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Multiomic characterization of disease progression in mice lacking dystrophin.

ABSTRACT: Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of age. Integration of RNA-seq, mass spectrometry-based metabolomic and lipidomic data obtained in muscle and blood samples by Multi-Omics Factor Analysis (MOFA) led to the identification of 8 latent factors that explained 78.8% of the variance in the multiomic dataset. Latent factors could discriminate dystrophic and healthy mice, as well as different time-points. MOFA enabled to connect the gene expression signature in dystrophic muscles, characterized by pro-fibrotic and energy metabolism alterations, to inflammation and lipid signatures in blood. Our results show that omic observations in blood can be directly related to skeletal muscle pathology in dystrophic muscle.

SUBMITTER: Signorelli M

PROVIDER: S-EPMC10065259 | biostudies-literature | 2023

REPOSITORIES: biostudies-literature

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Multiomic characterization of disease progression in mice lacking dystrophin.

Signorelli Mirko M Tsonaka Roula R Aartsma-Rus Annemieke A Spitali Pietro P

PloS one 20230331 3

Duchenne muscular dystrophy (DMD) is caused by genetic mutations leading to lack of dystrophin in skeletal muscle. A better understanding of how objective biomarkers for DMD vary across subjects and over time is needed to model disease progression and response to therapy more effectively, both in pre-clinical and clinical research. We present an in-depth characterization of disease progression in 3 murine models of DMD by multiomic analysis of longitudinal trajectories between 6 and 30 weeks of ...[more]

PMID: 37000843

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Project description:Ift88 gene mutations cause primary cilia loss and polycystic kidney disease (PKD) in mice. Nephron intraflagellar transport protein 88 (Ift88) knockout (KO) at 2 mo postnatal does not affect renal histology at 4 mo postnatal and causes PKD only in males by 11 mo postnatal. To identify factors associated with PKD development, kidneys from 4-mo-old male and female control and Ift88 KO mice underwent transcriptomic, proteomic, Western blot, metabolomic, and lipidomic analyses. mRNAs involved in extracellular matrix (ECM) synthesis and degradation were selectively upregulated in male KO mice. Proteomic analysis was insufficiently sensitive to detect most ECM components, while Western blot analysis paradoxically revealed reduced fibronectin and collagen type I in male KO mice. Only male KO mice had upregulated mRNAs encoding fibrinogen subunits and receptors for vascular endothelial growth factor and platelet-derived growth factor; period 2, period 3, and nuclear receptor subfamily 1 group D member 1 clock mRNAs were selectively decreased in male KO mice. Proteomic, metabolomic, and lipidomic analyses detected a relative (vs. the same-sex control) decrease in factors involved in fatty acid β-oxidation in female KO mice, while increased or unchanged levels in male KO mice, including medium-chain acyl-CoA dehydrogenase, 3-hydroxybutyrate, and acylcarnitine. Three putative mRNA biomarkers of cystogenesis in male Ift88 KO mice (similar control levels between sexes and uniquely altered by KO in males) were identified, including high levels (fibrinogen α-chain and stromal cell-derived factor 2-like 1) and low levels (BTG3-associated nuclear protein) in male KO mice. These findings suggest that relative alterations in renal ECM metabolism, fatty acid β-oxidation, and other pathways precede cystogenesis in Ift88 KO mice. In addition, potential novel biomarkers of cystogenesis in Ift88 KO mice have been identified.NEW & NOTEWORTHY Male, but not female, mice with nephron intraflagellar transport protein 88 (Ift88) gene knockout (KO) develop polycystic kidneys by ∼1 yr postnatal. We performed multiomic analysis of precystic male and female Ift88 KO and control kidneys. Precystic male Ift88 KO mice exhibited differential alterations (vs. females) in mRNA, proteins, metabolites, and/or lipids associated with renal extracellular matrix metabolism, fatty acid β-oxidation, circadian rhythm, and other pathways. These findings suggest targets for evaluation in the pathogenesis of Ift88 KO polycystic kidneys.

Dataset Information

Multiomic characterization of disease progression in mice lacking dystrophin.

Publications

Multiomic characterization of disease progression in mice lacking dystrophin.

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