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EMBO Mol Med. 2018 Dec;10(12). pii: e9091. doi: 10.15252/emmm.201809091.

Metabolomes of mitochondrial diseases and inclusion body myositis patients: treatment targets and biomarkers.

Author information

1
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland.
2
Department of Medicine, University of Helsinki and Helsinki University Hospital, Helsinki, Finland.
3
Minerva Foundation Institute for Medical Research, Helsinki, Finland.
4
Research Programs Unit, Diabetes and Obesity, Obesity Research Unit, University of Helsinki, Helsinki, Finland.
5
Abdominal Centre, Endocrinology, Helsinki University Central Hospital and University of Helsinki, Helsinki, Finland.
6
Department of Child Neurology, Children's Hospital, University of Helsinki, Helsinki, Finland.
7
Metabolomics Unit, Institute for Molecular Medicine Finland FIMM, HiLIFE, University of Helsinki, Helsinki, Finland.
8
Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's University of London, London, UK.
9
Research Programs Unit, Molecular Neurology, Biomedicum-Helsinki, University of Helsinki, Helsinki, Finland anu.wartiovaara@helsinki.fi.
10
Department of Neurosciences, Helsinki University Hospital, Helsinki, Finland.
11
Neuroscience Centre, Helsinki Institute Life Science, University of Helsinki, Helsinki, Finland.

Abstract

Mitochondrial disorders (MDs) are inherited multi-organ diseases with variable phenotypes. Inclusion body myositis (IBM), a sporadic inflammatory muscle disease, also shows mitochondrial dysfunction. We investigated whether primary and secondary MDs modify metabolism to reveal pathogenic pathways and biomarkers. We investigated metabolomes of 25 mitochondrial myopathy or ataxias patients, 16 unaffected carriers, six IBM and 15 non-mitochondrial neuromuscular disease (NMD) patients and 30 matched controls. MD and IBM metabolomes clustered separately from controls and NMDs. MDs and IBM showed transsulfuration pathway changes; creatine and niacinamide depletion marked NMDs, IBM and infantile-onset spinocerebellar ataxia (IOSCA). Low blood and muscle arginine was specific for patients with m.3243A>G mutation. A four-metabolite blood multi-biomarker (sorbitol, alanine, myoinositol, cystathionine) distinguished primary MDs from others (76% sensitivity, 95% specificity). Our omics approach identified pathways currently used to treat NMDs and mitochondrial stroke-like episodes and proposes nicotinamide riboside in MDs and IBM, and creatine in IOSCA and IBM as novel treatment targets. The disease-specific metabolic fingerprints are valuable "multi-biomarkers" for diagnosis and promising tools for follow-up of disease progression and treatment effect.

KEYWORDS:

biomarker; inclusion body myositis; metabolomics; mitochondrial diseases

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