Skeletal myopathy in CKD: a comparison of adenine-induced nephropathy and 5/6 nephrectomy models in mice

Abstract

Preclinical models of chronic kidney disease (CKD) are critical to investigate the mechanisms of disease and to evaluate novel therapeutics aimed to treat CKD-associated pathologies. The objective of the present study was to compare the adenine diet and 5/6 nephrectomy (5/6 Nx) models in mice. Male and female 10-week-old C57BL/6J mice (N=5-9/sex/group) were randomly allocated to CKD groups (0.2-0.15% adenine-supplemented diet or 5/6 Nx surgery) or corresponding control groups (casein diet or sham surgery). Glomerular filtration rate was reduced to a similar level in adenine and 5/6 Nx mice (adenine male: 81.1 ± 41.9 µL/min vs. 5/6 Nx male: 160 ± 80.9 µL/min, P=0.5875; adenine female: 112.9 ± 32.4 µL/min vs. 5/6 Nx female: 107.0 ± 45.7 µL/min, P=0.9995). Serum metabolomics analysis indicated that established uremic toxins were robustly elevated in both CKD models, although some differences were observed between CKD models (i.e. p-Cresol sulfate). Dysregulated phosphate homeostasis was observed in the adenine model only, whereas calcium homeostasis was disturbed in male mice with both models. Muscle mass and myofiber cross-sectional area of extensor digitorum longus and soleus muscles were ~18-24% smaller in male CKD mice regardless of model, but were not different in female CKD mice (P>0.05). Skeletal muscle mitochondrial respiratory function was significantly decreased (19-24%) in CKD mice in both models and sexes. These findings demonstrate that adenine diet and 5/6 Nx models of CKD have similar levels of renal dysfunction and skeletal myopathy, but had less mortality (P<0.05 for both sexes) compared with the 5/6 Nx model.