京都大学 / 0048 / 新制・課程博士 / 博士(医学) / 甲第19608号 / 医博第4115号 / 新制||医||1015(附属図書館) / 32644 / 京都大学大学院医学研究科医学専攻 / (主査)教授 大森 孝一, 教授 鈴木 茂彦, 教授 影山 龍一郎 / 学位規則第4条第1項該当 / Doctor of Medical Science / Kyoto University / DFAM

No description available.

Spinal Muscular Atrophy (SMA) is a debilitating neurodegenerative disease resulting in death of the lower motor neurons, muscle atrophy, and in severe cases death. Due to mutations or deletions in the Survival Motor Neuron 1 (SMN1) gene, levels of functional SMN protein product are decreased. While SMA was previously described as a motor neuron exclusive disorder, recent evidence suggests that many tissue and cell types throughout the body are affected. The objective of our study was to outline the effects of varying levels of SMN depletion on two genes of interest, namely Insulin-like growth factor 1 (Igf-1) and Tumor suppressor protein 53 (Trp53) in multiple tissues throughout disease course. The severe Smn2B/- and mild Smn2B/-; SMN2+/- mouse models of SMA were utilized in our studies to determine the levels of mRNA expression and subsequent protein output for these two genes. We employed RT-qPCR, western blot, and ELISA experimental methods. In Smn2B/- mice, Igf-1 mRNA was substantially decreased in symptomatic liver tissue. This was accompanied by widespread decrease in IGF-1 protein in peripheral tissues. Interestingly, this depletion effect on Igf-1 was not observed in the mild mouse model. Our analysis also showed that Trp53 mRNA was dramatically increased within tibialis anterior skeletal muscle of symptomatic Smn2B/- mice, alongside an upregulation of factors involved in p53 mediated apoptosis. Once again, this effect was not observed in the mild Smn2B/-; SMN2+/- mouse model. Overall, we have demonstrated that the extent of SMN depletion, determines whether the expression of Igf-1 and Trp53 is perturbed, suggesting that disease severity is an important factor in what pathways are affected. Finally, we show that alterations in gene expression patterns or subsequent protein levels act in a tissue-specific fashion. More investigation is encouraged to highlight IGF-1’s role as a potential SMN-independent therapeutic for SMA.

No description available.

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Thesis (Ph. D.)--University of Washington, 2007. / Vita. Includes bibliographical references (leaves 112-138).

Diss. (sammanfattning) Stockholm : Karolinska institutet, 2005. / Härtill 5 uppsatser.

Diss. (sammanfattning) Linköping : Univ., 2004. / Härtill 4 uppsatser.

No description available.

Denervation leads to skeletal muscle atrophy, which is a decrease in muscle mass and force; the latter exceeding expectation from mass loss. In some cases, nerve regeneration following an injury takes several months. During this time, muscle mass and force loss become severe as fibers are replaced by connective and fat tissue, which can further prolongs normal muscle function recovery once reinnervation occurs. The objectives of this study were 1) document the angiotensin 1-7 (Ang 1-7) hypertrophic effect in innervated mouse skeletal muscle; 2) test the hypothesis that Ang 1-7 prevents muscle atrophy and maintain force following short 2 and 4 week denervation; 3) as well as following long 16 week denervation. Innervated and denervated mice were treated with Ang 1-7 or diminazene aceturate (DIZE), an ACE2 activator, to increase plasma Ang 1-7 level. In normal innervated extensor digitorum longus (EDL) and soleus muscle, Ang 1-7 increased muscle weight, cross sectional area (CSA) and tetanic force, which represents the muscle maximum force. During the short denervation period (2-4 weeks), Ang 1-7 did not prevent muscle mass and CSA loss, but fully abolished the loss of normalized tetanic force to CSA while accentuating twitch force. Normalized tetanic force was maintained as Ang 1-7 partially reduced the extent of membrane depolarization which normally observed with denervation, and it fully prevented the loss of membrane excitability. The protective effect of Ang 1-7 on maximum tetanic force was also observed after 16 weeks of denervation, but only in EDL not in soleus. About 35-40% of denervated EDL and soleus muscle fibers became reinnervated over the 16 week period and Ang 1-7 enhanced the recovery of muscle mass and tetanic force in both EDL and soleus. All Ang 1-7 effects on twitch and tetanic force were completely blocked by A779, a Mas receptor (MasR) antagonist, and were not observed in MasR deficient (MasR / ) muscles. Ang 1-7 did not affect how denervation modulates changes in the protein content MuRF-1 atrogin-1, two atrophic proteins, total and phosphorylated Akt, S6K and 4EPB, three hypertrophic proteins. So, the Ang 1-7 effect involves an activation of its MasR, but it is not clear which intracellular pathway it then affects. This is the first study providing evidence that Ang 1-7 maintains normal muscle function in terms of tetanic force and membrane excitability during 2, 4 and 16 week denervation periods.