PGC-1β modulates statin-associated myotoxicity in mice

Area of Science:

• Muscle physiology
• Mitochondrial biology
• Pharmacology

Background:

• Statins are widely used to lower cholesterol but can cause myopathy.
• PGC-1β (peroxisome proliferator-activated receptor gamma coactivator 1-beta) is a key regulator of mitochondrial function and energy metabolism in skeletal muscle.
• Previous research suggests statins impair PGC-1β expression, implicating it in statin-induced myopathy.

Purpose of the Study:

• To investigate the interaction between atorvastatin and PGC-1β in skeletal muscle.
• To determine the effects of atorvastatin on muscle and mitochondrial function in the presence and absence of PGC-1β.
• To elucidate the role of PGC-1β in mediating statin-induced skeletal muscle adaptations and toxicity.

Main Methods:

• Treatment of wild-type and PGC-1β skeletal muscle knockout mice with oral atorvastatin for two weeks.
• Assessment of body parameters, muscle function, structure, and composition.
• Analysis of muscle mitochondrial function, biogenesis, and apoptotic pathways.

Main Results:

• In wild-type mice, atorvastatin impaired mitochondrial function in glycolytic muscle and induced a fiber type switch from oxidative to glycolytic.
• Conversely, atorvastatin enhanced mitochondrial function and biogenesis while decreasing apoptosis in the oxidative muscle of wild-type mice.
• In PGC-1β knockout mice, atorvastatin induced mitochondrial dysfunction, increased ROS production, impaired proliferation, and promoted apoptosis in both glycolytic and oxidative muscle.

Conclusions:

• Atorvastatin primarily affects glycolytic skeletal muscle in wild-type mice.
• PGC-1β is essential for maintaining oxidative muscle integrity and function during atorvastatin exposure.
• Targeting PGC-1β pathways may offer strategies to mitigate statin-induced myopathy.