Sarcolemmal ATP-Sensitive K+ Channels Control Energy Expenditure Determining Body Weight

Abstract

Summary Metabolic processes that regulate muscle energy use are major determinants of bodily energy balance. Here we find that sarcolemmal ATP-sensitive K+ (KATP) channels, which couple membrane excitability with cellular metabolic pathways, set muscle energy expenditure under physiological stimuli. Disruption of KATP channel function provoked, in conditions of unaltered locomotor activity and blood substrate availability, an extra energy cost of cardiac and skeletal muscle performance. Inefficient fuel metabolism in KATP channel-deficient striated muscles reduced glycogen and fat body depots promoting a lean phenotype. The propensity to lesser body weight imposed by KATP channel deficit persisted under a high-fat diet, yet obesity restriction was achieved at the cost of compromised physical endurance. Thus, sarcolemmal KATP channels govern muscle energy economy, and their down-regulation in a tissue-specific manner could present an anti-obesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise.

Regulation of Cardiac ATP-sensitive Potassium Channel Surface Expression by Calcium/Calmodulin-dependent Protein Kinase II

“…Taken together with previous findings that changes in K ATP channel surface abundance have a significant impact on cardiac energetics (23)(24)(25), sarcolemmal K ATP channel down-regulation via CaMKII-mediated endocytosis reveals a new mechanism for control of myocardial performance and energy use. Indeed, CaMKII inhibition has been investigated as a promising treatment and prevention strategy for heart failure (35); however, diverse tissue expression and pleiotropic vital functions of CaMKII make it a problematic target.…”

“…First, CaMKII is a vital regulator of cardiac excitation-contraction coupling and, thus, cardiac energy consumption (35)(36)(37). Second, CaMKII activation underlies increased cardiac performance during heart rate acceleration (38,50), an established trigger of K ATP channel opening (23,24). Finally, CaMKII has been linked to endocytosis of membrane proteins in other cell types (55,56).…”

“…When activated by a reduced ATP/ ADP ratio, reflecting either increased cellular metabolic demand or reduced cellular ATP generation, K ATP channel-dependent potassium efflux shortens cardiac action potential duration, allowing for a longer diastolic interval that supports myocardial relaxation and restoration of ion gradients and energetic resources as well as limits sodium and calcium entry into the cell and thus reduces energy requirements for ion transport/exchange and contraction (1,9,10,(23)(24)(25)(26)(27)(28).…”

“…sumption in the compartmentalized cellular environment (17,22) allows K ATP channel opening to be regulated not only by severe metabolic stress, such as during ischemia, but also by heart rate acceleration within the range induced by normal physical activity (23,24). When activated by a reduced ATP/ ADP ratio, reflecting either increased cellular metabolic demand or reduced cellular ATP generation, K ATP channel-dependent potassium efflux shortens cardiac action potential duration, allowing for a longer diastolic interval that supports myocardial relaxation and restoration of ion gradients and energetic resources as well as limits sodium and calcium entry into the cell and thus reduces energy requirements for ion transport/exchange and contraction (1,9,10,(23)(24)(25)(26)(27)(28).…”

Allele- and parent-of-origin-specific effects on expression of the KCNJ11 gene: A candidate for meat tenderness in cattle

“…This gene plays a role in the insulin pathway, which induces glycogen storage in cells. Alekseev et al (2010) showed that KCNJ11 knockout influenced muscle glycogen deposition and affected body fat in mice. Glycogen storage may affect meat tenderness because it influences the extension of glycolysis, which is the only source of ATP for cells following slaughter.…”