A solution to obesity? Muscles that act as an energy drain

The researchers from the Mayo Clinic and the University of Iowa have new insight into an important "fuel gauge" in muscle. They've also uncovered evidence in mice that treatments designed to disrupt those so-called sarcolemmal ATP-sensitive K+ (KATP) channels specifically in muscles might allow us to control our weight by increasing the number of calories our muscles will burn with regular activity or exercise.

"The channels sense even minor changes in nucleotide energy and respond by shortening the duration of action potentials and limiting energy-demanding muscle contractility and maintenance of ion composition," said Alexey Alekseev of the Mayo Clinic. "If you don't have the channel, you will consume more energy. The system normally has an energy-saving role, but with a sedentary lifestyle and excess of food, it favors obesity."

"In some ways it may seem paradoxical to fight against what is a very good system for fueling our muscles with energy efficiency," added Leonid Zingman of the University of Iowa. "On the other hand, it's also paradoxical that many of us today have an excessive food supply and we don't need to move."

Earlier work had shown that the KATP channels found at the surface of heart and skeletal muscle cells play a role under severely stressful conditions such as heart disease, acting as a kind of safety valve. But their everyday role remained unclear. After all, Alekseev said, ischemic heart disease really is a modern human problem, not one experienced by organisms living in their natural environments.

Now, they show that the KATP channels are responsible for keeping those muscle and heart cells pumping without expending any more energy than they have to. Animals with skeletal muscles that are deficient for the KATP channels store less glucose in the form of glycogen and less fat to become leaner. The animals' weight loss persists even when they eat diets that are high in fat. That reduction in stored muscle energy comes with a price of reduced physical endurance, however.

The researchers conclude that "sarcolemmal KATP channels govern muscle energy economy, and their downregulation in a tissue-specific manner could present an anti-obesity strategy by rendering muscle increasingly thermogenic at rest and less fuel efficient during exercise."

The findings also point Zingman to another general principle when it comes to our weight.

"For me, the most surprising thing was how small changes can translate to significant changes with time," he said, noting that mice with and without the channels start out the same in terms of body weight but start to diverge from one another by the time they reach four months in age. "Limiting energy consumption by a small fraction with every movement or beat of the heart can add up to a significant change in total energy consumption. Small actions may really make a huge difference."

The researchers include Alexey E. Alekseev, Mayo Clinic, Rochester, MN; Santiago Reyes, Mayo Clinic, Rochester, MN; Satsuki Yamada, Mayo Clinic, Rochester, MN; Denice M. Hodgson-Zingman, Mayo Clinic, Rochester, MN, University of Iowa, Iowa City, IA; Srinivasan Sattiraju, Mayo Clinic, Rochester, MN; Zhiyong Zhu, University of Iowa, Iowa City, IA; Ana Sierra, University of Iowa, Iowa City, IA; Marina Gerbin, Mayo Clinic, Rochester, MN; William A. Coetzee, New York University School of Medicine, New York, NY; David J. Goldhamer, University of Connecticut, Storrs, CT; Andre Terzic, Mayo Clinic, Rochester, MN; and Leonid V. Zingman, Mayo Clinic, Rochester, MN, University of Iowa, Iowa City, IA.