ATP-Sensitive K+ Channel Knockout Compromises the Metabolic Benefit of Exercise Training, Resulting in Cardiac Deficits

Abstract

Exercise training elicits a metabolic and cardiovascular response that underlies fitness. The molecular mechanisms that orchestrate this adaptive response and secure the wide-ranging gains of a regimented exercise program are poorly understood. Formed through association of the Kir6.2 pore and the sulfonylurea receptor, the stress-responsive ATP-sensitive K ؉ channels (K ATP channels), with their metabolic-sensing capability and broad tissue expression, are potential candidates for integrating the systemic adaptive response to repetitive exercise. Here, the responses of mice lacking functional Kir6.2-containing K ATP channels (Kir6.2-KO) were compared with wild-type controls following a 28-day endurance swimming protocol. While chronic aquatic training resulted in lighter, leaner, and fitter wild-type animals, the Kir6.2-KO manifested less augmentation in exercise capacity and lacked metabolic improvement in body fat composition and glycemic handling with myocellular defects. Moreover, the repetitive stress of swimming unmasked a survival disadvantage in the Kir6.2-KO, associated with pathologic calcium-dependent structural damage in the heart and impaired cardiac performance. Thus, Kir6.2-containing K ATP channel activity is required for attainment of the physiologic benefits of exercise training without injury. Diabetes 53 (Suppl. 3): S169 -S175, 2004 P hysical exertion elicits an array of metabolic and cardiovascular responses that allow the body to adapt to the demands of exercise, thereby achieving fitness, a state of enhanced aerobic capacity, and generalized well-being (1-4). Reinforced by frequent repetition of the exercise regimen, the specific systemic benefits of regular activity range from reductions in body weight and adiposity to improved glucose and insulin homeostasis (1-7). Moreover, the inverse relation of physical exercise with both cardiovascular disease and mortality has long been recognized (1,4,8,9). Yet, the molecular determinants that orchestrate the adaptive response to exercise and that assure the wide-ranging gains of a regimented training program are poorly understood.Unique metabolic-sensing capabilities and broad tissue expression point to the ATP-sensitive K ϩ channel (K ATP channel) as a potential candidate for integrating the systemic adaptive response and thereby securing the benefits of exercise training. K ATP channels are evolutionarily conserved plasma-membrane protein complexes, widely represented in tissue beds with high metabolic activity (10 -14). There, they are formed through the physical association of the inwardly rectifying potassium channel pore, most typically Kir6.2, and the regulatory sulfonylurea receptor subunit, an ATP-binding cassette protein (15)(16)(17). Energetic signals, received via tight integration with cellular metabolic pathways, are processed by the sulfonylurea receptor subunit that in turn gates the nucleotide sensitivity of the channel pore, thereby controlling membrane potential-dependent cellular functions (18 -21). Recent findings, elicited ...

ATP-sensitive K channel channel/enzyme multimer: Metabolic gating in the heart

“…These aberrances in catalysis generate defective K ATP channel phenotypes that are characterized by abnormal responses to both ATP and ADP. Suboptimal tolerance to stress and a propensity towards cardiomyopathy and arrhythmia in mice with genetic disruption of cardiac K ATP channels [10,19,21], supports the implication that the significant metabolic sensing deficit demonstrated in humans with cardiac K ATP channel mutations contributes to development of heart failure and thus further establishes the importance of proper SUR2A NBD2 ATPase kinetics in the metabolic signal decoding that permits the cardiac K ATP channel to fulfill its physiologic role. Hypothetical coordination of the ATP molecule within SUR.…”

“…Recent studies indicate an even broader function for cardiac K ATP channels in the tolerance of cardiomyocytes to numerous acute and chronic metabolic challenges, including sympathetic surge, and physical training [10,19]. Furthermore, the concept of K ATP channel-mediated myocardial protection has been expanded to include balancing increased performance to meet augmented demands of stress while avoiding an excessive response that could result in cellular injury and/or arrhythmia [10,[19][20][21]. The homeostatic role of K ATP channels is underscored by studies of altered channel behavior in heart disease.…”

“…Channel gene mutations that disrupt K ATP channel function [14] and/or defects in signaling pathways proximal to the channel site [20] compromise the channel's ability to optimally respond to metabolic challenge. Thus, proper metabolic gating of K ATP channels is vital in limiting acute adverse myocardial outcomes under stress, and in evading injury that precipitates the development or progression of chronic heart disease [10,11,14,19,20].…”

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).…”

Mice lacking sulfonylurea receptor 2 (SUR2) ATP-sensitive potassium channels are resistant to acute cardiovascular stress

“…Mice generated to lack the gene encoding Kir 6.2 (KCNJ11) are viable and lack K ATP channel activity in cardiomyocytes. Kir6.2 null animals were shown to have an impaired cardiac response to both acute and chronic stress [13][14][15][16]. Kir6.2 null mice were unable to maintain an elevated cardiac output following isoproterenol challenge and when subjected to treadmill stress tests exhibited a survival disadvantage [13].…”