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J Lipid Res. 2018 Feb;59(2):261-272. doi: 10.1194/jlr.M079459. Epub 2017 Nov 25.

Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B.

Author information

1
Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada.
2
St. Paul's Hospital, University of British Columbia, Vancouver, Canada.
3
Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada.
4
Providence Health Care, University of Northern British Columbia, Prince George, Canada.
5
Biomedical Research Centre, University of British Columbia, Vancouver, Canada.
6
Department of Medical Genetics, University of British Columbia, Vancouver, Canada.
7
Department of Pathology, Prince George, Canada.
8
Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada pascal.bernatchez@ubc.ca.

Abstract

Progressive limb and girdle muscle atrophy leading to loss of ambulation is a hallmark of dysferlinopathies, which include limb-girdle muscular dystrophy type 2B and Miyoshi myopathy. However, animal models fail to fully reproduce the disease severity observed in humans, with dysferlin-null (Dysf-/-) mice exhibiting minor muscle damage and weakness without dramatic ambulatory dysfunction. As we have previously reported significant Dysf expression in blood vessels, we investigated the role of vascular function in development of muscle pathology by generating a Dysf-deficient mouse model with vascular disease. This was achieved by crossing Dysf-/- mice with ApoE-/- mice, which have high levels of nonHDL-associated cholesterol. Double-knockout Dysf-/-ApoE-/- mice exhibited severe ambulatory dysfunction by 11 months of age. In limb-girdle muscles, histology confirmed dramatic muscle wasting, fibrofatty replacement, and myofiber damage in Dysf-/-ApoE-/- mice without affecting the ratio of centrally nucleated myofibers. Although there were no major changes in ex vivo diaphragm and soleus muscle function, histological analyses revealed these muscles to be untouched by damage and remodelling. In all, these data suggest that cholesterol may be deleterious to dysferlinopathic muscle and lead to ambulatory dysfunction. Moreover, differences in plasma lipid handling between mice and humans could be a key factor affecting dysferlinopathy severity.

KEYWORDS:

HDL; animal models; apolipoproteins; atherosclerosis; dysferlin; muscle; muscular dystrophy

PMID:
29175948
PMCID:
PMC5794421
[Available on 2019-02-01]
DOI:
10.1194/jlr.M079459

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