Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice

Abstract

EM. Impaired exercise tolerance and skeletal muscle myopathy in sulfonylurea receptor-2 mutant mice. Am J Physiol Regul Integr Comp Physiol 297: R1144 -R1153, 2009. First published August 12, 2009 doi:10.1152/ajpregu.00081.2009.-By sensing intracellular energy levels, ATP-sensitive potassium (K ATP) channels help regulate vascular tone, glucose metabolism, and cardioprotection. SUR2 mutant mice lack full-length K ATP channels in striated and smooth muscle and display a complex phenotype of hypertension and coronary vasospasm. SUR2 mutant mice also display baseline cardioprotection and can withstand acute sympathetic stress better than normal mice. We now studied response to a form of chronic stress, namely that induced by 4 wk of daily exercise on SUR2 mutant mice. Control mice increased exercise capacity by 400% over the training period, while SUR2 mutant mice showed little increase in exercise capacity. Unexercised SUR2 mutant showed necrotic and regenerating fibers in multiple muscle skeletal muscles, including quadriceps, tibialis anterior, and diaphragm muscles. Unlike exercised control animals, SUR2 mutant mice did not lose weight, presumably due to less overall exertion. Unexercised SUR2 mutant mice showed a trend of mildly reduced cardiac function, measured by fractional shortening, (46 Ϯ 4% vs. 57 Ϯ 7% for SUR2 mutant and control, respectively), and this decrease was not exacerbated by chronic exercise exposure. Despite an improved response to acute sympathetic stress and baseline cardioprotection, exercise intolerance results from lack of SUR2 K ATP channels in mice.K ATP channel; sulfonylurea receptor; SUR2; skeletal myopathy; exercise intolerance THE MECHANISMS THAT UNDERLIE the beneficial effects of regular exercise on metabolism and endurance are incompletely understood. ATP-sensitive potassium channels (K ATP channels) are found in muscle and the cardiovascular system and serve as cellular energy sensors. K ATP channels include a regulatory subunit, sulfonylurea receptor (SUR) 1 or 2, and a poreforming potassium channel, Kir6.1 or 6.2. Genetic deletion of the gene encoding Kir6.2 affects K ATP channels in the pancreas, heart, and skeletal muscle due to the lack of the poreforming subunit of K ATP channels (18). Two previous studies have investigated the role of K ATP channels in adaptation to chronic stress and exercise, and both demonstrated an impaired response in Kir6.2-null mice (15,24). Although defects in skeletal muscle and cardiovascular function were reported, the role of K ATP channel involvement is complicated by the ability of Kir6.2 to couple with either sulfonylurea receptor 1 (SUR1) or 2 (SUR2).In the heart, K ATP channels play critical roles during periods of sympathetic stress and protect the heart against ischemia (16,23,27). Kir6.2-null mice stressed with 21 days of experimental hypertension had significantly increased mortality compared with control mice (14). Cardiac function was impaired at baseline and after dobutamine exposure, and hypertensive Kir6.2-null mice developed ...

Muscle KATPChannels: Recent Insights to Energy Sensing and Myoprotection

“…SUR2 −/− animals do exhibit reduced exercise (both treadmill and swim training) capacity (388), similar to Kir6.2 −/− animals (203). Importantly, however, no exercise-induced decrement in cardiac function is reported in SUR2 −/− mice (388).…”

“…Instead, NADH flavoprotein I and mitochondrial isocitrate dehydrogenase were detected in high abundance indicating non-specificity of the antibodies. As discussed further below, short-form SUR2 subunits lacking the NBF1 domain have been identified in cardiac cells (328), and specifically localized to mitochondria (449), using antibodies raised against distal parts of the protein (329, 388). Although further studies are needed, these short forms may actually be a component of ‘mitoK ATP ’ (449).…”

“…Importantly, however, no exercise-induced decrement in cardiac function is reported in SUR2 −/− mice (388). Isoproterenol challenge does not affect survival and actually ameliorates the arrhythmias that accompany spontaneous coronary vasospasm in SUR2 −/− animals (388), with no ST-segment depression that is characteristic in the isoproterenol response of wild type mice. It is thus not entirely clear that it is the lack of cardiac KATP function that underlies the reduced exercise capacity in these animal models.…”

“…The targeting construct used in the generation of these animals contained a replacement of exons 12–16, coding for regions of NBF1 (55). Naturally transcribed short-form SUR2 subunits lacking the NBF1 domain have been identified using antibodies raised against distal parts of the protein (329, 388) and are reported to coassemble with Kir6.1 and Kir6.2 to form glibenclamide-insensitive, ATP-sensitive, currents in ventricular myocytes (328). A further recent study provides evidence that these short forms are present in mitochondria, and therefore may actually be a component of ‘mitoK ATP ’ (449).…”

Skeletal muscle fatigue – regulation of excitation–contraction coupling to avoid metabolic catastrophe

“…Being an ion channel, it also links the excitability of the sarcolemma to the metabolic state of the fiber. There is now clear evidence that activation of K ATP channels during repetitive stimulation coincides with the activation of Cl 2 channels as discussed above (Pedersen et al, 2009a), and that the channel is crucial in preventing fiber damage and severe muscle dysfunction during exercise and fatigue by decreasing muscle cell excitability (Cifelli et al, 2008;Cifelli et al, 2007;Kane et al, 2004;Stoller et al, 2009;Thabet et al, 2005).…”