TY - JOUR
T1 - The Rho guanine dissociation inhibitor α inhibits skeletal muscle Rac1 activity and insulin action
AU - Møller, Lisbeth L V
AU - Ali, Mona Sadek
AU - Davey, Jonathan
AU - Raun, Steffen Henning
AU - Andersen, Nicoline Resen
AU - Long, Jonathan Z
AU - Qian, Hongwei
AU - Jeppesen, Jacob Fuglsbjerg
AU - Henriquez-Olguin, Carlos
AU - Frank, Emma
AU - Jensen, Thomas Elbenhardt
AU - Højlund, Kurt
AU - Wojtaszewski, Jørgen
AU - Nielsen, Joachim
AU - Chiu, Tim T
AU - Jedrychowski, Mark P
AU - Gregorevic, Paul
AU - Klip, Amira
AU - Richter, Erik A.
AU - Sylow, Lykke
N1 - CURIS 2023 NEXS 152
PY - 2023
Y1 - 2023
N2 - The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.
AB - The molecular events governing skeletal muscle glucose uptake have pharmacological potential for managing insulin resistance in conditions such as obesity, diabetes, and cancer. With no current pharmacological treatments to target skeletal muscle insulin sensitivity, there is an unmet need to identify the molecular mechanisms that control insulin sensitivity in skeletal muscle. Here, the Rho guanine dissociation inhibitor α (RhoGDIα) is identified as a point of control in the regulation of insulin sensitivity. In skeletal muscle cells, RhoGDIα interacted with, and thereby inhibited, the Rho GTPase Rac1. In response to insulin, RhoGDIα was phosphorylated at S101 and Rac1 dissociated from RhoGDIα to facilitate skeletal muscle GLUT4 translocation. Accordingly, siRNA-mediated RhoGDIα depletion increased Rac1 activity and elevated GLUT4 translocation. Consistent with RhoGDIα's inhibitory effect, rAAV-mediated RhoGDIα overexpression in mouse muscle decreased insulin-stimulated glucose uptake and was detrimental to whole-body glucose tolerance. Aligning with RhoGDIα's negative role in insulin sensitivity, RhoGDIα protein content was elevated in skeletal muscle from insulin-resistant patients with type 2 diabetes. These data identify RhoGDIα as a clinically relevant controller of skeletal muscle insulin sensitivity and whole-body glucose homeostasis, mechanistically by modulating Rac1 activity.
KW - Insulin sensitivity
KW - Skeletal muscle
KW - Glucose uptake
KW - GLUT4 translocation
KW - Type 2 diabetes
KW - Mice
KW - Rho guanine nucleotide Dissociation Inhibitor alpha/metabolism
KW - Insulin resistance
KW - Diabetes Mellitus, Type 2 / Metabolism
U2 - 10.1073/pnas.2211041120
DO - 10.1073/pnas.2211041120
M3 - Journal article
C2 - 37364105
VL - 120
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
SN - 0027-8424
IS - 27
M1 - e2211041120
ER -