Abstract
Dysferlinopathies are a group of muscle disorders caused by mutations to dysferlin, a transmembrane protein involved in membrane patching events following physical damage to skeletal myofibers. We documented dysferlin expression in vascular tissues including non-muscle endothelial cells, suggesting that blood vessels may have an endogenous repair system that helps promote vascular homeostasis. To test this hypothesis, we generated dysferlin-null mice lacking apolipoprotein E (ApoE), a common model of atherosclerosis, dyslipidemia and endothelial injury when stressed with a high fat, and cholesterol-rich diet. Despite high dysferlin expression in mouse and human atheromatous plaques, loss of dysferlin did not affect atherosclerotic burden as measured in the aortic root, arch, thoracic, and abdominal aortic regions. Interestingly, we observed that dysferlin-null mice exhibit lower plasma high-density lipoprotein cholesterol (HDL-C) levels than their WT controls at all measured stages of the disease process. Western blotting revealed abundant dysferlin expression in protein extracts from mouse livers, the main regulator of plasma lipoprotein levels. Despite abnormal lipoprotein levels, Dysf/ApoE double knockout mice responded to cholesterol absorption blockade with lower total cholesterol and blunted atherosclerosis. Our study suggests that dysferlin does not protect against atherosclerosis or participate in cholesterol absorption blockade but regulates basal plasma lipoprotein composition. Dysferlinopathic patients may be dyslipidemic without greater atherosclerotic burden while remaining responsive to cholesterol absorption blockade.
Highlights
Dysferlin is a 237kDa member of the ferlin family of transmembrane proteins involved in calcium-dependent sarcolemma repair and vesicle trafficking [reviewed in Cardenas et al (2016) and Bulankina and Thoms (2020)]
Blood monocytes and macrophages express dysferlin (Nagaraju et al, 2008; Zhang et al, 2020), and its presence can be found at the intercalated disks of cardiomyocytes (Chase et al, 2009), whereas our team has documented its presence in endothelial cells (Sharma et al, 2010), suggesting that dysferlin may regulate more than sarcolemmal repair events following physical injury
We show that loss of dysferlin does not interfere with the efficacy of plasma lipid lowering mediated by cholesterol absorption blockade in mice lacking apolipoprotein E (ApoE)
Summary
Dysferlin is a 237kDa member of the ferlin family of transmembrane proteins involved in calcium-dependent sarcolemma repair and vesicle trafficking [reviewed in Cardenas et al (2016) and Bulankina and Thoms (2020)]. Despite its critical role in sarcolemmal repair, positive dysferlin expression can be observed in non-skeletal muscle tissues and cell types. Blood monocytes and macrophages express dysferlin (Nagaraju et al, 2008; Zhang et al, 2020), and its presence can be found at the intercalated disks of cardiomyocytes (Chase et al, 2009), whereas our team has documented its presence in endothelial cells (Sharma et al, 2010), suggesting that dysferlin may regulate more than sarcolemmal repair events following physical injury. We report positive dysferlin expression in the liver and small intestine, the sites of lipoprotein metabolism regulation and lipid absorption, respectively, and plasma lipoprotein analyses revealed that loss of dysferlin modulates the plasma lipoprotein profiles of mice. This work further suggests that dysferlinopathies may have a metabolic or endocrine component
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