Publications
Current Grant
09/25 – 08/26
Our research program focuses on the origins of and causal role played by intra-muscular and circulating cholesterol metabolism abnormalities in animal models of dysferlinopathies by focusing on the up-regulation of the HMGCR gene product we reported in dysferlin-deficient mice. We test statins, fatty acid-containing diets and transgenic approaches in dysferlin-null, dysferlin/low-density lipoprotein receptor (LDLR) double-null and severe dysferlin/apolipoprotein E double-null animals in an attempt to identify whether changes in muscle and/or circulating cholesterol levels correlate with changes in the dysferlinopathic muscle wasting process. This is done through histological analyses and functional assays. Dysferlin-deficient cultured myoblasts are used to better understand what leads to changes in cholesterol metabolism. The possibility that lipid metabolism controls regenerative signaling is investigated through advanced MRI imaging.
Project Results
Previous Grant Period
09/24 – 08/25
In a recent publication, we have characterized how an increase in ‘bad’ LDL cholesterol and decrease in ‘good’ HDL cholesterol through human CETP expression, an enzyme not expressed in rodents, in dysferlin-null mice does not exacerbate muscle lesions. This suggests that simple reversal of the HDL/LDL ratio without a raise in total cholesterol does not lead to the expected muscle wasting exacerbation observed with the apolipoprotein E-null background. Moreover treatment of dysferlin-null mice with niacin and fibrates lead to improvements in muscle pathology although the causal role of circulating cholesterol is under investigation. From a clinical perspective we have also described the high prevalence of low ‘good’ HDL-associated cholesterol in dysferlinopathic patients using data from the clinical outcomes study (COS) provided by the Jain Foundation. How this occurs is being investigated.
Previous Grant Period
09/23 – 08/24
Using data from the clinical outcomes study provided by the Jain Foundation, we have confirmed previous findings that dysferlinopathies cause reductions in ‘good’ HDL-associated cholesterol in patients. Having published that dietary cholesterol exacerbates the phenotype of severe Dysferlin-Apolipoprotein E double-null animals, preliminary data suggest that dietary fats have the opposite effects and protect against severe muscle wasting. We have also tested non-statin/ezetimibe lipid lowering medications and identified some that reduce muscle wasting in severe Dysferlin-Apolipoprotein E double-null mice. How this occurs is being investigated.
09/22 – 08/23
Our research program is interested in circulating and intra-muscular lipid abnormalities in LGMD2b. While it is clear that blood lipids play a role in the dysferlinopathic muscle wasting process, it appears some circulating lipids may be deleterious while others may be protective. Dietary lipids supplementation and medications that modulate circulating lipoprotein levels, such as fibrates or niacin, show promising effects on muscle wasting in dysferlin-deficient animals.
09/21 – 08/22
The objective was to humanize rodent models of LGMD2b. Our data suggest that LGDM2b patients are dyslipidemic, with abnormal levels of blood cholesterol. New mouse models of LGMD2b with humanized lipid levels could further improve disease modeling, although time will tell whether this materializes into more severe rodent phenotypes.
09/20 – 08/21
Recent data from our team show that LGMD2b mice have are highly susceptible to changes in cholesterol metabolism. Our most recent manuscript describes how LGMD2b mice have low plasma HDL levels and whether this might be linked to the muscle wasting process.
10/18 – 09/19
LGMD2B causes in patients a progressive loss of ambulation. However, despite showing a much milder form of the disease, histological analyses of muscles isolated from rodent models of LGMD2B have revealed characteristic fat-rich fibrofatty infiltrates that help rationalize the minor gait abnormalities behind dysferlin-deficient animals. To highlight the metabolic complications of LGMD2B and how these can play causal roles in the loss of ambulation, this project looked at whether modulation of sterol homeostasis could alter body weight changes, gait abnormalities and muscle morphology of dysferlin-deficient mice.
