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ATM protein as an important molecular regulator of mitochondrial function and glucose metabolism in muscle cells

Grant number: 14/10236-4
Support Opportunities:Scholarships in Brazil - Post-Doctorate
Effective date (Start): November 01, 2014
Effective date (End): January 12, 2016
Field of knowledge:Biological Sciences - Biochemistry - Metabolism and Bioenergetics
Principal Investigator:Leonardo dos Reis Silveira
Grantee:Amanda Roque Martins
Host Institution: Instituto de Biologia (IB). Universidade Estadual de Campinas (UNICAMP). Campinas , SP, Brazil


Insulin resistance in skeletal muscle is a common characteristic of diabetic patients. It was recently demonstrated a strong association between ATM deficiency and oxidative stress, a favorable condition for the development of neurodegenerative, metabolic and oncogenic diseases. Under oxidative stress state, the transcription of PGC1-± is downregulated, increasing evidence that activation of Akt may be strongly associated with PGC1-± activation. Therefore, we propose the hypothesis that ATM can regulate the expression of PGC1-± protecting muscle cells against oxidative stress and the installation of insulin resistance. Thus, we propose to investigate the effect of overexpression and also reduced expression of ATM in transcription and protein content of PGC1-±, oxygen consumption, Akt phosphorylation, in glucose uptake and expression of the antioxidants Sod, Cat, Gpx and Gr in control and insulin-resistant cells. Further, we aim to investigate the effect of ATM overexpression on the phosphorylation of proteins involved in the activation of PGC1-± including AMPK, CREB and 38 MAKP in control cells. As a control experiment we will investigate, in a mutant strain of fibroblasts A38 (Atm-/-) and A29 (Atm+/+), the effect of superexpression or inhibition of ATM on gene expression and content of PGC1-± protein, oxygen consumption, Akt phosphorylation, glucose uptake and the expression of antioxidants Sod, Cat, Gpx and Gr. Finally, knowing the mechanism by which the ATM protein regulates mitochondrial function protecting muscle tissue from oxidative damage may open new therapeutic perspectives in control type 2 diabetes.

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