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Characteristics and Mechanisms of Glucose Hypermetabolism in Denervated Skeletal Muscle : 탈신경근육에서 포도당대사 증진현상의 특성과 기전

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Authors
이승학
Advisor
이시욱
Major
의과대학 의학과
Issue Date
2017-08
Publisher
서울대학교 대학원
Keywords
peripheral nerve injurymuscle denervationglucose metabolism. l8F-fluorodeoxyglucosepositron emission tomographymechanistic target of rapamycin
Description
학위논문 (박사)-- 서울대학교 대학원 의과대학 의학과, 2017. 8. 이시욱.
Abstract
l8F-FDG PET scans were then taken serially to examine the temporal characteristics of glucose hypermetabolism. We also investigated the correlation between the severity of nerve injury and signal intensity of l8F-FDG uptake in a partial nerve injury model by partially ligating the peroneal division of the sciatic nerve. Western blot analyses were performed to investigate the expression of several important intracellular pathways involved in glucose metabolism. Finally, the effect of the mechanistic target of rapamycin (mTOR) pathway was examined by analyzing the changes in glucose metabolism in the denervated muscles of rats treated with rapamycin, an inhibitor of mTOR.
We calculated the mean lesion-to-normal counts ratio (LNRmean) as an quantitative value of l8F-FDG uptake signal. Our data showed that glucose metabolism in the denervated anterior compartment muscles of the complete injury model significantly increased starting from the second day of nerve injury (LNRmean, sham, 1.332 ± 0.205
LNRmean, denervation, 3.151 ± 0.822
n = 5
P < 0.05). Increased uptake of l8F-FDG continued for up to 12 weeks (LNRmean, sham, 1.316 ± 0.275
LNRmean, denervation, 2.661 ± 0.749
P < 0.05). In addition, the peak of glucose hypermetabolism appeared 1 week after nerve injury, and was more than seven-fold higher than that of the sham side (LNRmean, sham, 1.360 ± 0.452
LNRmean, denervation, 10.340 ± 4.094
P < 0.05). In the partial injury model, l8F-FDG uptake was lower compared to that in the complete nerve injury model
there was a strong correlation between the quantified nerve injury severity and l8F-FDG uptake signal in the denervated muscle (Pearsons correlation coefficient, 0.63
P < 0.05). Western blot analyses of denervated muscles 1 week after complete nerve injury showed significant increase in the expressions of mTOR (sham, 0.103 ± 0.118
denervation, 0.703 ± 0.466
n = 6
P < 0.05), phospho-mTOR (sham, 0.055 ± 0.0232
denervation, 0.981 ± 0.590
P < 0.05), Bax (sham, 0.358 ± 0.101
denervation, 1.006 ± 0.127
P < 0.05), and Bcl-2 (sham, 0.862 ± 0.128
denervation, 1.060 ± 0.062
Peripheral nerve injury is caused by various etiologies including trauma, leading to denervation of muscles. Muscle denervation is accompanied by extensive molecular changes related to muscle structure, dynamic properties, cell membrane properties, muscle activation processes, etc., over time. Among them, glucose hypermetabolism has been demonstrated through l8F-fluorodeoxyglucose (l8F-FDG) positron emission tomography (PET) in animal experiments
moreover, the same phenomenon has been confirmed in humans. The purpose of the present study is to investigate characteristics of glucose hypermetabolism in muscle denervation and explore its molecular mechanisms. Through this, the foundation for clinical applications of this physiological phenomenon can be established.
Sciatic nerves were transected in rats to generate a complete nerve injury model
P < 0.05). PET scans taken 1 week after complete sciatic nerve injury in rats, treated with rapamycin showed increased l8F-FDG uptake in denervated muscle compared to the sham side. However, it was about 40% of the signal intensity of the untreated complete injury model at the same time point. (LNRmean, denervation, rapamycin treated, 4.185 ± 1.253
LNRmean, denervation, rapamycin untrerated, 10.340 ± 4.094
P < 0.05)
The present study showed that glucose hypermetabolism in the denervated muscle begins at day 2, lasts up to 12 weeks, and is maximal at 1 week after denervation in a rat sciatic transection model. Increased glucose uptake was related to the degree of nerve injury severity. The molecular mechanism of this phenomenon seems to be heterogeneous and multiphasic. The mTOR pathway is thought to play an important role, especially at the time of maximal hypermetabolism. Based on these results, a new functional imaging study can be developed for diagnosis and evaluation of peripheral neuromuscular disorders.
Language
English
URI
https://hdl.handle.net/10371/137060
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College of Medicine/School of Medicine (의과대학/대학원)Dept. of Medicine (의학과)Theses (Ph.D. / Sc.D._의학과)
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