Transgenic overexpression of miR-486 and sAnk1.5 does not alter glucose handling in mice

Recent studies have shown that the C allele of SNP rs508419 is associated with susceptibility to Type 2 diabetes (T2D). This SNP lies within the muscle-specific P2 promoter of human ANK1, which drives transcription of the sAnk1.5 isoform and miR-486. The C allele increases P2 promoter activity, resulting to higher levels of sAnk1.5 transcript and protein in striated muscles. We now present the first evidence that in skeletal muscle of individuals homozygous for the rs508419 C allele, also the hsa-miR-486-5p is transcribed at higher levels. This raises the question of whether T2D susceptibility may be associated with simultaneous overexpression of miR-486-5p and sAnk1.5. To test this hypothesis, we generated and characterized double transgenic (D-Tg) mice that selectively overexpress both mmu-miR-486-5p and sAnk1.5 in skeletal muscle tissue. Analysis of sAnk1.5 and miR-486-5p expression in D-Tg mouse showed that despite both transgenes were significantly upregulated, a discrepancy between sAnk1.5 mRNA and protein levels was observed, suggesting that sAnk1.5 protein levels are further regulated by post-translational mechanism. D-Tg mice were monitored from 2 to 12 months of age to assess body weight, fat and lean mass, blood glucose levels under fasting conditions, as well as during intraperitoneal glucose tolerance tests and insulin tolerance tests, performed under either standard or high fat diet conditions. No differences were observed between D-Tg and age-matched wild type control mice for any of the parameters tested, indicating that the link between rs508419 and susceptibility to T2D cannot be ascribed to increased expression of miR-486-5p and sAnk1.5 in skeletal muscle.