TY - JOUR

T1 - Multiple signalling pathways redundantly control glucose transporter GLUT4 gene transcription in skeletal muscle

AU - Murgia, Marta

AU - Elbenhardt Jensen, Thomas

AU - Cusinato, Marzia

AU - Garcia, Marta

AU - Richter, Erik A.

AU - Schiaffino, Stefano

N1 - CURIS 2009 5200 111

PY - 2009

Y1 - 2009

N2 - Increased GLUT4 expression in skeletal muscle is an important benefit of regular exercise, resulting in improved insulin sensitivity and glucose tolerance. The Ca2+/calmodulin-dependent-kinase II (CaMKII), calcineurin and AMPK pathways have been implicated in GLUT4 gene regulation based on pharmacological evidence. Here, we have used a more specific genetic approach to establish the relative role of the three pathways in fast and slow muscles. Plasmids coding for protein inhibitors of CaMKII or calcineurin were co-transfected in vivo with a GLUT4 enhancer-reporter construct either in normal mice or in mice expressing a dominant negative AMPK mutant. GLUT4 reporter activity was not inhibited in the slow soleus muscle by blocking either CaMKII or calcineurin alone, but was inhibited by blocking both pathways. GLUT4 reporter activity was likewise unchanged in the soleus of dnAMPK mice, but was significantly reduce by incapacitation of either CaMKII or calcineurin in these mice. On the other hand, in the fast tibialis anterior muscle, calcineurin appears to exert a prominent role in the control of GLUT4 reporter activity, independent of CaMKII and AMPK. The results point to a muscle type-specific and redundant regulation of GLUT4 enhancer based on the interplay of multiple signalling pathways, all of which are known to affect MEF2 transcriptional activity, a point of convergence of different pathways on muscle gene regulation.

AB - Increased GLUT4 expression in skeletal muscle is an important benefit of regular exercise, resulting in improved insulin sensitivity and glucose tolerance. The Ca2+/calmodulin-dependent-kinase II (CaMKII), calcineurin and AMPK pathways have been implicated in GLUT4 gene regulation based on pharmacological evidence. Here, we have used a more specific genetic approach to establish the relative role of the three pathways in fast and slow muscles. Plasmids coding for protein inhibitors of CaMKII or calcineurin were co-transfected in vivo with a GLUT4 enhancer-reporter construct either in normal mice or in mice expressing a dominant negative AMPK mutant. GLUT4 reporter activity was not inhibited in the slow soleus muscle by blocking either CaMKII or calcineurin alone, but was inhibited by blocking both pathways. GLUT4 reporter activity was likewise unchanged in the soleus of dnAMPK mice, but was significantly reduce by incapacitation of either CaMKII or calcineurin in these mice. On the other hand, in the fast tibialis anterior muscle, calcineurin appears to exert a prominent role in the control of GLUT4 reporter activity, independent of CaMKII and AMPK. The results point to a muscle type-specific and redundant regulation of GLUT4 enhancer based on the interplay of multiple signalling pathways, all of which are known to affect MEF2 transcriptional activity, a point of convergence of different pathways on muscle gene regulation.

U2 - 10.1113/jphysiol.2009.174888

DO - 10.1113/jphysiol.2009.174888

M3 - Journal article

C2 - 19596898

VL - 587

SP - 4319

EP - 4327

JO - The Journal of Physiology

JF - The Journal of Physiology

SN - 0022-3751

IS - 17

ER -