Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterised by the selective loss of motor neurons, muscular atrophy, and degeneration. Statins, as 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, are the most widely prescribed drugs to lower cholesterol levels and used for the treatment of cardiovascular and cerebrovascular diseases. However, statins are seldom used in muscular diseases, primarily because of their rare statin-associated myopathy. Recently, statins have been shown to reduce muscular damage and improve its function. Here, we investigated the role of statins in myopathy using G93ASOD1 mice. Our results indicated that simvastatin significantly increased the autophagic flux defect and increased inflammation in the skeletal muscles of G93ASOD1 mice. We also found that increased inflammation correlated with aggravated muscle atrophy and fibrosis. Nevertheless, long-term simvastatin treatment promoted the regeneration of damaged muscle by activating the mammalian target of rapamycin pathway. However, administration of simvastatin did not impede vast muscle degeneration and movement dysfunction resulting from the enhanced progressive impairment of the neuromuscular junction. Together, our findings highlighted that simvastatin exacerbated skeletal muscle atrophy and denervation in spite of promoting myogenesis in damaged muscle, providing new insights into the selective use of statin-induced myopathy in ALS.
['Wang|Yafei|Y|', 'Bai|Lin|L|', 'Li|Shuai|S|', 'Wen|Ya|Y|', 'Liu|Qi|Q|', 'Li|Rui|R|', 'Liu|Yaling|Y|http://orcid.org/0000-0002-6221-6021']
D000818:Animals D001343:Autophagy D003714:Denervation D005260:Female D005355:Fibrosis D007249:Inflammation D008822:Mice, Transgenic D009043:Motor Activity D024510:Muscle Development D018482:Muscle, Skeletal D009133:Muscular Atrophy D009154:Mutation D009469:Neuromuscular Junction D010641:Phenotype D066329:Protein Aggregates D012038:Regeneration D015398:Signal Transduction D019821:Simvastatin D013482:Superoxide Dismutase D058570:TOR Serine-Threonine Kinases
Inflammation G93ASOD1 Amyotrophic lateral sclerosis Statin Autophagy Skeletal muscle regeneration