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AANS Beyond 2021: Scientific Papers Collection
Carboxyl Terminal Modulator Protein Knockout Mitig ...
Carboxyl Terminal Modulator Protein Knockout Mitigates Denervation Atrophy in a Mouse Model of Sciatic Nerve Injury
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Video Transcription
Hi, I'm Chris Wilson from Indiana University, and I'll be presenting my research on carboxyl terminal modulator protein knockout and the fact that it mitigates denervation atrophy in a mouse model of sciatic nerve injury. CTMP, or carboxyl terminal modulator protein, is an endogenous inhibitor of AKT kinase activation. AKT kinase, or phosphokinase B as it's otherwise known, when it's active promotes cell survival. Thus, during downregulation in skeletal muscle that's afflicted by trauma or neurodegeneration, that results in muscle atrophy. The discovery of CTMP as it relates to AKT was in glioblastoma cell culture lines, and what was noticed is that activated AKT expression was actually elevated in GBM cell lines relative to those in the normal brain. It was also found that CTMP co-localizes with AKT, which resulted in hypotheses of their interaction. Along the same lines, CTMP expression was downregulated in GBM cell lines, thus furthering the hypothesis that as CTMP is downregulated, that results somehow in AKT upregulation. Notably, during cell stress, CTMP was increased and AKT activity was also decreased. Our hypothesis for our project was that CTMP knockout, or elimination of the function of this protein, would limit denervation-mediated muscle atrophy in mice after a sciatic nerve injury compared to those with wild-type function. To test this hypothesis, we evaluated 13 wild-type mice and 12 CTMP global knockout mice and transected their right sciatic nerve. We then allowed them to recover for seven days and euthanized the mice thereafter and completed protein analysis as well as histology and immunolabeling. We found that in denervated muscles in the wild-type mice, CTMP activity and presence increased relative to the under-injured mice. We did also confirm that CTMP was in fact knocked out in our knockout mice and was very much present and active in the wild-type mice. Phenotypically, we found that in the knockout mice, there was less muscle atrophy in the setting of injury when compared to the wild-type injured mice, which had more muscle atrophy. Now, how does this occur? There may be several mechanisms by which CTMP knockout limits denervation atrophy. However, some of them are likely related to a decrease in the expression of myostatin, MRF1, and LC3-2, all of which are associated with muscle atrophy and autophagosome and apoptosome creation. We also found that nearly universally, inflammatory marker expression was reduced in the knockout mice relative to the wild-type denervated mice, and these were six of the inflammatory markers that we evaluated, all of which were significantly decreased in the knockout mice. Denervated muscle in the knockout mice also had more expression of cell survival and anabolic proteins. This included AKT, as well as protein S6, which is involved in ribosome and protein production, GSK3β, which is associated with glycogenesis, and 4-EBP1 protein, which is also associated with ribosome protein production, as well as translation. So, in conclusion, we found that CTMP knockout reduces muscle atrophy after denervation by multiple mechanisms, including reducing atrophy-promoting genes, reducing apoptosome construction, as well as reducing inflammatory responses to the injury, and increasing anabolic pathways. We have ongoing study regarding cell culture, axonal regeneration across the injury site, and lumbar spinal cord growth factor, cell body atrophy, and dendrite retraction, as well as functional analysis of the mice. Here are our references. Thank you.
Video Summary
In this video, Chris Wilson from Indiana University presents research on the role of carboxyl terminal modulator protein (CTMP) in mitigating denervation atrophy in a mouse model of sciatic nerve injury. CTMP inhibits AKT kinase activation, which promotes cell survival. The study found that CTMP expression is downregulated in glioblastoma cell lines, leading to increased AKT activation. To test their hypothesis, the researchers evaluated wild-type mice and CTMP knockout mice after sciatic nerve injury. They discovered that knockout mice experienced less muscle atrophy compared to wild-type mice. The study suggests that CTMP knockout reduces muscle atrophy through mechanisms such as reducing atrophy-promoting genes and inflammatory responses, and increasing anabolic pathways. Ongoing studies include cell culture, axonal regeneration, and functional analysis.
Keywords
carboxyl terminal modulator protein
CTMP
denervation atrophy
sciatic nerve injury
AKT kinase activation
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