Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity: The role of RhoGDIα and group I PAKs

Publikation: Bog/antologi/afhandling/rapportPh.d.-afhandlingForskning

Skeletal muscle is the largest organ and critical for whole-body glycemic control. Furthermore, skeletal muscles are crucial for maintaining an independent lifestyle, and muscle strength is inversely associated with death from all causes. Since skeletal muscle wasting is common in several metabolic pathological conditions associated with muscle insulin resistance, understanding the molecular mechanisms underlying this phenomenon is vital. In response to insulin but also muscle contraction, glucose transporter (GLUT)-4 is translocated to the plasma membrane of the muscle fibre resulting in increased glucose uptake. Although the intracellular signalling mechanisms in response to insulin and muscle contraction has been extensively studied, the signalling pathways are still incompletely understood. The Rho family GTPase Rac1 has been implicated in both insulin- and contraction-stimulated GLUT4 translocation. However, the upstream regulators involved in the increased Rac1 activity and downstream mechanisms are incompletely understood. The present PhD thesis aimed to identify the Rac1 interactome and reveal potential candidates involved in the regulation of Rac1 activity and downstream mechanisms. In continuation, the effect of RhoGDIα overexpression or knockdown on insulin-stimulated Rac1-activity, GLUT4 translocation and glucose uptake were investigated in muscle cells and mouse. Using a pharmacological inhibitor and transgenic mice, the role of group I PAKs, downstream of Rac1, in the regulation of glucose uptake in response to insulin and muscle contraction was explored. In the present PhD thesis, RhoGDIα was identified as an endogenous inhibitor of Rac1 in skeletal muscle cells and additionally a negative regulator of insulin sensitivity in vivo. Musclespecific RhoGDIα overexpression impaired whole-body glucose tolerance in mice. Moreover, RhoGDIα protein content was increased in skeletal muscle from insulin-resistant patients with type 2 diabetes potentially explaining the previously reported dysfunctional insulin-stimulatedRho GTPase signalling in these subjects. Interestingly, RhoGDIα was also identified as a negative regulator of muscle mass. Lastly, downstream of Rac1, glucose uptake in response to insulin and electrically-induced muscle contraction was found to partly depend on PAK2, but not PAK1, in glycolytic mouse skeletal muscle. In conclusion, RhoGDIα is identified as a novel regulator of muscle mass and insulin sensitivity and evidence is provided that Rac1-mediated glucose uptake partly depends on PAK2, but not PAK1.
OriginalsprogEngelsk
ForlagDepartment of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen
Antal sider243
StatusUdgivet - 2020

ID: 243343729