In this post of the Dysferlin Research blog, we highlight the work of Dr. Pascal Bernatchez and his team at the University of British Columbia that shows a link between dysferlin and cholesterol, which is the topic of his published paper titled: “ApolipoproteinE Knockout, but Not Cholesteryl Ester Transfer Protein (CETP)-AssociatedHigh-Density Lipoprotein Cholesterol (HDL-C) Lowering, Exacerbates Muscle Wasting in Dysferlin-Null Mice.”  (Credit: The image used to represent this post on the blog category page is Figure 5 from the paper above.)

Dysferlinopathy patients and mice show cholesterol metabolism anomalies that are likely related to the muscle wasting process. The link between dysferlin and cholesterol was discovered when Dr. Bernatchez’s lab crossed ApoE knockout mice with dysferlin-deficient mice, creating a double knockout mouse with very high cholesterol levels, no dysferlin, and a dramatically worse muscle phenotype.

To further explore why elevating cholesterol makes dysferlinopathy worse, Dr. Bernatchez’s lab created mice that express transgenes (CETP and ApoB) that should “humanize” the mice and make their excellent cholesterol profile moderately worse. While the transgenes did give the mice a worse cholesterol profile, including reducing HDL-C (good cholesterol), they did not worsen the muscle pathology caused by the absence of dysferlin. The authors note that maintaining intracellular cholesterol balance is crucial for myofiber integrity and that experimental strategies may be need to address both circulating and intracellular cholesterol metabolism to produce predictable effects.

Q&A with Dr. Bernatchez

Q: How did you get interested in Lipid metabolism and Dysferlinopathy?
A: We identified dysferlinin caveolae/lipids rafts microdomains of endothelial cells. These microdomains are rich in cholesterol, and endothelial cells regulate the passage of cholesterol-rich lipoproteins from the blood to sub-endothelial tissues. To stress the interplay between dysferlin and cholesterol, we generated dysferlin KO mice on the Apolipoprotein E KO background, which drastically increased non HDL ‘bad’ cholesterol. The Dysf/ApoE double KO mice lose ambulation ataround 11mo of age, which mimics human dysferlinopathy and indicated that cholesterol may play a role in muscular dystrophy in general.

Q: What are the best methods for assessing lipids in muscle?
A. Lipidomics are great, but quantifying cholesterol is done through filipin staining, HPLC and commercial kits.

Q: In your view, what are the best strategies to advance the field in relation to lipids and dysferlinopathy?
A: Finding the right lipid medication or approach to prevent muscle damage, regenerate lost tissue. Whether this is through cardiovascular medications that focus on circulating cholesterol, triglycerides or muscle lipid accumulation is unknown.