Muscle Cell Fatigue after Extreme Exercise Found Similar to Heart Failure Fatigue

What do marathoners and heart failure patients have in common? More than one might think, according to physiologists at Columbia University Medical Center (CUMC).

A new study published in the February 12 Proceedings of the National Academy of Sciences* shows that the fatigue which marathoners and other extreme athletes feel at the end of a race is caused by the same tiny leaks inside the calcium channels in muscles that probably also sap the energy from patients with heart failure. [And may be part of the dysregulated biochemical cycle in ME/CFS/FM patients described by Dr. Martin L. Pall, PhD and others.]

Calcium Leakage Inside Muscle Cells
A continuous leak of calcium inside muscle cells seems to weaken the force produced by the muscle and also turns on a protein-digesting enzyme that damages the muscle fibers. The study found the leak was present in the muscles of mice after an intense three-week regimen of daily swimming and in athletes after three days of intense daily bicycling. Andrew Marks, MD, chairman of physiology and cellular biophysics, and director of the Clyde and Helen Wu Center for Molecular Cardiology at CUMC, previously discovered that this calcium leak existed in mice with heart failure.

“After this finding, we had a hunch that the process that produces fatigue in heart failure patients also may be responsible for the fatigue felt by athletes after a marathon or extreme training,” says Dr. Marks, the study’s principal investigator.

The involvement of defects in calcium channels in limiting muscle performance and producing exercise fatigue makes sense because the flow of calcium in and out of intracellular stores in the sarcoplasmic reticulum of muscle cells controls contraction, according to first author Andrew Bellinger, PhD, who is currently finishing his medical degree at P&S.

The new study also found that an experimental drug developed by the researchers alleviated muscle fatigue in mice after exercise, suggesting that the drug also may provide relief from the severe exhaustion that afflicts heart failure patients.

Leak & Damage Constant in Heart Failure
“Our work does not show that exercise is bad for you,” says Dr. Marks, the principal investigator of the study. “We only saw the leak in animals and human athletes who exercised three hours a day at very high intensities for several days or weeks in a row until they became exhausted.” Athletes’ muscles, however, return to normal after several days of rest and any muscle damage will be repaired after several days or weeks depending on the degree of exercise.

On the contrary, the arm, leg and respiratory muscles of patients with heart failure do not recover.

“People with chronic heart failure are subject to this same kind of muscle leak and constant damage even without doing any exercise,” says Dr. Marks. [Note: In congestive heart failure the heart struggles and enlarges in an effort to pump more blood, but fails; and as it does the lungs become fluid filled (congested).] “In these patients, muscle weakness and fatigue can be so severe that they can’t get out of bed, brush their teeth, or feed themselves.”

The researchers decided to test their hypothesis that fatigue in heart failure patients also may be responsible for the fatigue felt by athletes after a marathon or extreme training by using an experimental drug that could increase exercise capacity and reduce fatigue. They gave the drug, which plugs the calcium leak, to mice before the animals started a three-week regimen of daily three-hour swims. With the drug, the animals had increased exercise capacity and their muscles showed fewer signs of calcium leakage and muscle damage.

Will the Drug Help Heart Failure?
Plans are under way to test the drug at other medical centers in patients with heart failure to see if it relieves fatigue and improves heart function. Even if successful, it will take several years before the drug is commercially available. The athletes who participated in the current study were not given the experimental drug.

“The discovery of the calcium leak in fatigued animals and athletes is the first time anyone has pinpointed a precise mechanism for the involvement of a defect in calcium handling in limiting exercise capacity,” Dr. Marks says.

* To read an abstract and free full text of the article, “Remodeling of ryanodine receptor complex causes ‘leaky’ channels: A molecular mechanism for decreased exercise capacity,” by AR Bellinger and AR Marks, et al. [E-mail:], click here.

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