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Effects of hyperlipidemia on dysferlin- and dystrophin-deficient muscular dystrophies in double-disease mouse models

University of British Columbia

Muscular dystrophy (MD) is a class of diseases marked by progressive muscle wasting and impaired ambulatory function. Dysferlin- and dystrophin-deficiencies lead to MD and both are expressed in myofibers as well as smooth muscle and endothelial cells lining the vasculature, suggesting vascular function may be a contributing factor to muscle pathology seen in MD. However, murine models of MD develop only mild pathology compared to patients, making therapeutic drug development challenging. Since mice are known to have endogenously low lipid levels and superior vascular health, disrupted vascular function may be aggravating MD progression in humans. We seek to investigate the effect of impaired vascular function on MD pathology through the generation and characterization of doubledisease murine models affected by both hyperlipidemia and MD. Firstly, the dysferlin-null (Dysf-KO) model of limb-girdle type 2B MD (LGMD2B) and the dystrophin-null (mdx) model of Duchenne MD (DMD) were crossed with apolipoprotein E-KO (ApoE-KO) hyperlipidemia model to generate Dysf-ApoE and Mdx-ApoE double-knockout mice (DKO). To further confirm the effects vascular disease on MD using a more human-relevant model, the Dysf-KO model was also crossed with the milder low-density-lipoprotein receptor-knockout (LDLRKO) model of hyperlipidemia. Significant worsening of ambulatory function and muscle pathology was observed in the Dysf-ApoE DKO model, displaying reduced stride length, sometimes complete loss of ambulation, and increased muscle wasting, necrosis, fibrosis and fat infiltration. Although the Mdx-ApoE model showed no exacerbation of ambulation decline, significant worsening of muscle necrosis and fibrofatty replacement was observed in MdxApoE DKO mice. However, few Dysf-LDLR DKOs were produced; all were maloccluded runts with abnormal gait, though without observable muscle pathology upon histological analysis. In all, the Dysf-ApoE and Mdx-ApoE mice demonstrate that hyperlipidemia and associated vascular disease can dramatically aggravate muscle pathology in MD. These double-disease models mimic more closely the severity of human MD and may be useful for evaluating therapeutic interventions. In addition, these data suggest that lipid-lowering and vascular-targeted therapies may be beneficial in LGMD2B and DMD.

Text

2018-03-31

Attribution-NonCommercial-NoDerivatives 4.0 International

http://hdl.handle.net/2429/60999

Pharmacology

University of British Columbia

UBCV

http://creativecommons.org/licenses/by-nc-nd/4.0/