Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle

Lykke Sylow; Thomas Elbenhardt Jensen; Maximilian Kleinert; Joshua Roger Mouatt; Stine Just Maarbjerg; Jacob Fuglsbjerg Jeppesen; Clara Prats Gavalda; Tim T Chiu; Shlomit Boguslavsky; Amira Klip; Peter Schjerling; Erik Richter

doi:10.2337/db12-0491

Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle

Lykke Sylow, Thomas Elbenhardt Jensen, Maximilian Kleinert, Joshua Roger Mouatt, Stine Just Maarbjerg, Jacob Fuglsbjerg Jeppesen, Clara Prats Gavalda, Tim T Chiu, Shlomit Boguslavsky, Amira Klip, Peter Schjerling, Erik Richter

95 Citations (Scopus)

Abstract

In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contractioninduced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice ((∼60-100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of musclespecific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

Original language	English
Journal	Diabetes
Volume	62
Issue number	4
Pages (from-to)	1139-1151
Number of pages	13
ISSN	0012-1797
DOIs	https://doi.org/10.2337/db12-0491
Publication status	Published - Apr 2013

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title = "Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle",

abstract = "In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contractioninduced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice ((∼60-100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of musclespecific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.",

author = "Lykke Sylow and Jensen, {Thomas Elbenhardt} and Maximilian Kleinert and Mouatt, {Joshua Roger} and Maarbjerg, {Stine Just} and Jeppesen, {Jacob Fuglsbjerg} and {Prats Gavalda}, Clara and Chiu, {Tim T} and Shlomit Boguslavsky and Amira Klip and Peter Schjerling and Erik Richter",

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doi = "10.2337/db12-0491",

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T1 - Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle

AU - Sylow, Lykke

AU - Jensen, Thomas Elbenhardt

AU - Kleinert, Maximilian

AU - Mouatt, Joshua Roger

AU - Maarbjerg, Stine Just

AU - Jeppesen, Jacob Fuglsbjerg

AU - Prats Gavalda, Clara

AU - Chiu, Tim T

AU - Boguslavsky, Shlomit

AU - Klip, Amira

AU - Schjerling, Peter

AU - Richter, Erik

N1 - CURIS 2013 NEXS 015

PY - 2013/4

Y1 - 2013/4

N2 - In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contractioninduced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice ((∼60-100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of musclespecific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

AB - In skeletal muscle, the actin cytoskeleton-regulating GTPase, Rac1, is necessary for insulin-dependent GLUT4 translocation. Muscle contraction increases glucose transport and represents an alternative signaling pathway to insulin. Whether Rac1 is activated by muscle contraction and regulates contractioninduced glucose uptake is unknown. Therefore, we studied the effects of in vivo exercise and ex vivo muscle contractions on Rac1 signaling and its regulatory role in glucose uptake in mice and humans. Muscle Rac1-GTP binding was increased after exercise in mice ((∼60-100%) and humans (∼40%), and this activation was AMP-activated protein kinase independent. Rac1 inhibition reduced contraction-stimulated glucose uptake in mouse muscle by 55% in soleus and by 20-58% in extensor digitorum longus (EDL; P < 0.01). In agreement, the contraction-stimulated increment in glucose uptake was decreased by 27% (P = 0.1) and 40% (P < 0.05) in soleus and EDL muscles, respectively, of musclespecific inducible Rac1 knockout mice. Furthermore, depolymerization of the actin cytoskeleton decreased contraction-stimulated glucose uptake by 100% and 62% (P < 0.01) in soleus and EDL muscles, respectively. These are the first data to show that Rac1 is activated during muscle contraction in murine and human skeletal muscle and suggest that Rac1 and possibly the actin cytoskeleton are novel regulators of contraction-stimulated glucose uptake.

U2 - 10.2337/db12-0491

DO - 10.2337/db12-0491

M3 - Journal article

C2 - 23274900

SN - 0012-1797

VL - 62

SP - 1139

EP - 1151

JO - Diabetes

JF - Diabetes

IS - 4

ER -

Rac1 is a novel regulator of contraction-stimulated glucose uptake in skeletal muscle

Abstract

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