Acetylation and contraction-mediated glucose uptake

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PROJECT SUMMARY Contraction-stimulated glucose uptake is important to the maintenance of ATP production during exercise, especially exercise of high-intensity. It is also a cornerstone for the treatment and prevention of clinical hyperglycemia and the development of type 2 diabetes. Thus, understanding the regulation of contraction- stimulated glucose uptake is important for the development of strategies to optimize skeletal muscle glucose metabolism. The long-term objective of this research is to elucidate the mechanisms that regulate contraction- stimulated glucose uptake. The fundamental premise of this application is that lysine acetylation of GLUT4- trafficking proteins is necessary for contraction-stimulated glucose uptake. Accordingly, in this application our primary objective is to elucidate the importance of the acetyltransferases, p300 (E1A binding protein p300) and CBP (cAMP response element-binding protein binding protein) to contraction-stimulated glucose uptake, and to identify the GLUT4 trafficking proteins that are acetylated in response to contraction. Our central hypothesis is that p300 and CBP regulate contraction-stimulated glucose uptake through acetylation of GLUT4-trafficking proteins, and that they do so independent of their common role as transcriptional regulators. To address this hypothesis, we will measure basal and contraction-stimulated glucose uptake and plasma membrane GLUT4 abundance in mouse skeletal muscle in which p300 and CBP acetyltransferase activity is acutely regulated. Specifically, Aim #1 will investigate the contributions of p300/CBP to contraction-stimulated glucose uptake and plasma membrane GLUT4 translocation, including the importance of gene transcription to their regulatory effects. Aim #2 will define the GLUT4 trafficking proteins that are acetylated in response to contraction, including the contributions of p300/CBP. Altogether, these studies will provide insight into the contribution of p300/CBP and lysine acetylation to contraction-stimulated glucose uptake. Altogether, because of this work, an improved understanding of the signalling that regulates glucose uptake by skeletal muscle is anticipated, which by extension is expected to translate into tangible benefits to human health.