The K_ATP channel is a molecular sensor of atrophy in skeletal muscle

Abstract

The involvement of ATP-sensitive K + (K ATP ) channels in the atrophy of slow-twitch (MHC-I) soleus (SOL) and fast-twitch (MHC-IIa) flexor digitorum brevis (FDB) muscles was investigated in vivo in 14-day-hindlimb-unloaded (14-HU) rats, an animal model of disuse, and in vitro in drug-induced muscle atrophy. Patch-clamp and gene expression experiments were performed in combination with measurements of fibre diameters used as an index of atrophy, and with MHC labelling in 14-HU rats and controls. A down-regulation of K ATP channel subunits Kir6.2, SUR1 and SUR2B with marked atrophy and incomplete phenotype transition were observed in SOL of 14-HU rats. The observed changes in K ATP currents were well correlated with changes in fibre diameters and SUR1 expression, as well as with MHC-IIa expression. Half of the SOL fibres of 14-HU rats had reduced diameter and K ATP currents and were labelled by MHC-I antibodies. Non-atrophic fibres were labelled by MHC-IIa (22%) antibodies and had enhanced K ATP currents, or were labelled by MHC-I (28%) antibodies but had normal current. FDB was not affected in 14-HU rats and this is related to the high expression/activity of Kir6.2/SUR1 subunits characterizing this muscle phenotype. The long-term incubation of the control muscles in vitro with the K ATP channel blocker glibenclamide (10 −6 m) reduced the K ATP currents with atrophy and these effects were prevented by the K ATP channel opener diazoxide (10 −4 m). The in vivo down-regulation of SUR1, and possibly of Kir6.2 and SUR2B, or their in vitro pharmacological blockade activates atrophic signalling in skeletal muscle. All these findings suggest a new role for the K ATP channel as a molecular sensor of atrophy.

Mitochondrial KATP channels in skeletal muscle: are protein kinases C and G, and nitric oxide synthase involved in the fatigue process?

“…1 These channels have been reported in several tissues, including β-pancreatic cells, 2 skeletal muscle fibers of amphibians, 3 mammals, [4][5][6] and birds, 7,8 and in the liver-derived internal membrane mitochondria of the rat. 9 K ATP channels connect cell excitability with its metabolism and play an important role in several cellular functions by detecting the intracellular ATP/ADP relationship.…”

“…12 The skeletal muscle K ATP channel phenotype varies in its molecular composition, biophysical properties, and pharmacological response depending on the type of muscle. 5,6 Garlid et al 13 demonstrated that mitoK ATP activation by diazoxide, a specific activator, was greater than sarcolemmal K ATP activation.…”

Association Between KCNJ11 Gene E23K Polymorphism and Body Composition Together with Its Response to Endurance Training

“…KATP couples cellular energy metabolism and bioelectrical activity, and thus participates in important functions in energy metabolism, regulate hormone secretion, sports fatigue and cell protection [4-6]. The study found KCNJ11 gene and E23K polymorphism can inhibit insulin secretion, increase the secretion of glucagon, and with diabetes and elevated glucagon related disease [7, 8].…”

Structural Nucleotide Analogs Are Potent Activators/Inhibitors of Pancreatic β Cell KATP Channels: An Emerging Mechanism Supporting Their Use as Antidiabetic Drugs

“…Therapeutic concentrations of sulfonylureas and high doses of glinides induce the apoptosis of ␤ cells, ␤ cell lines, or cell lines that express the recombinant KATP channel subunits, and these effects are mediated by SUR1 (Maedler et al, 2005;Hambrock et al, 2006). Glibenclamide also causes atrophy of the skeletal muscles (Tricarico et al, 2010). It has been proposed that sulfonylurea-induced atrophy contributes to the loss of ␤ cell mass that characterizes the progression of diabetes (Takahashi et al, 2007).…”

“…Diazoxide protects the ␤ cells from sulfonylurea-induced apoptosis, high glucose, and cytokine-induced toxicity, which preserves the insulin stores (Teshima et al, 2003). In skeletal muscle, diazoxide prevents glibenclamide-induced atrophy (Tricarico et al, 2010). The SUR1-selective openers have been proposed to treat epilepsy and neurodegenerative disorders, in which the SUR1/Kir6.2-Kir6.1 subunits play a role (Carosati et al, 2007).…”