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Congestive Heart Failure and Muscular Fatigue
 
 
 

A common inquiry among exercise enthusiasts is the specific physiological cause of muscular fatigue. Scientists at Columbia declare that they have not only come up with a response, but have also devised an experimental drug that has been tested in mice that can actually prolong exercise time to exhaustion. The physiological cause of muscular fatigue has been largely ignored and misunderstood for decades. Muscular fatigue due to lactic acid release was a popular theory early on , but exercise physiologists realized it is simply a plausible component based on intensity and physical condition and has since been discredited as the main cause of muscular fatigue according to Dr. George Brooks, from the University of California, Berkeley. In a recent report published in an early online edition of Proceedings of the National Academy of Sciences, Dr. Andrew Marks, the principal investigator of the new study, claims that calcium flow inside the muscle cells is the most likely cause of fatigue.

 

Calcium stimulates muscle contractions when it is released from the sarcoplasmic reticulum in response to an electrical signal, known as an action potential, from the nervous system. Under normal resting conditions, a weak bond exists between the myofilaments myosin and actin. When calcium is released it binds to the troponin allowing actin and myosin to strengthen this bond into an active state. If adequate amounts of ATP are present, this active state can produce tension when the high-energy phosphate bond is broken, resulting in an end product ADP and an inorganic phosphate. After prolonged activity, it seems that the responsive of the calcium channels is dampened. When muscles become fatigued and tired, the sarcoplasmic reticulum becomes less functional and calcium tends to leak out of the tissue through tiny channels, thereby weakening the contractions. Furthermore, the calcium leakage kindles enzyme activity that negatively affects the actions of the muscle fiber, thereby contributing to localized muscle exhaustion.

 

Dr. George Brooks of the University of California, Berkley, states that the new work in mice is very “exciting and provocative.” The findings of Dr. Marks’ research actually came about as a result of very different research. As a cardiologist, Dr. Marks was conducting research on congestive heart failure and methods to improve treatment for his patients with the disease. Congestive heart failure is a chronic and debilitating condition affecting nearly 4.8 million Americans. The disease may be described as having a damaged heart, which usually occurs from a heart attack or high blood pressure. Struggling to pump blood, the heart undergoes centralized hypertrophy, or an enlargement. As the disease progresses, the heart struggles to continually pump blood, and eventually a backup of fluid fills the lungs. Individuals with congestive heart failure often complain of extreme fatigue. This is due to the combination of a poorly functioning heart and the buildup of fluid in the lungs. Approximately 50% of those diagnosed with congestive heart failure die within 5 years of their diagnosis.

 

Dr. Marks began to investigate why the heart weakens by focusing on the heart’s molecular and physiological events. As the body’s demand for oxygen increases, the heart’s contractile capacity, the ability to pump out oxygenated blood efficiently, must increase with that increased oxygen demand. The nervous system, specifically the sympathetic branch, stimulates the release of epinephrine and norepinephrine, the body’s fight or flight hormones, in an attempt to encourage the heart to satisfy the body’s oxygen demands. Eventually, due to the inefficiency of the heart, there comes a point where the brain is constantly stimulating the release of these hormones, resulting in over-stimulation of the calcium channels within the heart. This ultimately leads to calcium leakage and decreased contractility of the heart.

 

Once this mechanism for fatigue and decreased contractility was understood, researchers were able to develop experimental classes of drugs that would reduce the calcium leakage, thereby allowing for prolonged, sustained efficiency of the working muscle, in this case the heart. The drugs, originally created to assist in better managing and lowering blood pressure, were altered by Dr. Marks and his colleagues, and called rycals since they attached to the ryanodine receptor/calcium release channel in cardiac muscle. This resulted in minimized calcium leakage and more efficient contractions. When the rycals were tested on mice, it was determined that the mice experienced fewer arrhythmias and were less likely to develop heart failure.

 

Since skeletal muscle tissue operates in a very similar manner to cardiac muscle tissue with regard to the calcium channel system, Dr. Marks wondered whether the mechanism he discovered may apply to skeletal muscle tissue. Patients suffering from heart failure tend to complain that their muscles are extremely weak. Dr. Marks and his colleagues tested their theory by making mice exercise to exhaustion, swimming and then running on a treadmill, an amount of activity that resulted in fatigue. Upon examination of the muscles of the mice at the point of exhaustion, the calcium channels were determined to be leaky. Investigators then gave the mice the experimental drug and surprisingly enough the mice were able to run 10%-20% longer. The fact that the leakage of calcium was minimized resulted in increased exercise duration and performance. The practicality of a drug like this could result in significant ergogenic effects for endurance athletes.

 

A human study was conducted at Appalachian State University in Boone, N.C. by Dr. David Nieman to find out if endurance athletes experienced fatigue for similar reasons as congestive heart failure patients testing the calcium leakage theory. A group of highly trained cyclists were subjected to intense training for three consecutive days. As a control, other highly trained cyclists did not perform the high intensity training. At the culmination of the three day protocol, muscle biopsies were taken from both groups of trained cyclists – those who rode at a high intensity for three days and those who were sedentary for three days – and sent to Dr. Marks for review. Upon examination of the muscle biopsies, it was determined that the athletes who intensely trained for three days had muscle fibers with leaky calcium channels, a possible cause of fatigue. Within a couple days, the muscle tissue had repaired itself and the calcium channels were back to normal working condition.

 

Dr. Marks’ intentions are to develop the drug in an on-going effort to improve the quality of life of his congestive heart failure patients. Hopefully, the drug will slow down the progress of congestive heart failure and allow individuals to continue to function at a reasonable level with minimal fatigue. A concern is that athletes might also be tempted to take the drug for its possible ergogenic potential – increased endurance capabilities and longer time to exhaustion. Dr. W. Robb McClellan, a heart disease researcher at U.C.L.A., says that the odds are against the drug being approved and says, “In heart failure, there are three medications that improve mortality, but there have probably been 10 times that many tested.” Dr. McClellan states that even if the first drug that prevents calcium leakage doesn’t get approved or work perfectly, the important thing to take away from this research is a greater understanding of the physiological and molecular workings of the body related to congestive heart failure and muscular fatigue so that proper therapies can be developed.