RNA or GAPDH as an internal control (C t ; relative expression ϭ 2 (sample Ct Ϫ 18 S Ct)…”

Persistent Inflammation as a Catalyst for Other Risk Factors in Chronic Kidney Disease

“…In addition, a synergism between IL-6 and other catabolic substances that produce muscle loss have recently been demonstrated. First, Zhang et al (26) demonstrated a previously unrecognized role for serum amyloid A in acting synergistically with IL-6 to impair insulin/ IGF-1 signaling by increasing SOCS3 transcription, which results in muscle proteolysis (Figure 2A). They proposed that angiotensin II may stimulate an interaction between the liver and the skeletal muscle because the liver becomes the major source of IL-6 and serum amyloid A.…”