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Exploratory Profiling of Urine MicroRNAs in the dy2J/dy2J Mouse Model of LAMA2-CMD: Relation to Disease Progression.

ABSTRACT: Circulating microRNAs (miRNAs) are being considered as non-invasive biomarkers for disease progression and clinical trials. Congenital muscular dystrophy with deficiency of laminin ?2 chain (LAMA2-CMD) is a very severe form of muscular dystrophy, for which no treatment is available. In order to identify LAMA2-CMD biomarkers we have profiled miRNAs in urine from the dy2J /dy2J mouse model of LAMA2-CMD at three distinct time points (representing asymptomatic, initial and established disease). We demonstrate that unique groups of miRNAs are differentially expressed at each time point. We suggest that urine miRNAs can be sensitive biomarkers for different stages of LAMA2-CMD.

SUBMITTER: Moreira Soares Oliveira B

PROVIDER: S-EPMC6140833 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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Exploratory Profiling of Urine MicroRNAs in the dy2J/dy2J Mouse Model of LAMA2-CMD: Relation to Disease Progression.

Moreira Soares Oliveira Bernardo B Gawlik Kinga I KI Durbeej Madeleine M Holmberg Johan J

PLoS currents 20180827

Circulating microRNAs (miRNAs) are being considered as non-invasive biomarkers for disease progression and clinical trials. Congenital muscular dystrophy with deficiency of laminin α2 chain (LAMA2-CMD) is a very severe form of muscular dystrophy, for which no treatment is available. In order to identify LAMA2-CMD biomarkers we have profiled miRNAs in urine from the dy2J /dy2J mouse model of LAMA2-CMD at three distinct time points (representing asymptomatic, in ...[more]

PMID: 30430039

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Project description:IntroductionCongenital muscular dystrophy is a distinct group of diseases presenting with weakness in infancy or childhood and no current therapy. One form, MDC1A, is the result of laminin alpha-2 deficiency and results in significant weakness, respiratory insufficiency and early death. Modification of apoptosis is one potential pathway for therapy in these patients.Methodsdy(2J) mice were treated with vehicle, 0.1 mg/kg or 1 mg/kg of omigapil daily via oral gavage over 17.5 weeks. Untreated age matched BL6 mice were used as controls. Functional, behavioral and histological measurements were collected.Resultsdy(2J) mice treated with omigapil showed improved respiratory rates compared to vehicle treated dy(2J) mice (396 to 402 vs. 371 breaths per minute, p<0.03) and similar to control mice. There were no statistical differences in normalized forelimb grip strength between dy(2J) and controls at baseline or after 17.5 weeks and no significant differences seen among the dy(2J) treatment groups. At 30-33 weeks of age, dy(2J) mice treated with 0.1 mg/kg omigapil showed significantly more movement time and less rest time compared to vehicle treated. dy(2J) mice showed normal cardiac systolic function throughout the trial. dy(2J) mice had significantly lower hindlimb maximal (p<0.001) and specific force (p<0.002) compared to the control group at the end of the trial. There were no statistically significant differences in maximal or specific force among treatments. dy(2J) mice treated with 0.1 mg/kg/day omigapil showed decreased percent fibrosis in both gastrocnemius (p<0.03) and diaphragm (p<0.001) compared to vehicle, and in diaphragm (p<0.013) when compared to 1 mg/kg/day omigapil treated mice. Omigapil treated dy(2J) mice demonstrated decreased apoptosis.ConclusionOmigapil therapy (0.1 mg/kg) improved respiratory rate and decreased skeletal and respiratory muscle fibrosis in dy(2J) mice. These results support a putative role for the use of omigapil in laminin deficient congenital muscular dystrophy patients.

Dataset Information

Exploratory Profiling of Urine MicroRNAs in the dy2J/dy2J Mouse Model of LAMA2-CMD: Relation to Disease Progression.

Publications

Exploratory Profiling of Urine MicroRNAs in the <i>dy<sup>2J</sup>/dy<sup>2J</sup></i> Mouse Model of LAMA2-CMD: Relation to Disease Progression.

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