Ketogenic diet containing medium-chain triglyceride ameliorates transcriptome disruption in skeletal muscles of rat models of duchenne muscular dystrophy

• Published in: Biochemistry and biophysics reports Vol. 32; p. 101378
• Main Authors: Fujikura, Yuri, Yamanouchi, Keitaro, Sugihara, Hidetoshi, Hatakeyama, Masaki, Abe, Tomoki, Ato, Satoru, Oishi, Katsutaka
• Format: Journal Article
• Language: English
• Published: Elsevier B.V 01.12.2022; Elsevier
• Subjects: Duchenne muscular dystrophy; Ketogenic diet; Ketone bodies; Short Communication; Skeletal muscle; Transcriptome; Transcriptome; DEG; KR; GO; Ketone bodies; MCTKD; SERCA; FPKM; TA; Ketogenic diet; Skeletal muscle; DAPC; PC; Duchenne muscular dystrophy; ND; KD; DMD; WT; MCT
• ISSN: 2405-5808; 2405-5808
• DOI: 10.1016/j.bbrep.2022.101378

Duchenne muscular dystrophy (DMD) is a myopathy characterized by progressive muscle weakness caused by a mutation in the dystrophin gene on the X chromosome. We recently showed that a medium-chain triglyceride-containing ketogenic diet (MCTKD) improves skeletal muscle myopathy in a CRISPR/Cas9 gene-edited rat model of DMD. We examined the effects of the MCTKD on transcription profiles in skeletal muscles of the model rats to assess the underlying mechanism of the MCTKD-induced improvement in DMD. DMD rats were fed MCTKD or normal diet (ND) from weaning to 9 months, and wild-type rats were fed with the ND, then tibialis anterior muscles were sampled for mRNA-seq analysis. Pearson correlation heatmaps revealed a one-node transition in the expression profile between DMD and wild-type rats. A total of 10,440, 11,555 and 11,348 genes were expressed in the skeletal muscles of wild-type and ND-fed DMD rats the MCTKD-fed DMD rats, respectively. The MCTKD reduced the number of DMD-specific mRNAs from 1624 to 1350 and increased the number of mRNAs in common with wild-type rats from 9931 to 9998. Among 2660 genes were differentially expressed in response to MCTKD intake, the mRNA expression of 1411 and 1249 of them was respectively increased and decreased. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses suggested that the MCTKD significantly suppressed the mRNA expression of genes associated with extracellular matrix organization and inflammation. This suggestion was consistent with our previous findings that the MCTKD significantly suppressed fibrosis and inflammation in DMD rats. In contrast, the MCTKD significantly increased the mRNA expression of genes associated with oxidative phosphorylation and ATP production pathways, suggesting altered energy metabolism. The decreased and increased mRNA expression of Sln and Atp2a1 respectively suggested that Sarco/endoplasmic reticulum Ca2+-ATPase activation is involved in the MCTKD-induced improvement of skeletal muscle myopathy in DMD rats. This is the first report to examine transcription profiles in the skeletal muscle of CRISPR/Cas9 gene-edited DMD model rats and the effect of MCTKD feeding on it. •We evaluated the effects of an MCTKD on the global transcriptome of DMD rats.•DMD rats are suitable models of human DMD for assessing transcriptome changes.•MCTKD suppressed fibrosis and inflammatory pathways at the transcriptional level.•MCTKD upregulated oxidative phosphorylation and ATP production pathways.•MCTKD might activate SERCA at the transcriptional level.