Statins, Muscle Disease and Mitochondria

Abstract

Cardiovascular disease (CVD) accounts for >17 million deaths globally every year, and this figure is predicted to rise to >23 million by 2030. Numerous studies have explored the relationship between cholesterol and CVD and there is now consensus that dyslipidaemia is a causal factor in the pathogenesis of atherosclerosis. Statins have become the cornerstone of the management of dyslipidaemia. Statins have proved to have a very good safety profile. The risk of adverse events is small compared to the benefits. Nevertheless, the potential risk of an adverse event occurring must be considered when prescribing and monitoring statin therapy to individual patients. Statin-associated muscle disease (SAMS) is by far the most studied and the most common reason for discontinuation of therapy. The reported incidence varies greatly, ranging between 5% and 29%. Milder disease is common and the more serious form, rhabdomyolysis is far rarer with an incidence of approximately 1 in 10,000. The pathophysiology of, and mechanisms leading to SAMS, are yet to be fully understood. Literature points towards statin-induced mitochondrial dysfunction as the most likely cause of SAMS. However, the exact processes leading to mitochondrial dysfunction are not yet fully understood. This paper details some of the different aetiological hypotheses put forward, focussing particularly on those related to mitochondrial dysfunction.

Using Machine Learning Methods and Structural Alerts for Prediction of Mitochondrial Toxicity

“…Later on, the severe adverse effects were linked to mitochondrial toxicity In 2007 Dykens and Will raised the awareness of the commonality of drug induced mitochondrial toxicities . Since then, the interest in mitochondrial toxicity has increased, as it could not only be linked to acute (idiosyncratic) toxicities (e. g .…”

Statin‐dependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content

“…In rare cases, damage to muscles progresses to fatal rhabdomyolysis (5)(6)(7). Although some evidence suggests that mitochondrial dysfunction might be the cause of statin-induced myopathies, the molecular mechanisms remain undetermined (8).…”

Impact of statins on cellular respiration and de‐differentiation of myofibroblasts in human failing hearts

“…Direct inhibition of GGPP synthase by DGBP is enough to affect the cellular respiration and induce de‐differentiation ( Figure ), suggesting GGPP as an important intermediate signalling molecule influencing OCR; however, GGPP supplementation alone does not enhance the OCR ( Figure ). In muscle cells, statin‐induced deficiency of Coenzyme Q 10 (CoQ 10 )/Ubiquinone is believed to be the aetiology of mitochondrial dysfunction . However, it becomes complicated across different tissue types; unlike in skeletal muscles, statins seem to protect mitochondria in cardiac myocytes from oxidative stress, and hence, statin effects on cellular respiration cannot be generalized across various cell types/tissues/organs.…”