Muscle mitochondrial metabolism and calcium signaling impairment in patients treated with statins

Effect of simvastatin on vascular tone in porcine coronary artery: Potential role of the mitochondria

“…Although studies demonstrate that simvastatin inhibits mitochondrial function, the mechanism by which it does this is unknown. Previous studies in skeletal muscle have suggested that simvastatin inhibits complex I (Sirvent et al, 2005;Sirvent et al, 2012). Other studies have hypothesized that the effect on mitochondria is due to a reduction in the expression of co-enzyme Q10, which is part of complex III (Tavintharan et al, 2007;Larsen et al, 2013;Vaughan et al, 2013).…”

Statin intolerance – an attempt at a unified definition. Position paper from an International Lipid Expert Panel

“…In an animal model of statin-induced myopathy, administration of simvastatin impaired phosphatidylinositol 3-kinase (PI3k)/Akt signaling in muscle, inducing ubiquitin and lysosomal proteolysis through up-regulation of the FOXO downstream target genes of muscle atrophy such as cathepsin-L mRNA, muscle RING finger-1 (MuRF-1), and F-box (MAFbx), and dephosphorylation of the forkhead box protein O (FOXO) (1 and 3) transcription factors [80]. In skeletal muscle tissue statin therapy can cause mitochondrial dysfunction limited typically to complex I of the respiratory chain, which increases mitochondrial NADH and the intracellular redox potential (NADH/NAD + ratio), activates pyruvate dehydrogenase kinase (PDK), and inhibits flux via the pyruvate dehydrogenase complex (PDC) [81,82]. Another possible mechanism for statin-induced myopathy during exercise might be the down-regulation of atrogin-1 gene expression, a critical component of the ubiquitin proteasome pathway and of muscle protein catabolism [83].…”

“…These unwanted effects of statins do not correlate with the degree of cholesterol lowering effect of the compound used (drug class effect) but are dose-related [87,88], and are related to the impairment of mitochondrial function and muscle calcium homeostasis [89].…”

The Effects of Statin Medications on Aerobic Exercise Capacity and Training Adaptations

“…There is increasing evidence in human and animal models that mitochondrial dysfunction plays a role in the negative effects of statins [25,79,[89][90][91]. The mitochondria have a crucial role in cellular metabolism and energy production; hence any defect in mitochondrial function could possibly affect muscle performance and aerobic exercise capacity.…”