The molecular mechanisms underlying the statin induced adverse effects and the role of HMGCR

We aim to study the role of the statin target HMGCR with a focus on statins side effects on muscle and metabolism. We created an unique conditional mouse model where the Hmgcr is knocked down in adulthood.

The model has provided very exciting preliminary results with specific metabolic shifts involving an increase in long chain acylcarnitines (LCACs) while carbohydrates are decreased.

This is interesting since LCACs are implicated both in diabetes and myopathy, which are known effects of long term statin treatment.

Moreover, metabolomics, whole genome transcriptomics and functional enzyme assays suggest novel effects on peroxisomal functions that could precede the effects on mitochondria.

Our tissue specific knockdowns of Hmgcr in flies show specific muscular phenotype enabling studies of the neuromuscular signaling as well for the tissue specific role of Hmgcr.

Our data implicate that the energy demanding neuromuscular junction may be vulnerable after knockdown of Hmgcr and statin treatment.

Both fly and mouse studies will be pursued through the four years, first with verification of current data followed by experiments to determine the order of events. Our research may also benefit understanding of other drug induced myopathies.

The team behind the application is strong and has been very productive within the field of molecular metabolism and pharmacology. The impact of published papers from our team is high and growing, receiving more than 9000 citations 2019-21.