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| Status |
Public on Sep 17, 2019 |
| Title |
The effect of an NAD+ precursor vitamin B3, niacin, on muscle transcriptomic profiles of mitochondrial myopathy patients and healthy controls |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by high throughput sequencing
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| Summary |
Purpose: We examined the impact of niacin on muscle gene expression in mitochondrial myopathy patients and healthy controls.
Methods: Muscle transcriptomics profiles were generated using global transcriptomics analysis by RNA sequencing which was performed by the Beijing Genomic Institute (BGI) using their standard protocols
Results: The pathway enrichment analysis of RNA-sequencing data indicated that phagosome formation, serine/glycine/one-carbon pathways (de novo serine biosynthesis, purine degradation, glutathione metabolism), LXR/RXR activation, eicosanoid, glycoprotein 6, atherosclerosis, iron homeostasis and cAMP-mediated signalling pathways were among the most significantly changed in patients. Only five and two of the disease associated pathways remained significantly changed after 4- and 10-month supplementation, respectively, in patients as compared to controls. The most prominent niacin-related transcriptomic change in patients’ muscle (patient 10-months on niacin vs patient baseline) was wide-spread downregulation of mTOR-dependent cytoplasmic translation, involving a large number of cytoplasmic ribosome subunits as well as translation initiation factor eIF1. In patients, niacin activated also the peroxisome proliferator-activated receptor signaling pathway, known to induce mitochondrial biogenesis. Niacin also led to decreased atherosclerosis signaling including lowered apolipoprotein expression in patients. The healthy control muscles showed only few changes after 4-months of niacin. To examine in detail the effects of NAD-booster niacin in the mitochondrial integrated stress response (ISRmt), we studied the effects NAD+ boosting for the expression of 24 ISRmt target genes in the patients’ muscle. The analysis confirmed wide-spread induction of these genes, but their expression was unaffected by niacin (ATF5 and its targets ASNS, TRIB3, FGF21, GDF15, MTHFD2, and MTHFD1L; de novo synthesis of serine, PSAT1, PHGDH and SHMT2; glutathione metabolism GPX3 and GSR; and unfolded protein response ER CHOP).
Conclusions: These results showed that niacin modulated the expression of disease associated pathways and suppressed mTOR signalling in patients but niacin did not affect disease-related ISRmt signalling.
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| Overall design |
In this small open-label study, we recruited five PEO patients either with sporadic single mtDNA deletions or a mutation in a mtDNA maintenance gene Twinkle. For every patient, two gender- and age-matched healthy controls were recruited. Two controls discontinued after 2 months. Patients manifested with only myopathic symptoms. Study subjects were supplemented with a 1 g/day dose of niacin, which is an NAD+ precursor vitamin B3 form with a proven safety record in humans. Clinical examinations and collection of blood samples and muscle biopsies were performed in patients at the time points 0, 4 and 10 months and in controls at 0 and 4 months.
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| Contributor(s) |
Pirinen E, Suomalainen Wartiovaara A |
| Citation(s) |
31523008 |
| Submission date |
Apr 15, 2019 |
| Last update date |
Sep 17, 2019 |
| Contact name |
Virginia Brilhante |
| Organization name |
University of Helsinki
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| Department |
Stem Cells and Metabolism Research Program
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| Lab |
Suomalainen-Wartiovaara
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| Street address |
Haartmaninkatu 8
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| City |
Helsinki |
| State/province |
Uusimaa |
| ZIP/Postal code |
00290 |
| Country |
Finland |
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| Platforms (1) |
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| Samples (29)
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| Relations |
| BioProject |
PRJNA532885 |
| SRA |
SRP192572 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE129811_AWVM29samples.DESeq.normCounts.csv.gz |
3.9 Mb |
(ftp)(http) |
CSV |
| GSE129811_AWVM29samples.HTSeq.counts.tsv.gz |
1.4 Mb |
(ftp)(http) |
TSV |
| GSE129811_Readme_PatientControlMatching.txt |
147 b |
(ftp)(http) |
TXT |
SRA Run Selector |
| Raw data are available in SRA |
| Processed data are available on Series record |
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