Unveiling the Mechanisms for Statin-Associated Sleep Problems and Myopathy : Statin Medication, Sleep Problems and Myopathy Mechanisms

• Statins (3-hydroxy-3-methylglutaryl-CoA reductase, HMGCR, inhibitors) comprise the gold standard for the management of hypercholesterolaemia and prevention of cardiovascular disease (CVDs). However, they are accompanied by potential adverse effects, notably muscle pain and sleep disturbance. These side effects can significantly impact patient adherence to statin therapy and thus increase the risk for CVDs. Despite extensive research, the underlying mechanisms of statin-associated myopathy and sleep disturbance are poorly understood. In Paper I, we conducted a cross-sectional cohort study to investigate the association between statin use and genetic variants for HMGCR with the risk for insomnia and chronotype using UK biobank cohort data. Statin use, insomnia and chronotype were assessed by a self-report touchscreen questionnaire. Statin treatment was associated with an increased risk of insomnia compared to controls, while genetic variants for HMGCR inhibition were associated with a reduced risk for insomnia. No association with late evening chronotype were observed with statin use or genetic variants for HMGCR. In Paper II, we employed Drosophila melanogaster to examine the effect of statins and the role of central inhibition of Hmgcr on sleep behaviour. Flies were treated with fluvastatin for five days and Hmgcr was knocked down in pan neurons and pars intercerebralis (PI), equivalent to the mammalian hypothalamus. Sleep patterns were recorded and analysed. Pan-neuronal- as well as PI inhibition of Hmgcr recapitulates fluvastatin-induced enhanced sleep latency and reduced sleep duration. In Paper III, we deciphered the underlying mechanisms for statin-induced myopathy using D. melanogaster. We found that fluvastatin treatment induced muscular damage, mitochondrial phenotypes, lowered locomotion, reduced climbing activity and was associated with lipotoxicity, impaired muscle differentiation and regeneration, and lowered expression of skeletal muscle chloride channels. Interestingly, selective inhibition of skeletal muscle chloride channels recapitulates fluvastatin-induced myofibrillar damage and lowered climbing activity, while selective Hmgcr inhibition in the skeletal muscles recapitulates fluvastatin-induced mitochondrial round-shape and reduced locomotion activity. In Paper IV, we explored the sequential events of myofibril damage and mitochondrial phenotypes associated with fluvastatin and examined whether inhibition of Hmgcr in the skeletal muscles recapitulates fluvastatin effects on mitochondrial respiratory parameters using D. melanogaster. Acute fluvastatin treatment was associated with reduced mitochondrial content and roundness of the mitochondria without noticeable myofibrillar damage. Intriguingly, chronic fluvastatin treatment was associated with stronger mitochondrial phenotypes along with severe myofibrillar damage, which suggests that mitochondrial phenotypes precede myofibrillar damage. Moreover, selective Hmgcr inhibition did not impact mitochondrial respiratory functions. 

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine (hsv//eng)

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine (hsv//eng)

Nyckelord

Farmakoepidemiologi

Pharmacoepidemiology

Biology with specialization in Molecular Biology

Biologi med inriktning mot molekylärbiologi

Genetics

Genetik

Neuroscience

Neurovetenskap

Pharmacology

Farmakologi

Publikations- och innehållstyp

vet (ämneskategori)

dok (ämneskategori)