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\begin{document}

\title{Statin-activation of RyR1 is a class effect but separable from HMG-CoA
reductase inhibition}



\author[1]{Chris Lindsay}%
\author[2]{Maria Musgaard}%
\author[1]{Angela  Russell}%
\author[1]{Rebecca Sitsapesan}%
\affil[1]{University of Oxford}%
\affil[2]{OMass Therapeutics Ltd}%


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  \date{May 23, 2024}


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\begin{abstract}
Background and purpose Statins, inhibitors of HMG-CoA reductase, are
mainstay treatment for hypercholesterolemia. However, muscle pain and
weakness prevent many patients from benefiting from their
cardioprotective effects. We previously demonstrated that simvastatin
activates skeletal ryanodine receptors (RyR1), an effect that could be
important in initiating myopathy. We therefore investigated if RyR1
activation is a standard property of commonly-prescribed statins. Using
a range of structurally-diverse statin analogues we examined structural
features associated with RyR1 activation, aiming to identify statins
lacking this property. Experimental Approach Compounds were screened for
RyR1 activity utilising {[}\textsuperscript{3}H{]}ryanodine binding.
Mechanistic insight into RyR1 activity was studied by incorporating RyR1
channels from sheep, mouse or rabbit skeletal muscle into bilayers. Key
Results All UK-prescribed statins activated RyR1 at nanomolar
concentrations. Cerivastatin, withdrawn from the market due to
life-threatening muscle-related side effects, was more effective than
currently-prescribed statins and possessed the unique ability to open
RyR1 channels independently of cytosolic Ca\textsuperscript{2+}. We
synthesised the statin pharmacophore and it did not activate RyR1. We
also identified five analogues retaining potent HMG-CoA reductase
inhibition that inhibited RyR1 and four analogues that lacked the
ability to activate RyR1. Conclusion and Implications That cervistatin
activates RyR1 most strongly supports the hypothesis that RyR1
activation is implicated in statin-induced myopathy. Demonstrating that
statin-regulation of RyR1 and HMG-CoA reductase are separable effects
allows the role of RyR1 in statin-induced myopathy to be further
elucidated by the tool compounds identified, thus paving the way for the
development of effective cardioprotective statins with improved patient
tolerance.%
\end{abstract}%



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