Metabolic Advantage of 25(OH)D(3) versus 1,25(OH)(2)D(3) Supplementation in Infantile Nephropathic Cystinosis-Associated Adipose Tissue Browning and Muscle Wasting

Manifestations of infantile nephropathic cystinosis (INC) often include cachexia and deficiency of circulating vitamin D metabolites. We examined the impact of 25(OH)D(3) versus 1,25(OH)(2)D(3) repletion in Ctns null mice, a mouse model of INC. Six weeks of intraperitoneal administration of 25(OH)D(3) (75 μg/kg/day) or 1,25(OH)(2)D(3) (60 ng/kg/day) resulted in Ctns(−/−) mice corrected low circulating 25(OH)D(3) or 1,25(OH)(2)D(3) concentrations. While 25(OH)D(3) administration in Ctns(−/−) mice normalized several metabolic parameters characteristic of cachexia as well as muscle function in vivo, 1,25(OH)(2)D(3) did not. Administration of 25(OH)D(3) in Ctns(−/−) mice increased muscle fiber size and decreased fat infiltration of skeletal muscle, which was accompanied by a reduction of abnormal muscle signaling pathways. 1,25(OH)(2)D(3) administration was not as effective. In conclusion, 25(OH)D(3) supplementation exerts metabolic advantages over 1,25(OH)(2)D(3) supplementation by amelioration of muscle atrophy and fat browning in Ctns(−/−) mice.