Sarcolemmal ATP-sensitive potassium channels modulate skeletal muscle function under low-intensity workloads

ATP-sensitive potassium (K-ATP) channels have the unique ability to adjust membrane excitability and functions in accordance with the metabolic status of the cell. Skeletal muscles are primary sites of activity-related energy consumption and have K-ATP channels expressed in very high density. Previously, we demonstrated that transgenic mice with skeletal muscle-specific disruption of K-ATP channel function consume more energy than wild-type littermates. However, how K-ATP channel activation modulates skeletal muscle resting and action potentials under physiological conditions, particularly low-intensity workloads, and how this can be translated to muscle energy expenditure are yet to be determined. Here, we developed a technique that allows evaluation of skeletal muscle excitability in situ, with minimal disruption of the physiological environment. Isometric twitching of the tibialis anterior muscle at 1 Hz was used as a model of low-intensity physical activity in mice with normal and genetically disrupted K-ATP channel function. This workload was sufficient to induce K-ATP channel opening, resulting in membrane hyperpolarization as well as reduction in action potential overshoot and duration. Loss of K-ATP channel function resulted in increased calcium release and aggravated activity-induced heat production. Thus, this study identifies low-intensity workload as a trigger for opening skeletal muscle K-ATP channels and establishes that this coupling is important for regulation of myocyte function and thermogenesis. These mechanisms may provide a foundation for novel strategies to combat metabolic derangements when energy conservation or dissipation is required.