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VAChT overexpression increases acetylcholine at the synaptic cleft and accelerates aging of neuromuscular junctions

Overview of attention for article published in Skeletal Muscle, October 2016
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  • In the top 25% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (84th percentile)
  • Good Attention Score compared to outputs of the same age and source (70th percentile)

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Title
VAChT overexpression increases acetylcholine at the synaptic cleft and accelerates aging of neuromuscular junctions
Published in
Skeletal Muscle, October 2016
DOI 10.1186/s13395-016-0105-7
Pubmed ID
Authors

Satoshi Sugita, Leland L. Fleming, Caleb Wood, Sydney K. Vaughan, Matheus P. S. M. Gomes, Wallace Camargo, Ligia A. Naves, Vania F. Prado, Marco A. M. Prado, Cristina Guatimosim, Gregorio Valdez

Abstract

Cholinergic dysfunction occurs during aging and in a variety of diseases, including amyotrophic lateral sclerosis (ALS). However, it remains unknown whether changes in cholinergic transmission contributes to age- and disease-related degeneration of the motor system. Here we investigated the effect of moderately increasing levels of synaptic acetylcholine (ACh) on the neuromuscular junction (NMJ), muscle fibers, and motor neurons during development and aging and in a mouse model for amyotrophic lateral sclerosis (ALS). Chat-ChR2-EYFP (VAChT(Hyp)) mice containing multiple copies of the vesicular acetylcholine transporter (VAChT), mutant superoxide dismutase 1 (SOD1(G93A)), and Chat-IRES-Cre and tdTomato transgenic mice were used in this study. NMJs, muscle fibers, and α-motor neurons' somata and their axons were examined using a light microscope. Transcripts for select genes in muscles and spinal cords were assessed using real-time quantitative PCR. Motor function tests were carried out using an inverted wire mesh and a rotarod. Electrophysiological recordings were collected to examine miniature endplate potentials (MEPP) in muscles. We show that VAChT is elevated in the spinal cord and at NMJs of VAChT(Hyp) mice. We also show that the amplitude of MEPPs is significantly higher in VAChT(Hyp) muscles, indicating that more ACh is loaded into synaptic vesicles and released into the synaptic cleft at NMJs of VAChT(Hyp) mice compared to control mice. While the development of NMJs was not affected in VAChT(Hyp) mice, NMJs prematurely acquired age-related structural alterations in adult VAChT(Hyp) mice. These structural changes at NMJs were accompanied by motor deficits in VAChT(Hyp) mice. However, cellular features of muscle fibers and levels of molecules with critical functions at the NMJ and in muscle fibers were largely unchanged in VAChT(Hyp) mice. In the SOD1(G93A) mouse model for ALS, increasing synaptic ACh accelerated degeneration of NMJs caused motor deficits and resulted in premature death specifically in male mice. The data presented in this manuscript demonstrate that increasing levels of ACh at the synaptic cleft promote degeneration of adult NMJs, contributing to age- and disease-related motor deficits. We thus propose that maintaining normal cholinergic signaling in muscles will slow degeneration of NMJs and attenuate loss of motor function caused by aging and neuromuscular diseases.

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Mendeley readers

Mendeley readers

The data shown below were compiled from readership statistics for 78 Mendeley readers of this research output. Click here to see the associated Mendeley record.

Geographical breakdown

Country Count As %
United Kingdom 1 1%
Unknown 77 99%

Demographic breakdown

Readers by professional status Count As %
Student > Ph. D. Student 19 24%
Researcher 13 17%
Student > Bachelor 7 9%
Student > Master 7 9%
Other 4 5%
Other 8 10%
Unknown 20 26%
Readers by discipline Count As %
Neuroscience 19 24%
Agricultural and Biological Sciences 12 15%
Biochemistry, Genetics and Molecular Biology 11 14%
Medicine and Dentistry 7 9%
Immunology and Microbiology 2 3%
Other 4 5%
Unknown 23 29%
Attention Score in Context

Attention Score in Context

This research output has an Altmetric Attention Score of 11. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 26 October 2017.
All research outputs
#2,714,778
of 22,890,496 outputs
Outputs from Skeletal Muscle
#71
of 362 outputs
Outputs of similar age
#48,162
of 319,501 outputs
Outputs of similar age from Skeletal Muscle
#3
of 10 outputs
Altmetric has tracked 22,890,496 research outputs across all sources so far. Compared to these this one has done well and is in the 87th percentile: it's in the top 25% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 362 research outputs from this source. They typically receive more attention than average, with a mean Attention Score of 8.2. This one has done well, scoring higher than 80% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 319,501 tracked outputs that were published within six weeks on either side of this one in any source. This one has done well, scoring higher than 84% of its contemporaries.
We're also able to compare this research output to 10 others from the same source and published within six weeks on either side of this one. This one has scored higher than 7 of them.