Acute exposure of L6 myotubes to cis-9, trans-11 and trans-10, cis-12 conjugated linoleic acid isomers stimulates glucose uptake by modulating Ca²⁺/calmodulin-dependent protein kinase II

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• 作者：Suresh K. Mohankumar^a ; ^c ; Carla G. Taylor^a ; ^b ; ^c ; Linda Siemens^a ; ^c ; Peter Zahradka^a ; ^b ; ^c ; ^{peterz@sbrc.ca}
• 关键词：AIP ; autocamtide 2-related inhibitory peptide ; AMP ; adenosine 5-monophosphate ; AMPK ; AMP-activated protein kinase ; AS160 ; Akt substrate-160  ; kDa ; Cai2+ ; intracellular calcium ; CaMK ; Ca2+/calmodulin-dependent protein kinase ; CaMKII ; Ca2+/calmodulin-dep
• 刊名：The International Journal of Biochemistry and Cell Biology
• 出版年：2012
• 期刊代码：127_13572725
• 类别：med
• 出版时间：August, 2012
• 卷：44
• 期：8
• 页码：1321-1330
• 文件大小：1317 K

摘要

Conjugated linoleic acid (CLA), a dietary fat, has been considered beneficial in metabolic syndrome. Despite several findings indicating that CLA improves glucose clearance, little information is available regarding the cellular dynamics of CLA on skeletal muscle. We sought to investigate the role of Ca²⁺/calmodulin-dependent protein kinase II (CaMKII) in cis-9, trans-11(c9,t11) and trans-10, cis-12 (t10,c12) CLA isomer-mediated glucose transport by L6 myotubes. t10,c12-CLA stimulated both intracellular Ca²⁺ release (Ca_i²⁺) and CaMKII phosphorylation, whereas c9,t11-CLA showed only modest effects on both. Sequestering Ca_i²⁺ with BAPTA/AM abrogated the effect of both CLA isomers on Akt substrate-160 kDa (AS160) phosphorylation and glucose uptake by myotubes. Exposing myotubes to KN-93 or autocamtide 2-related inhibitory peptide to block CaMKII activity prevented both CLA isomers from inducing AS160 phosphorylation and glucose transport. Likewise, genetic knockdown of CaMKII in myotubes using siRNA completely abolished CLA isomer-mediated glucose uptake. These results indicate that CLA isomers require Ca_i²⁺-CaMKII to mediate glucose uptake. Evidence that CaMKII blockers inhibit t10,c12-CLA-mediated AMP-activated protein kinase (AMPK) activation indicated that CaMKII acts upstream of AMPK in response to t10,c12-CLA. Lastly, CLA isomers stimulated the formation of reactive oxygen species but had no effect on stress-activated protein kinase/c-jun NH₂-terminal kinase. These data establish that t10,c12-CLA acts via Ca_i²⁺-CaMKII-AMPK-AS160 to stimulate skeletal muscle glucose transport, whereas the mechanism of c9,t11-CLA remains unclear. Given that impairments in muscle glucose utilisation are apparent in metabolic syndrome, delineating the molecular mechanisms by which CLA isomers mediate muscle glucose uptake may identify new approaches to manage this condition.