MicroRNAs (miRNAs) are short noncoding RNAs that regulate gene expression post-transcriptionally and have been implicated in metabolic regulation. In metabolic disease states, including type 2 diabetes (T2D), miRNA profiles can be altered at the level of cells and in circulation. It has been unclear whether these alterations reflect the in vivo environment or are intrinsic to the affected cell type. This study examined whether skeletal muscle displays cell-intrinsic changes in miRNA expression and secretion that could act as epigenetic regulators of protein expression and intercellular metabolic signaling.
To isolate cell-autonomous effects, the authors used a disease-in-a-dish approach. Induced pluripotent stem cells (iPSCs) derived from donors with T2D and from control donors were differentiated into myoblasts (referred to as iMyos). This in vitro system enables assessment of miRNA expression and secretion by muscle-lineage cells in the absence of circulating factors and tissue milieu present in vivo.
Profiling of intracellular miRNAs in iMyos revealed that myoblasts derived from T2D donors exhibited distinct, cell-intrinsic alterations in miRNA expression compared with control iMyos. These alterations were present in the cellular miRNA complement, indicating that skeletal muscle cells retain disease-associated miRNA signatures independent of systemic influences.
The study integrated miRNA predicted targets with parallel transcriptomic (mRNA) and proteomic datasets from the same iMyos. miRNAs altered in T2D iMyos were associated with coordinated changes in their predicted target genes. Notably, the influence of altered miRNAs was substantially more evident at the protein level than at the mRNA level, consistent with predominant post-transcriptional regulation by miRNAs. The differential impact on protein versus mRNA expression was further supported by downstream validation experiments described below.
To validate the regulatory potential of miRNAs identified as upregulated in T2D iMyos, the authors overexpressed selected miRNAs in control iMyos. Overexpression recapitulated the pattern observed in T2D cells, confirming that increased levels of these miRNAs can drive changes in target protein expression. The validation emphasizes that altered miRNA abundance in muscle cells can function as an epigenetic regulator of protein networks.
Beyond intracellular changes, iMyos from T2D donors displayed pronounced changes in miRNAs packaged into small extracellular vesicles (sEVs)/exosomes. The sEV-associated miRNA profile in T2D iMyos suggested altered miRNA sorting and release mechanisms in diseased muscle cells. Predicted targets of secreted miRNAs were enriched for metabolic pathways, including insulin signaling and mitochondrial metabolism, indicating potential distal effects of muscle-derived vesicular miRNAs on other tissues.
The functional consequences of differential sEV miRNA content were tested using recipient human white adipocytes. sEVs harvested from control iMyos increased glucose uptake and improved mitochondrial function in adipocytes, demonstrating a beneficial intercellular signaling capacity. In contrast, sEVs derived from T2D iMyos failed to enhance glucose uptake or mitochondrial function, indicating that disease-associated changes in secreted miRNAs impair the ability of muscle-derived vesicles to favorably modulate adipocyte metabolism.
These findings support a model in which skeletal muscle in T2D harbors cell-intrinsic changes in both miRNA expression and selective miRNA secretion via sEVs/exosomes. Altered miRNAs act primarily at the protein level to regulate pathways related to respiration, membrane trafficking, RNA metabolism, insulin signaling, and mitochondrial function. The differential effect of sEVs on adipocyte glucose uptake and mitochondrial activity suggests that muscle-derived miRNAs could contribute to intertissue metabolic dysregulation in T2D. The results highlight miRNA expression and vesicular miRNA sorting as potential targets for mechanistic study and, ultimately, therapeutic modulation; however, details such as the specific miRNA identities, donor numbers, and quantitative effect sizes were not reported in the provided abstract.
The authors declared no competing interests in the source report.
(Reference: Nawaz A et al., Signal Transduct Target Ther. 2026; PMID: 42680724; DOI: 10.1038/s41392-026-02846-7.)