Sarcoglycan Alpha Mitigates Neuromuscular Junction Decline in Aged Mice by Stabilizing LRP4

Zhao, Kai; Shen, Chengyong; Li, Lei; Wu, Haitao; Xing, Guanglin; Dong, Zhaoqi; Jing, Hongyang; Chen, Wenbing; Zhang, Hongsheng; Tan, Zhibing; Pan, Jin-Xiu; Xiong, Lei; Wang, Hongsheng; Cui, Wanpeng; Sun, Xiangdong; Li, Shihua; Huang, Xincheng; Xiong, Wen-Cheng; Mei, Lin

doi:10.1523/jneurosci.0860-18.2018

Cited by 41 publications

(72 citation statements)

References 101 publications

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“…4a-d). In line with previous reports 37, 44 , we observed lower density of postsynaptic AChRs in cross sections from EDL muscles of 30mCON (trend) as well as 9mTSCmKO mice, (Fig. 4e).…”

Section: Resultssupporting

confidence: 93%

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

et al. 2020

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With human median lifespan extending into the 80s in many developed countries, the societal burden of age-related muscle loss (sarcopenia) is increasing. mTORC1 promotes skeletal muscle hypertrophy, but also drives organismal aging. Here, we address the question of whether mTORC1 activation or suppression is beneficial for skeletal muscle aging. We demonstrate that chronic mTORC1 inhibition with rapamycin is overwhelmingly, but not entirely, positive for aging mouse skeletal muscle, while genetic, muscle fiber-specific activation of mTORC1 is sufficient to induce molecular signatures of sarcopenia. Through integration of comprehensive physiological and extensive gene expression profiling in young and old mice, and following genetic activation or pharmacological inhibition of mTORC1, we establish the phenotypically-backed, mTORC1-focused, multi-muscle gene expression atlas, SarcoAtlas (https://sarcoatlas.scicore.unibas.ch/), as a user-friendly gene discovery tool. We uncover inter-muscle divergence in the primary drivers of sarcopenia and identify the neuromuscular junction as a focal point of mTORC1-driven muscle aging.

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“…4a-d). In line with previous reports 37, 44 , we observed lower density of postsynaptic AChRs in cross sections from EDL muscles of 30mCON (trend) as well as 9mTSCmKO mice, (Fig. 4e).…”

Section: Resultssupporting

confidence: 93%

The neuromuscular junction is a focal point of mTORC1 signaling in sarcopenia

et al. 2020

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“…A paper recently reported reduced levels of Lrp4 protein expression and MuSK activation in muscle of aged mice, suggesting impaired MuSK-mediated signaling due to loss of Lrp4 protein. Indeed, the authors demonstrated that transgenic expression of Lrp4 in skeletal muscle from the embryonic stage alleviates NMJ denervation and improves neuromuscular transmission and muscle strength in aged mice ( Zhao et al., 2018 ). Also, they found that Lrp4 interacts with sarcoglycan α (SGα) and demonstrated that intramuscular injection with an AAV serotype 9 vector expressing SGα fused with green fluorescent protein (GFP) (AAV9-SGα-GFP) at 22.5 months of age resulted in increased NMJ innervation, neuromuscular transmission, and muscle strength as compared with the AAV9-GFP-treated controls in 24-mo mice.…”

Section: Discussionmentioning

confidence: 99%

DOK7 Gene Therapy Enhances Neuromuscular Junction Innervation and Motor Function in Aged Mice

et al. 2020

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Summary Muscle denervation at the neuromuscular junction (NMJ), the essential synapse between motor neuron and skeletal muscle, is associated with age-related motor impairment. Therefore, improving muscle innervation at aged NMJs may be an effective therapeutic strategy for treating the impairment. We previously demonstrated that the muscle protein Dok-7 plays an essential role in NMJ formation, and, indeed, its forced expression in muscle enlarges NMJs. Moreover, therapeutic administration of an adeno-associated virus vector encoding human Dok-7 ( DOK7 gene therapy) suppressed muscle denervation and enhanced motor activity in a mouse model of amyotrophic lateral sclerosis (ALS). Here, we show that DOK7 gene therapy significantly enhances motor function and muscle strength together with NMJ innervation in aged mice. Furthermore, the treated mice showed greatly increased compound muscle action potential (CMAP) amplitudes compared with the controls, suggesting enhanced neuromuscular transmission. Thus, therapies aimed at enhancing NMJ innervation have potential for treating age-related motor impairment.

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“…However, CMS is not a degenerative disorder like aging but a developmental disorder, which has been reviewed previously ( Engel et al, 2010 , 2015 ; Webster, 2018 ). In aged mice, the agrin-LRP4-MuSK-AChR signaling pathway is implicated in aging-associated NMJ deficits ( Zhao et al, 2018 ). LRP4 protein levels are decreased in aged muscles and restoring the levels of LRP4 by transgenic expression or stabilization with sarcoglycan alpha maintained NMJ innervation, alleviated AChR fragmentation, and improved synaptic transmission ( Zhao et al, 2018 ).…”

Section: Comparison With Other Diseases That Affect the Nmjmentioning

confidence: 99%

“…In aged mice, the agrin-LRP4-MuSK-AChR signaling pathway is implicated in aging-associated NMJ deficits ( Zhao et al, 2018 ). LRP4 protein levels are decreased in aged muscles and restoring the levels of LRP4 by transgenic expression or stabilization with sarcoglycan alpha maintained NMJ innervation, alleviated AChR fragmentation, and improved synaptic transmission ( Zhao et al, 2018 ). Furthermore, viral-mediated upregulation of DOK7 in aged mouse muscle significantly enhanced motor function, muscle strength, NMJ innervation, and compound muscle action potential amplitudes ( Ueta et al, 2020 ).…”

Section: Comparison With Other Diseases That Affect the Nmjmentioning

confidence: 99%