Introduction and Objective: miRNAs are emerging as significant metabolic regulators and are altered at both the cellular and secreted levels in diseases, including type 2 diabetes (T2D). However, to what extent alterations in miRNA content and secretion are cell-intrinsic, and how they play a role in disease pathogenesis, remains unclear.Methods: In the present study, we have addressed these questions using a human disease-in-a-dish model in which iPS cells from T2D patients and controls were differentiated into myoblasts (iMyos) and their cellular and secreted miRNAs were assessed.Results: We show that iMyos from T2D exhibit cell-intrinsic alterations in both miRNA expression and their secretion in small extracellular vesicles (sEVs/exosomes). Integration of miRNA-predicted targets with transcriptomic and proteomic analyses revealed that cellular miRNAs altered in T2D iMyos were associated with coordinated changes in their predicted targets, with a substantially greater impact on protein abundance than on mRNA levels. This pattern was confirmed experimentally. Thus, overexpression of selected T2D-associated miRNAs in control iMyos reduced target-protein expression, often with minimal change in target mRNA level. miRNAs secreted in sEVs from T2D iMyos displayed even more pronounced changes than cellular miRNAs, indicating T2D also affects miRNA sorting and release. Interestingly, these secreted-miRNAs were enriched for those targeting pathways involved in insulin signaling and mitochondrial metabolism. Indeed, while treatment of human white adipocytes with sEVs derived from healthy iMyos donors enhanced glucose uptake, treatment with sEVs from T2D iMyos or their miRNAs blunted glucose uptake and impaired mitochondrial functions in recipient fat.Conclusion: Thus, both dysregulated miRNA expression and secretion contribute to altered gene/protein expression in the myoblast itself, as well as targeting metabolic and signaling gene/protein in other tissues, such as adipose tissue, thereby contributing to the pathogenesis of T2D.
A. Nawaz: None. M. Lino: None. Y. Watanabe: None. A. Ghosh: None. N. Haider: None. A. Gattu: None. C. Kahn: Consultant; Current; TIXiMED, Alnylam Pharmaceuticals, Inc. Board Member; Current; 1825 Therapeutics. Consultant; Ended; Cellarity.
NIH grant (DK082659 to C.R.K)Manpei Suzuki Diabetes Foundation Fellowship to A.N
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