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, under 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 downregulation in a tissue-specific manner could present an antiobesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise.
This study demonstrates that sarcolemmal KATP channels not only respond to metabolic stress but continuously control energy use by cardiac and skeletal muscles, thereby promoting body energy conservation. Positive energy balance favoring obesity would therefore be moderated by tissue-specific interruption of KATP channel-driven optimization of energy use, offering a paradigm in weight control.
“By sensing cellular energy content, KATP channels continuously, at any activity level, optimize energy use and define the balance between energy availability and consumption,” explains Dr. Alekseev. “In principle, a positive energy balance favoring weight gain could be reversed by targeting muscle KATP channels to control obesity in patients with low to moderate exercise capacity imposed by the overweight state.”