Changes of insulin-like growth factor 1 axis in chronic kidney disease and its role in skeletal muscle atrophy

Abstract

Objective: To investigate the changes of insulin-like growth factor 1 (IGF-1) axis in chronic kidney disease (CKD) and its role in skeletal muscle atrophy. Methods: A total of 240 patients with CKD stage 1-5 (without dialysis treatment) were included between August 2016 and February 2017. Serum IGF-1 and IGF-1 binding protein-3 (IGFBP-3) were measured using chemiluminescence, and the influencing factors of serum IGF-1 and IGFBP-3 were analyzed. Besides, male Sprague-Dawley rats (200-250 g) were randomly assigned to the sham-operated control group (Control, n=15) and the 5/6 nephrectomy group (n=15) as CKD animal model. The expressions of local IGF-1 and IGF-1 receptor (IGF-1R) of skeletal muscles were evaluated at the level of transcription and protein by real-time PCR and Western blotting. Results: There was no significant correlation between changes of serum IGF-1 level and estimated glomerular filtration rate (eGFR) (r=-0.066, P=0.307). However, after multivariable adjustment, serum IGFBP-3 increased with decreasing of eGFR (r=-0.181, P=0.005) in adult CKD patients. In multivariate analysis, age, eGFR, serum cholesterol level and 24 h urinary protein quantification were independent factors of serum IGFBP-3 in patients with CKD (R2=0.243, P<0.001). Animal experiments showed that the expression of IGF-1 mRNA and protein decreased in skeletal muscles of CKD rats. Expressions of IGF-1R mRNA and protein were slightly reduced and phosphorylation of IGF-1R was severely impaired in skeletal muscles of CKD rats. Conclusions: IGF-1 levels seem to be independent of renal function, but IGFBP-3 levels increased with decreasing of eGFR, which may cause a low affinity of IGF-1 with IGF-1R in skeletal muscles. Low affinity of IGF-1 with IGF-1R, as well as the decreasing of IGF-1 synthesis could lead to disorders of IGF-1R phosphorylation, and thus cause atrophy of skeletal muscles.