Myotoxicity of Statins on Muscle Function and Metabolism

Panajatovic, Miljenko / MP. Myotoxicity of Statins on Muscle Function and Metabolism. 2023, Doctoral Thesis, University of Basel, Faculty of Science.

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Statins have important benefits in lowering the risk for cardiovascular events, which can lead to increased patient life span and lowering the healthcare costs required for treatment of cardiovascular-related events. Positive effects of statin treatment are diminished due to low patient adherence since it is required for statins to be taken for more than a few years in order to achieve therapeutic goals. One of the most common complaints for statin treatment are muscle-related symptoms. Impaired muscle function can impede motoric activity and even exacerbate to kidney failure. Muscle metabolism also plays an important role in whole body glucose homeostasis, which could be the cause for earlier diabetes development seen in certain risk populations treated with statins. We assumed that observed issues with skeletal muscle function and metabolism could be explained by mitochondrial impairments. We based our assumptions on previous research, where oxidative skeletal muscles with more mitochondria have greatly reduced cellular death as opposed to glycolytic muscles with less mitochondria after statin treatment. Mitochondria are important cellular organelles responsible for skeletal muscle glucose and lipid utilisation thereby producing energy substrate ATP for muscle contraction at a steady constant rate. They are also involved in calcium buffering for muscle contractions and more importantly as focal point for cellular death. We tested our hypothesis by using mouse models with differentially expressing PGC-1α in the skeletal muscles. PGC-1α is an exercise dependent transcriptional co-activator responsible for metabolic phenotype switch in skeletal muscles by stimulating mitochondrial biogenesis, angiogenesis, and an overall oxidative metabolic phenotype.
The first project of the thesis tests the hypothesis whether PGC-1α has an important role in myotoxicity of simvastatin on skeletal muscle function during exercise and the mitochondrial function. Indeed, overexpression of PGC-1α in skeletal muscles protected against simvastatin- associated impairments on endurance exercise, grip strength, mitochondrial function, and the damaging reactive oxygen species production in wild-type mice. Knocking out PGC-1α in the skeletal muscle caused further impairments on the mitochondrial function in the normally resistant oxidative skeletal muscles.
The second project delved into the possible mechanisms of mitochondrial repair in wild-type mice and in mice overexpressing PGC-1α in the skeletal muscles. simvastatin increases mitochondrial fragmentation, mitophagy and apoptosis in C2C12 cells, while overexpression of PGC-1α prevented apoptosis of C2C12 cells exposed to simvastatin. We confirmed these findings in wild- type mice, where simvastatin induced mitochondrial fragmentation and apoptosis. In comparison, mice with overexpression of PGC-1α in skeletal muscle were protected from apoptosis through positive effects of PGC-1α on mitochondrial function and stimulation of mitochondrial biogenesis. Lastly, we conclude that the mitochondrial network is preserved due to increased mitophagy rate present in the mouse glycolytic skeletal muscles and in C2C12 myoblasts with PGC-1α overexpression.
The third project investigated how does simvastatin impair glucose homeostasis. We found that simvastatin led to increased circulating glucose levels due to impaired skeletal muscle glucose uptake in mice. The impaired glucose uptake mechanism is further explained in a cellular model with C2C12 myotubes. In short, simvastatin reduced the activity of mTORC2 that led to reduced activity of Akt kinase. Akt is an important signalling hub, which is also involved in glucose uptake. Reduced activity of Akt results in reduced phosphorylation of GSK3β, and therefore reduced Glucose transporter type 4 (GLUT4) translocation to the membrane. GLUT4 is an important glucose transporter during insulin stimulation. This could explain reduced insulin sensitivity of the skeletal muscles in the mice that resulted in impaired glucose homeostasis.
The fourth project continued to investigate the effects of simvastatin on the glucose homeostasis. The aim was to see whether PGC-1α has an important role on the glucose homeostasis affected by simvastatin treatment. PGC-1α has an important role in storage, uptake, and metabolism of glucose in the skeletal muscle which could help alleviate the impairments in glucose homeostasis. As expected, PGC-1α overexpression rescued the impaired glucose uptake, which was affected by simvastatin treatment. Glucose uptake improvements were mediated through increased GLUT4 and HK2 expression and increased insulin release. However, PGC-1α overexpression did not improve whole-body glucose homeostasis during simvastatin treatment. We concluded that PGC- 1α overexpression led to improved muscle insulin sensitivity, while the whole-body insulin sensitivity remained impaired.
The fifth project discussed in this thesis continued the story regarding glucose homeostasis by investigating lipid homeostasis within the skeletal muscle. Simvastatin increased the number of lipid droplets within the glycolytic muscles of mice with PGC-1α overexpression, which could indicate that there is a possibility of lipotoxicity. However, reactive oxygen species production remained low and glucose uptake was even increased in skeletal muscles of simvastatin treated mice with PGC-1α overexpression, which excluded the possibility of lipotoxicity. PGC-1α overexpression increased the transport of lipids into the skeletal muscle that could explain the presence of lipid droplets within the muscle. Simvastatin treatment further increased the size and number of lipid droplets by increasing lipid flux and storage into the muscle. Simvastatin stimulated the lipid flux by increasing the expression of fatty acid transporter protein 4 and increased the storage capacity by increasing the expression of perilipin 5. To conclude, simvastatin treatment protected against possible lipotoxicity in the skeletal muscle with PGC-1α overexpression through increased lipid flux and lipid storage.
The last 4 years of work and publications gave important insights into the mechanisms and possible ways to mitigate simvastatin myotoxicity. PGC-1α was found to be an important factor in managing the skeletal muscle symptoms in regards to muscle function and metabolism. Simvastatin was found to affect the skeletal muscle exercise capabilities in mice, which was linked with mitochondrial function and dynamics. These effects were ameliorated by increasing the expression of PGC-1α and subsequently mitochondrial biogenesis and repair through mitophagy. Simvastatin also impaired glucose homeostasis in mice by reducing the signalling through the Akt/mTOR pathway, which resulted in decreased glucose uptake and impaired whole-body glucose homeostasis. PGC-1α made small improvements with impaired glucose handling after simvastatin treatment by increasing glucose uptake, lipid storage, and mitochondrial function. However, whole- body insulin sensitivity remained impaired with after simvastatin treatment, which could be explained by impaired glucose regulation in other organs such as the liver and pancreas.
Advisors:Krähenbühl, Stephan and Handschin, Christoph and Jetter, Alexander
Faculties and Departments:05 Faculty of Science > Departement Pharmazeutische Wissenschaften > Ehemalige Einheiten Pharmazie > Pharmakologie (Krähenbühl)
UniBasel Contributors:Krähenbühl, Stephan and Handschin, Christoph
Item Type:Thesis
Thesis Subtype:Doctoral Thesis
Thesis no:14965
Thesis status:Complete
Number of Pages:1 Band (verschiedene Seitenzählungen)
Identification Number:
  • urn: urn:nbn:ch:bel-bau-diss149653
edoc DOI:
Last Modified:11 Mar 2023 05:30
Deposited On:10 Mar 2023 15:05

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