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Patients with heart failure often don't have the energy to perform everyday tasks such as getting out of bed, cooking and shopping. But it's not just the heart's inability to pump adequate amounts of blood and oxygen that causes such severe fatigue. Researchers have suspected that changes in skeletal muscle also contribute to the tiredness and shortness of breath. Until now, however, no molecular change had been found to explain why skeletal muscle, including the diaphragm, fatigues more quickly in heart failure patients.

P&S cardiologists have found that a leaky calcium channel in skeletal muscle contributes to these symptoms. "For the first time we have a tangible mechanism for skeletal muscle fatigue that new drugs could target," says the study's senior author, Dr. Andrew Marks, Wu Professor of Molecular Cardiology, director of the Center for Molecular Cardiology, and chairman of the Department of Physiology and Cellular Biophysics. The research was published in the March 17 Journal of Cell Biology.

One of the intriguing paradoxes of heart failure is that heart function does not always correlate with the severity of fatigue. Some patients whose hearts pump little blood can walk for miles, while other patients whose hearts pump fairly well are unable to walk around the block. The lack of a correlation suggested other mechanisms were at work.

In his previous work on cardiac muscle, Dr. Marks found that during heart failure, changes in a calcium channel, RyR2, eventually weaken the heart. The changes are caused by the chronic stimulation of the sympathetic, or "fight-or-flight," nervous system that is characteristic of heart failure. Because a similar channel, RyR1, exists in skeletal muscle, the researchers wanted to see if the same changes also would weaken skeletal muscle.

The process, they found, is analogous to what occurs in cardiac muscle. Normally RyR1 must be phosphorylated by a neighboring protein to open its calcium channel in times of stress. Phosphorylation causes another protein, FKBP12, to move away from the channel. The dissociation of FKBP12 opens the calcium channel, and calcium flows from the sarcoplasmic reticulum into the cell to help contract the muscle. The more calcium that enters, the stronger the contraction.

In heart failure, the calcium channel, which has four phosphorylation sites, becomes covered in phosphates, with three to four per channel instead of the normal zero to one. The resulting hyperphosphorylation causes the calcium channel to leak, so that calcium builds up in the muscle cell. In the heart, calcium build-up eventually leads to a weaker heart and sometimes sets up a fatal arrhythmia.

But does the hyperphosphorylated channel also cause skeletal muscle fatigue? The researchers found the answer is yes. Muscle from rats with heart failure fatigued faster than normal muscle, and the degree of channel phosphorylation correlated with how quickly the muscle fatigued. More recent, and as yet unpublished, data show that the channel in skeletal muscle from people with heart failure is also hyperphosphorylated.

Dr. Marks says a drug that targets the calcium channel might be useful in treating the weakening muscle in both the heart and the skeletal muscle. Aetas, a company in Japan, says it has already developed a drug that stops the leak in the cardiac channel and improves heart function in dogs. Dr. Marks is currently trying to obtain the drug to test it on skeletal muscle.

"Current therapy for heart failure only focuses on the heart and not on skeletal muscle," Dr. Marks says. "If we can find a way to increase the exercise capacity of these patients and decrease their shortness of breath, it would change their lives."

The research was supported by the National Institutes of Health.