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

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.