The loss of the microRNA miR-378 improved the dystrophic phenotype in a mouse model (mdx) with Duchenne muscular dystrophy (DMD), according to a new study published in Scientific Reports.

“The most important finding is that we identified miR-378 as a factor that regulates not only muscle-related dysfunctions, as we showed previously, but also metabolic disturbances in the mdx model of DMD, as reported in the current study,” the authors said.

Hepatic transcriptome analysis identified 194 differentially expressed genes between mdx mice and mdx mice devoid of miR-378 (mdx/miR-378−/−). Those were particularly associated with lipid and carbohydrate metabolism.


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Several genes involved in the regulation of glucose metabolism were upregulated in dystrophic mice, while genes related to lipid metabolism disorder were both upregulated and downregulated. Muscle-specific microRNAs were also found to be differentially expressed in mdx and mdx/miR-378−/− mice, in particular miR-1 and miR-133. Serum levels of these microRNAs were higher in mdx mice compared to wild-type (WT) mice but decreased with miR-378 knockdown.

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The lack of miR-378 in mdx mice led to a faster glucose clearance in the glucose tolerance test (GTT). The authors observed a slightly lower glucose level in mdx/miR-378−/− mice compared to WT and mdx mice even under fed conditions (random glucose). The mdx mice showed mild glucose intolerance during GTT. However, glucose was rapidly cleared in mdx/miR-378−/− mice, and it was kept at lower levels than those observed in mdx mice at every time point.

The mdx/miR-378−/− mice were also able to normalize the content of glycogen in the liver, which was markedly reduced in mdx mice when compared to WT mice. They also exhibited higher serum insulin concentration under fed conditions. Moreover, the lack of miR-378 decreased the levels of hepatic interleukin-6, tumor necrosis factor α, and its receptor, which have been associated with glycogen degradation and insulin resistance.

“Although more mechanistic studies are warranted, we believe that the downregulation of miR-378 might serve as a promising therapeutic approach to mitigate the multifaceted symptoms of DMD,” the authors concluded.

miR-378 is a well-recognized metabolism regulator and this study shows for the first time its importance for metabolic alterations under dystrophic conditions.

Reference

Podkalicka P, Mucha O, Kaziród K, et al. miR-378 affects metabolic disturbances in the mdx model of Duchenne muscular dystrophy. Sci Rep. 2022;12(1):3945. doi:10.1038/s41598-022-07868-z