Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1
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Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice Yafei Wang 1,2 & Lin Bai 1,2 & Shuai Li 1,2 & Ya Wen 1,2 & Qi Liu 1,2 & Rui Li 1,2 & Yaling Liu 1,2 Received: 2 September 2020 / Accepted: 16 November 2020 # Springer Science+Business Media, LLC, part of Springer Nature 2020
Abstract 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. Keywords Amyotrophic lateral sclerosis . G93ASOD1 . Statin . Skeletal muscle regeneration . Autophagy . Inflammation
Introduction Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterised by the degeneration of motor neurons in the brain and spinal cord, as well as rapidly progressive muscular atrophy, weakness, and paralysis. Although most ALS cases are sporadic, approximately 10% are familial. Mutations in the gene that encodes for the superoxide dismutase 1 (SOD1) account for almost 20% of familial ALS and 5% sporadic ALS cases [1]. To date, the exact aetiology of ALS remains unclear, and no therapy substantially improves patient outcomes. ALS clinically begins with local muscle weakness * Rui Li [email protected] * Yaling Liu [email protected] 1
Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang 050000, Hebei, People’s Republic of China
2
Neurological Laboratory of Hebei Province, Shijiazhuang 050000, Hebei, People’s Republic of China
and gradually spreads to all the voluntary muscles. Typical muscle pathology includes denervated atrophy, as well as myopathic features [2], muscle fibrosis, and inflammation [3, 4]. Skeletal muscle roughly accounts for 40
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