Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B
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−/−...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Elsevier
2018-02-01
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| Series: | Journal of Lipid Research |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227520342309 |
| _version_ | 1819055285722939392 |
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| author | Stephanie L. Sellers Nadia Milad Zoe White Chris Pascoe Rayleigh Chan Geoffrey W. Payne Chun Seow Fabio Rossi Michael A. Seidman Pascal Bernatchez |
| author_facet | Stephanie L. Sellers Nadia Milad Zoe White Chris Pascoe Rayleigh Chan Geoffrey W. Payne Chun Seow Fabio Rossi Michael A. Seidman Pascal Bernatchez |
| author_sort | Stephanie L. Sellers |
| collection | DOAJ |
| description | 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 |
| first_indexed | 2024-12-21T13:05:06Z |
| format | Article |
| id | doaj.art-911d2daccceb42e4b489cba6e1a10d88 |
| institution | Directory Open Access Journal |
| issn | 0022-2275 |
| language | English |
| last_indexed | 2024-12-21T13:05:06Z |
| publishDate | 2018-02-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj.art-911d2daccceb42e4b489cba6e1a10d882022-12-21T19:03:03ZengElsevierJournal of Lipid Research0022-22752018-02-01592261272Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2BStephanie L. Sellers0Nadia Milad1Zoe White2Chris Pascoe3Rayleigh Chan4Geoffrey W. Payne5Chun Seow6Fabio Rossi7Michael A. Seidman8Pascal Bernatchez9Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, CanadaDepartment of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, CanadaDepartment of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, CanadaSt. Paul's Hospital, University of British Columbia, Vancouver, Canada; Department of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, CanadaDepartment of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, CanadaProvidence Health Care, University of Northern British Columbia, Prince George, CanadaDepartment of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, CanadaDepartment of Pathology and Laboratory Medicine, University of British Columbia, Vancouver, Canada; Biomedical Research Centre, University of British Columbia, Vancouver, Canada; Department of Medical Genetics, University of British Columbia, Vancouver, CanadaSt. Paul's Hospital, University of British Columbia, Vancouver, Canada; Department of Pathology, Prince George, CanadaTo whom correspondence should be addressed.; Department of Anesthesiology, Pharmacology & Therapeutics and UBC Centre for Heart Lung Innovation, University of British Columbia, Vancouver, Canada; St. Paul's Hospital, University of British Columbia, Vancouver, Canada; To whom correspondence should be addressed.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 severityhttp://www.sciencedirect.com/science/article/pii/S0022227520342309dysferlinmuscular dystrophyatherosclerosisapolipoproteinsmuscleHDL |
| spellingShingle | Stephanie L. Sellers Nadia Milad Zoe White Chris Pascoe Rayleigh Chan Geoffrey W. Payne Chun Seow Fabio Rossi Michael A. Seidman Pascal Bernatchez Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B Journal of Lipid Research dysferlin muscular dystrophy atherosclerosis apolipoproteins muscle HDL |
| title | Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B |
| title_full | Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B |
| title_fullStr | Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B |
| title_full_unstemmed | Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B |
| title_short | Increased nonHDL cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of LGMD2B |
| title_sort | increased nonhdl cholesterol levels cause muscle wasting and ambulatory dysfunction in the mouse model of lgmd2b |
| topic | dysferlin muscular dystrophy atherosclerosis apolipoproteins muscle HDL |
| url | http://www.sciencedirect.com/science/article/pii/S0022227520342309 |
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