PGC-1β modulates statin-associated myotoxicity in mice

Statins inhibit cholesterol biosynthesis and lower serum LDL-cholesterol levels. Statins are generally well tolerated, but
can be associated with potentially life-threatening myopathy of unknown mechanism. We have shown previously that
statins impair PGC-1β expression in human and rat skeletal muscle, suggesting that PGC-1β may play a role in statininduced
myopathy. PGC-1β is a transcriptional co-regulator controlling the expression of important genes in mitochondrial
biogenesis, antioxidative capacity and energy metabolism. The principle aim of the current study was to investigate the
interaction between atorvastatin and PGC-1β in more detail. We therefore treated wild-type mice and mice with selective
skeletal muscle knockout of PGC-1β (PGC-1β(i)skm−/− mice) with oral atorvastatin (5 mg/kg/day) for 2 weeks. At the end of
treatment, we determined body parameters, muscle function, structure, and composition as well as the function of muscle
mitochondria, mitochondrial biogenesis and activation of apoptotic pathways. In wild-type mice, atorvastatin selectively
impaired mitochondrial function in glycolytic muscle and caused a conversion of oxidative type IIA to glycolytic type IIB
myofibers. Conversely, in oxidative muscle of wild-type mice, atorvastatin enhanced mitochondrial function via activation of
mitochondrial biogenesis pathways and decreased apoptosis. In PGC-1β(i)skm−/− mice, atorvastatin induced a switch towards
glycolytic fibers, caused mitochondrial dysfunction, increased mitochondrial ROS production, impaired mitochondrial proliferation
and induced apoptosis in both glycolytic and oxidative skeletal muscle. Our work reveals that atorvastatin mainly
affects glycolytic muscle in wild-type mice and demonstrates the importance of PGC-1β for oxidative muscle integrity during
long-term exposure to a myotoxic agent.