Cholesterol absorption blocker ezetimibe prevents muscle wasting in severe dysferlin-deficient and mdx mice.BACKGROUND
 Severe mdx and dysferlin knock-out mice lacking ApoE were treated with ezetimibe (15 mg/kg/day), a clinically approved drug exhibiting few pleiotropic effects.  Treatment of severe DMD and LGMD2B mice with ezetimibe completely prevented clinical signs of ambulatory dysfunction (0% incidence vs. 33% for vehicle treatment; P < 0.05).  Histological analyses revealed that ezetimibe-reduced fibro-fatty infiltration up to 84% and 63% in severely affected triceps (P ≤ 0.0001) and gastrocnemius (P ≤ 0.003) muscles, resulting in a respective 1.9-fold and 2.2-fold retention of healthy myofibre area (P ≤ 0.0001).  Specific inhibition of cholesterol absorption with ezetimibe may safely attenuate human MD severity and delay death.
ezetimibe
We have previously shown severe human-like muscle pathology in mdx [Duchenne MD (DMD)] and dysferlin-deficient limb-girdle MD type 2B (LGMD2B) mice by inactivating the gene encoding for apolipoprotein E (ApoE), a lipid transporter synthesized by the liver, brain and adipocytes to regulate lipid and fat metabolism.  Severe mdx and dysferlin knock-out mice lacking ApoE were treated with ezetimibe (15 mg/kg/day), a clinically approved drug exhibiting few pleiotropic effects. 
ApoE
Muscles were assessed histologically for changes in collagen and adipocyte infiltration and both transcriptomic and cellular changes by RNA-seq and fluorescence-activated cell sorting analysis.


 Parallel RNA-seq analyses revealed that injury in cholesterol-fed mice also modulated the expression of 3671 transcripts (1953 up-regulated), with fibrogenic, inflammatory and programmed cell death-associated pathways among the most enriched. 
RNA-seq
Muscles were assessed histologically for changes in collagen and adipocyte infiltration and both transcriptomic and cellular changes by RNA-seq and fluorescence-activated cell sorting analysis.



Fluorescence-activated cell sorting analysis