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Evidence for the involvement of CaMKII and AMPK in Ca²⁺-dependent signaling pathways regulating FA uptake and oxidation in contracting rodent muscle

Departments of Kinesiology and Biological Sciences, College of Letters, Arts, and Sciences, University of Southern California, Los Angeles, California

Submitted 5 December 2007 ; accepted in final form 27 February 2008

Calcium-calmodulin/dependent protein kinase II (CaMKII), AMP-activated protein kinase (AMPK), and extracellular signal-regulated kinase (ERK1/2) have each been implicated in the regulation of substrate metabolism during exercise. The purpose of this study was to determine whether CaMKII is involved in the regulation of FA uptake and oxidation and, if it is involved, whether it does so independently of AMPK and ERK1/2. Rat hindquarters were perfused at rest with (n = 16) or without (n = 10) 3 mM caffeine, or during electrical stimulation (n = 14). For each condition, rats were subdivided and treated with 10 µM of either KN92 or KN93, inactive and active CaMKII inhibitors, respectively. Both caffeine treatment and electrical stimulation significantly increased FA uptake and oxidation. KN93 abolished caffeine-induced FA uptake, decreased contraction-induced FA uptake by 33%, and abolished both caffeine- and contraction-induced FA oxidation (P < 0.05). Caffeine had no effect on ERK1/2 phosphorylation (P > 0.05) and increased ₂-AMPK activity by 68% (P < 0.05). Electrical stimulation increased ERK1/2 phosphorylation and ₂-AMPK activity by 51% and 3.4-fold, respectively (P < 0.05). KN93 had no effect on caffeine-induced ₂-AMPK activity, ERK1/2 phosphorylation, or contraction-induced ERK1/2 phosphorylation (P > 0.05). Alternatively, it decreased contraction-induced ₂-AMPK activity by 51% (P < 0.05), suggesting that CaMKII lies upstream of AMPK. These results demonstrate that regulation of contraction-induced FA uptake and oxidation occurs in part via Ca²⁺-independent activation of ERK1/2 as well as Ca²⁺-dependent activation of CaMKII and AMPK.

fatty acid uptake; erk1/2; caffeine; KN93; electrical stimulation

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