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

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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.

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Acknowledgements

We thank Weisong Duan, HongranWu, and Zhongyao Li for their suggestions and technical assistance.

Funding

This work was supported by the National Natural Science Foundation of China (NSFC; 81871001) and the Key Project of Technical Health Research and Achievement Transformation of Hebei Provincial Department of Health (zh2018004) and Training Project for Professional Leaders of Hebei Provincial Department of Finance.

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  1. Department of Neurology, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, People’s Republic of China

    Yafei Wang, Lin Bai, Shuai Li, Ya Wen, Qi Liu, Rui Li & Yaling Liu

  2. Neurological Laboratory of Hebei Province, Shijiazhuang, 050000, Hebei, People’s Republic of China

    Yafei Wang, Lin Bai, Shuai Li, Ya Wen, Qi Liu, Rui Li & Yaling Liu

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Contributions

YL and RL conceptualised and designed the experiments. YW, LB, SL, YW, and QL performed all the experiments. YW and RL analysed and interpreted the data. YL, RL, and YW wrote the manuscript.

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Correspondence to Rui Li or Yaling Liu.

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All animals were kept in a pathogen-free environment with chow food and clean water. All experiments were approved by the Research Ethics Committee of the Second Hospital of Hebei Medical University (Shijiazhuang, Hebei, People’s Republic of China, Approval No. 2020P023). All applicable institutional and government regulations regarding the use of animals were followed.

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Fig. S1

Simvastatin did not Affect Autophagic Flux in the TA Muscle of WT Mice. a Representative images of immunostaining for p62 and LC3 in Tibialis anterior (TA) muscle of WT and G93ASOD1 mice treated or untreated with simvastatin at end-stage. (b) Western blot analysis of p62 and LC3 in TA muscle of WT and G93ASOD1 mice treated or untreated with simvastatin at end-stage. (c) Graphs show quantification of p62 and LC3 protein relative to GAPDH. (d) Graphs show quantification of p62- or LC3-positive cells at different stage of G93Acon and G93ASim mice. Scale bars, 100 μm. All data are presented as mean ± SEM, n = 5, 3 times independent experiments. Statistical significance was assessed by one-way ANOVA, *P ≤ 0.05, **P ≤ 0.01, ***P ≤ 0.001. (PNG 1910 kb)

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Fig. S2

Effects of Simvastatin on Inflammation in G93ASOD1 and WT Mice. (a) Western blot showing the expression of TNF-α and Arginase in Tibialis anterior (TA) of WT and G93ASOD1 mice treated or untreated with simvastatin at end-stage. (b) Graphs quantifying TNF-α and Arginase relative to α-tubulin for each group. (c) Western blot showing the expression of TNF-α and Arginase in TA of G93ASOD1 mice with or without simvastatin at different stages. (d) Graphs quantifying TNF-α and Arginase relative to α-tubulin for each group. (e) Representative images of immunostaining for TNF-α in G93ASim and G93Acon mice at day 90, 120, and end-stage. Scale bars, 20 μm. All data are presented as mean ± SEM, n = 5, 3 times independent experiments. Statistical significance was assessed by one-way ANOVA, *P ≤ 0.05, **P ≤ 0.01. (PNG 2033 kb)

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Wang, Y., Bai, L., Li, S. et al. Simvastatin Enhances Muscle Regeneration Through Autophagic Defect-Mediated Inflammation and mTOR Activation in G93ASOD1 Mice. Mol Neurobiol 58, 1593–1606 (2021). https://doi.org/10.1007/s12035-020-02216-6

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