Abstract
Although Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. We propose that microRNA-378a (miR-378) alters carbohydrate and lipid metabolism in dystrophic mdx mice. In our study, we utilized double knockout animals which lacked both dystrophin and miR-378 (mdx/miR-378−/−). RNA sequencing of the liver identified 561 and 194 differentially expressed genes that distinguished mdx versus wild-type (WT) and mdx/miR-378−/− versus mdx counterparts, respectively. Bioinformatics analysis predicted, among others, carbohydrate metabolism disorder in dystrophic mice, as functionally proven by impaired glucose tolerance and insulin sensitivity. The lack of miR-378 in mdx animals mitigated those effects with a faster glucose clearance in a glucose tolerance test (GTT) and normalization of liver glycogen levels. The absence of miR-378 also restored the expression of genes regulating lipid homeostasis, such as Acly, Fasn, Gpam, Pnpla3, and Scd1. In conclusion, we report for the first time that miR-378 loss results in increased systemic metabolism of mdx mice. Together with our previous finding, demonstrating alleviation of the muscle-related symptoms of DMD, we propose that the inhibition of miR-378 may represent a new strategy to attenuate the multifaceted symptoms of DMD.
Highlights
Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder
Both aspartate aminotransferase (AST, Fig. 1D) and alanine aminotransferase (ALT, Fig. 1E), whose levels increase as a result of both liver and muscle damage—as in the case of DMD—were markedly elevated in the mdx mice under normal fed conditions and after fasting overnight
We comprehensively described the secondary consequences of dystrophin loss associated with alterations in systemic metabolism and we proposed the inhibition of miR-378 as a novel approach to mitigating those abnormalities, at least partially
Summary
Duchenne muscular dystrophy (DMD) primarily affects muscle tissues, the alterations to systemic metabolism manifested in DMD patients contribute to the severe phenotype of this fatal disorder. Systemic alterations in the metabolism of carbohydrates and lipids accompanied by cases of impaired glucose tolerance and insulin sensitivity are manifested by DMD patients and mouse models of the disease, including mdx mice and golden retriever muscular dystrophy (GRMD) d ogs[9–13]. Though a few mutation-specific compounds are used in clinical settings and other cell and gene therapybased approaches are under extensive investigation, drugs that act mostly as anti-inflammatory agents, such as glucocorticoids (GCs), still serve as the gold standard of care for all patients suffering from DMD14 Apart from their indisputable beneficial effects in prolonging ambulation and improving the quality of the patient’s life, they, entail a list of multi-organ side effects[15]. We have recently studied miR-378a (miR-378), embedded in the first intron of the peroxisome proliferator-activated receptor-gamma coactivator 1β (Ppargc1b) gene
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