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Title: Investigating mitochondrial impairment as a mechanism of statin-induced muscle toxicity
Author: Jones, S. W.
Awarding Body: University of Liverpool
Current Institution: University of Liverpool
Date of Award: 2019
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Statins, also known as 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoAR) inhibitors, are currently the pharmaceutical intervention strategy of choice for the primary and secondary prevention of atherosclerotic disorders that are related to hypercholesterolemia. In most recipients, statin therapy is effective and well tolerated, however the most significant barrier to cardiovascular disease (CVD) risk reduction is the development of adverse effects, of which statin-related myopathies (SRM) are the most frequently reported. The aetiological basis of SRM is both complex and multifaceted, with no clear dose-response relationship and a plethora of generalised and genetic risk factors identified to date. However, the deleterious effects of statins upon mitochondrial function has been implicated as one of several putative mechanisms by which myopathic symptoms may be potentiated in some patients. Therefore, the aim of this research was to establish the effects of statin chemical species (i.e. inactive lactones versus active ß-hydroxy acids) upon the functionality of the mitochondrial electron transport chain using high resolution respirometry. Thereafter, the remainder of the thesis focussed upon the development of three-dimensional, bioengineered micro-tissue models of human skeletal muscle to identify functional bioenergetic factors which may confer enhanced or diminished risk of statin-mediated mitochondrial dysfunction. Finally, due to the governance of respiratory chain assembly, stability and functionality by the mitochondrial genome, next generation sequencing (NGS) of patient mitochondrial DNA was performed for a statin myopathy case-control cohort to determine if there was an association between mitochondrial genotype and patient phenotype. Preliminary in vitro investigations performed using the L6 myoblast cell line identified succinate dehydrogenase (complex II) driven respiration as a major, but not an exclusive target of simvastatin-mediated mitochondrial dysfunction over acute and extended dosing regimens. Following the assessment of simvastatin-mediated mitochondrial dysfunction in a murine cell line, a cohort of statin-naïve, statin-tolerant and statin-intolerant patients were recruited via the Liverpool Musculoskeletal Biobank (LMB) before isolation of satellite cells from skeletal muscle biopsy samples. The satellite cells were then used to generate biomimetic, engineered micro-tissues known as myobundles. Examination of baseline bioenergetic parameters in patient derived myobundles showed that individuals belonging to the statin-tolerant group exhibited a greater spare respiratory capacity than both the statin-naïve and statin-intolerant patients, a trait linked to increased succinate dehydrogenase activity and cell survival. Finally, the mitochondrial DNA haplogroups of 264 statin myopathy cases, 291 statintolerant controls and 342 healthy volunteers were resolved using NGS and HaploGrep2 software (phylotree build 17) before performing a haplogroup-disease association study. Within this study, a significant association between mitochondrial macro-haplogroup assignment and statin related myopathy was not identified. The distribution of mitochondrial haplogroups in both the case and control groups resembled that of the healthy volunteer cohort and the Northern European population. To conclude, statin-mediated mitochondrial dysfunction has a role to play in the development of myopathic symptoms amongst susceptible patients. However, this research has also identified enhanced spare respiratory capacity as a potential protective factor amongst statin-tolerant individuals. What is less clear is the relative contributions of direct respiratory inhibition and/or modulation of peripheral pathways which interact with the wider mitochondrial signalling network, to the overall pathophysiological mechanism.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral