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Potential therapies and biomarkers for LAMA2-CMD. Does the microRNA hype deliver?

Moreira Soares Oliveira, Bernardo LU orcid (2018) In Lund University, Faculty of Medicine Doctoral Dissertation Series 2018(98).
Abstract
Laminin α2 chain-deficient muscular dystrophy, or LAMA2-CMD, is a very severe disease caused by mutations in the LAMA2 gene. Skeletal muscle is the most affected tissue, with patients presenting symptoms such as hypotonia at birth, joint contractures and progressive muscle wasting. Changes in the central nervous system include white matter abnormalities, delayed motor milestones and compromised action potential propagation. To date, there is no cure and most therapeutic interventions aim at alleviating secondary complications. In the last two decades microRNAs (miRNAs) have been explored as biomarkers or therapeutic targets in various diseases. In this thesis we have profiled miRNAs in quadriceps muscle of the dy3K/dy3K mouse model of... (More)
Laminin α2 chain-deficient muscular dystrophy, or LAMA2-CMD, is a very severe disease caused by mutations in the LAMA2 gene. Skeletal muscle is the most affected tissue, with patients presenting symptoms such as hypotonia at birth, joint contractures and progressive muscle wasting. Changes in the central nervous system include white matter abnormalities, delayed motor milestones and compromised action potential propagation. To date, there is no cure and most therapeutic interventions aim at alleviating secondary complications. In the last two decades microRNAs (miRNAs) have been explored as biomarkers or therapeutic targets in various diseases. In this thesis we have profiled miRNAs in quadriceps muscle of the dy3K/dy3K mouse model of LAMA2-CMD as an initial screening. We then investigated the effects of genetically removing a pro-fibrotic miRNA, i.e. miR-21, in two mouse models of LAMA2-CMD. We showed that the single deletion of this miRNA is not enough to reduce fibrosis and improve muscle phenotype or function in LAMA2-CMD mouse models. We further explored miRNAs as non-invasive biomarkers of disease progression. Urine miRNAs were profiled at 3 time points representing no symptoms, initial symptoms and severe disease (3, 4 and 6 weeks of age). We found distinct panels of differentially expressed miRNAs at these time points, suggesting that miRNAs can be used as biomarkers for LAMA2-CMD progression. Finally, we explored metabolism as a therapeutic target in a metformin intervention study. We found that metformin treatment improved grip strength in treated dy2J/dy2J mice, despite unaffected muscle weights. Energy efficiency was improved in treated dy2J/dy2J females, which resulted in improved weight gain. Central nucleation decreased in treated dy2J/dy2J mice, which suggests reduced muscle damage. We found a significant reduction of small fibres in dy2J/dy2J females with metformin. White adipose tissue weight increased in treated dy2J/dy2J mice; in contrast, brown adipose tissue weight was reduced in treated dy2J/dy2J males. (Less)
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author
supervisor
opponent
  • professor Nagaraju, Kanneboyina, Binghamton
organization
publishing date
type
Thesis
publication status
published
subject
keywords
muskeldystrofi, genetic-markers, Small non-coding RNAs
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
volume
2018
issue
98
pages
54 pages
publisher
Lund University: Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
defense date
2018-09-01 10:00:00
ISSN
1652-8220
ISBN
978-91-7619-666-3
language
English
LU publication?
yes
id
765eb0a2-0ad2-4654-843b-62429cfc3db7
date added to LUP
2018-08-02 14:16:43
date last changed
2019-11-19 13:49:39
@phdthesis{765eb0a2-0ad2-4654-843b-62429cfc3db7,
  abstract     = {{Laminin α2 chain-deficient muscular dystrophy, or LAMA2-CMD, is a very severe disease caused by mutations in the LAMA2 gene. Skeletal muscle is the most affected tissue, with patients presenting symptoms such as hypotonia at birth, joint contractures and progressive muscle wasting. Changes in the central nervous system include white matter abnormalities, delayed motor milestones and compromised action potential propagation. To date, there is no cure and most therapeutic interventions aim at alleviating secondary complications. In the last two decades microRNAs (miRNAs) have been explored as biomarkers or therapeutic targets in various diseases.  In this thesis we have profiled miRNAs in quadriceps muscle of the dy3K/dy3K mouse model of LAMA2-CMD as an initial screening. We then investigated the effects of genetically removing a pro-fibrotic miRNA, i.e. miR-21, in two mouse models of LAMA2-CMD. We showed that the single deletion of this miRNA is not enough to reduce fibrosis and improve muscle phenotype or function in LAMA2-CMD mouse models. We further explored miRNAs as non-invasive biomarkers of disease progression. Urine miRNAs were profiled at 3 time points representing no symptoms, initial symptoms and severe disease (3, 4 and 6 weeks of age). We found distinct panels of differentially expressed miRNAs at these time points, suggesting that miRNAs can be used as biomarkers for LAMA2-CMD progression. Finally, we explored metabolism as a therapeutic target in a metformin intervention study. We found that metformin treatment improved grip strength in treated dy2J/dy2J mice, despite unaffected muscle weights. Energy efficiency was improved in treated dy2J/dy2J females, which resulted in improved weight gain. Central nucleation decreased in treated dy2J/dy2J mice, which suggests reduced muscle damage. We found a significant reduction of small fibres in dy2J/dy2J females with metformin. White adipose tissue weight increased in treated dy2J/dy2J mice; in contrast, brown adipose tissue weight was reduced in treated dy2J/dy2J males.}},
  author       = {{Moreira Soares Oliveira, Bernardo}},
  isbn         = {{978-91-7619-666-3}},
  issn         = {{1652-8220}},
  keywords     = {{muskeldystrofi; genetic-markers; Small non-coding RNAs}},
  language     = {{eng}},
  number       = {{98}},
  publisher    = {{Lund University: Faculty of Medicine}},
  school       = {{Lund University}},
  series       = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
  title        = {{Potential therapies and biomarkers for LAMA2-CMD. Does the microRNA hype deliver?}},
  volume       = {{2018}},
  year         = {{2018}},
}