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

Standard

Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity : The role of RhoGDIα and group I PAKs. / Møller, Lisbeth L V.

Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2020. 243 s.

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

Harvard

Møller, LLV 2020, Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity: The role of RhoGDIα and group I PAKs. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen.

APA

Møller, L. L. V. (2020). Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity: The role of RhoGDIα and group I PAKs. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen.

Vancouver

Møller LLV. Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity: The role of RhoGDIα and group I PAKs. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2020. 243 s.

Author

Møller, Lisbeth L V. / Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity : The role of RhoGDIα and group I PAKs. Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen, 2020. 243 s.

Bibtex

@phdthesis{d41bfeb1f30042148e05e8db8360f1bc,
title = "Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity: The role of RhoGDIα and group I PAKs",
abstract = "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.",
author = "M{\o}ller, {Lisbeth L V}",
year = "2020",
language = "English",
publisher = "Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen",

}

RIS

TY - BOOK

T1 - Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity

T2 - The role of RhoGDIα and group I PAKs

AU - Møller, Lisbeth L V

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

M3 - Ph.D. thesis

BT - Novel molecular mechanisms in Rho GTPasemediated regulation of muscle mass and insulin sensitivity

PB - Department of Nutrition, Exercise and Sports, Faculty of Science, University of Copenhagen

ER -

ID: 243343729