Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice

Autor: Rui Li, Ya Wen, Qi Liu, Shuai Li, Yafei Wang, Lin Bai, Yaling Liu
Rok vydání: 2020
Předmět:
0301 basic medicine
medicine.medical_specialty
Simvastatin
Statin
medicine.drug_class
Neuroscience (miscellaneous)
Neuromuscular Junction
Mice
Transgenic
Motor Activity
Muscle Development
03 medical and health sciences
Cellular and Molecular Neuroscience
Protein Aggregates
0302 clinical medicine
Atrophy
Internal medicine
Autophagy
Medicine
Animals
Regeneration
cardiovascular diseases
Amyotrophic lateral sclerosis
Myopathy
Muscle
Skeletal
Denervation
Inflammation
business.industry
Myogenesis
Superoxide Dismutase
TOR Serine-Threonine Kinases
nutritional and metabolic diseases
medicine.disease
Fibrosis
Muscle atrophy
Muscular Atrophy
030104 developmental biology
Endocrinology
Phenotype
Neurology
Mutation
lipids (amino acids
peptides
and proteins)
Female
medicine.symptom
business
030217 neurology & neurosurgery
medicine.drug
Signal Transduction
Zdroj: Molecular neurobiology. 58(4)
ISSN: 1559-1182
Popis: 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.
Databáze: OpenAIRE
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