Muscle Wasting Disease

Sarcopeniaâ€|the word itself conjures a lost island empire.

But it's no Aegean dream, this sarcopenia (pronounced sar-ko-PEE-nee-ya). Instead, it's about biological loss. Sarcopenia is the natural and progressive loss of muscle fiber due to aging. The term "sarcopenia" derives from the Latin roots, "sarco" for muscle, and "penia" for wasting, making it the "muscle wasting disease."

Mayo Clinic endocrinologist K. Sreekumran Nair, Ph.D., M.D., is a leading researcher on muscle metabolism and its role in aging. He also is director of Mayo's CTSA Clinical Research Unit (CRU), which is the oldest center of its kind in the country, and funded by the National Institutes of Health.

Dr. Nair's research shows that sarcopenia is intimately involved in activating the aging process. In particular, a reaction within tiny intracellular organelles called mitochondria appears to be a powerful determinant of sarcopenia and other physical changes the body experiences as it ages.

Says Dr. Nair: "My main interest is trying to understand the pathophysiology of aging-related change in muscle. One of the first things that happens as people age is there is a decline in muscle mass, muscle strength, and endurance. Associated with this is decline in aerobic capacity, and so people become easily fatigued. This happens beginning in the 30s, with rapid deterioration in the mid-60s. One of the interesting things is why does it happen with aging? We don't know the biology of aging, yet we all go through it."

Diminished Muscle Mass Starts Vicious Cycle

Muscle protein production begins to naturally slow down in people when they age. Muscle proteins are the functional molecules that have specific tasks. The decrease in muscle protein production can impact on muscle functions. The age at which it begins and the rate at which it progresses depends on an individual's genetic make-up and level of physical activity. Muscle fibers also decline with age. Fewer muscle fibers translate into reduced numbers of components from which to make muscles. The result: less muscle mass. As muscle and its protein content diminish they become fatigued more easily. This leads to a sedentary lifestyle. If this slow-down in activity and hence, muscle metabolism isn't reversed through changes in diet and exercise, the slide toward sarcopenia begins.

Dr. Nair's research is aimed at understanding the biology of aging for the purpose of helping patients age more enjoyably and more gracefully. "I would like to target muscle metabolism and other organs that appear to be key to the aging process with the idea of eventually improving the quality of life for aging people,'' he says. "Not with a goal of prolonging life, necessarily, but helping people stay more independent and healthy for the years they do have."

This goal takes on new urgency in the 21st century as both longevity and medical care costs increase. The cost factor is especially true for diseases associated with aging. Chief among them: cancer, diabetes, obesity, degenerative diseases and joint problems.

From Worms to Mitochondria

To study the basics of aging, investigators conduct research not only in humans but also in a kind of worm called a nematode Caenorhabditis elegan. It is extensively studied as a model for aging because it can be easily managed in a laboratory and has many structural similarities to vertebrates, including humans as well as some remarkable capabilities as it ages.

For example, the journal Nature (419, 808, 2002) reported that C. elegans shows remarkable preservation of the nervous system, even in advanced old age. This is in marked contrast to a gradual, progressive deterioration of muscle, resembling human sarcopenia. In humans with sarcopenia, the sarcomeres, the apparatus involved in muscle contractile activity, become disorganized in old muscle and have significantly fewer myosin thick filaments. Myosin is a key protein for muscle mechanical function and Dr. Nair's group has shown that synthesis of this key protein is reduced with age in humans.

To appreciate how this might be so, it helps to review some muscle basics. An organism takes in nutrients from the food it digests. Food is converted into chemical energy in the form of ATP (a complex chemical process called oxidative phosphorylation) in every tissue. ATP is the currency of a cell and is the key energy form needed for all cellular functions. This process of ATP formation takes place in tiny organelles within each cell known as mitochondria, which are the power houses of the cell. For muscle to perform its mechanical functions, ATP must be converted to ADP to release chemical energy into mechanical energy. ATP is also essential for remodeling tissues and various other life-maintaining functions. In fact, a shortage of ATP could result in eventual dysfunction of an organ.

In their research, Dr. Nair and colleagues found that myosin production decreases with age due to reduced gene expression that results in the production of a specific type of myosin needed for fast physical action. Normally this gene produces messenger RNA that translates the gene's instructions into a specific form of myosin the muscle can use. "But with aging, the specific messenger RNAs are reduced for many essential proteins,'' Dr. Nair says. As a result, production of myosin slows. This myosin-deficit impairs the muscle's ability to convert chemical energy into the mechanical energy it needs.

"Based on our evidence, this deficit of myosin is specific to the myosin form that is involved in fast actions," Dr. Nair explains. "This, in combination with depleting mitochondria, makes muscle weak and impairs their ability to perform. When this happens, Sarcopenia muscle wasting begins." As it develops, sarcopenia sets the stage for further physical complications of aging.

"Once you lose muscle mass, metabolic syndrome begins," Dr. Nair explains. "Muscle is one of the major organs involved in metabolism and in setting the body's metabolic rate and fuel burning following a meal. So when a person loses activity and loses muscle mass, and if they continue to maintain caloric intake, they become overweight, especially in the abdominal region. This excess weight contributes to glucose intolerance or resistance to insulin action."

Glucose intolerance is the inability of the body to efficiently metabolize blood sugar, a condition that leads to type II diabetes and so called metabolic syndrome. Worldwide, type II diabetes is on the rise. It is associated both with aging and with the physical decline begun by sarcopenia. In addition to increased glucose level and reduced insulin action, metabolic syndrome involves abdominal obesity, changes in lipid levels, hypertension, and increased ability to clot. These conditions all lead to increased risk for cardiovascular deaths.

But Dr. Nair is optimistic that the work his lab, as well as in other Mayo Clinic groups, can help reverse these trends. His aim is to develop preventive measures that keep the sarcopenia cycle from taking over.

In addition to the CTSA Clinical Research Unit (CRU) that he directs, Dr. Nair also is affiliated with the Mayo Clinic Department of Medicine's new Center on Aging and the core group of physicians and researchers addressing diabetes. In whatever collaborations he takes part, his motivation remains the same: improved patient care.

"I'm a physician. I see patients and see their distress," he says. "My overall mission is to really improve patient care and quality of life. But to do that, I have to understand the mechanism of disease. If we can prevent age-related changes in muscle, we can reduce the onset of diabetes and obesity and associated disorders and all of that can contribute substantially to the quality of life. The goal is to maintain the best possible quality of life during a reasonable life expectancy."

Creative Collaborations

One of the great strengths of Mayo Clinic is its tradition of collegiality and the frequent collaboration it fosters over a wide range of research areas. Dr. Nair considers himself to be uniquely fortunate in having some outstanding collaborators who make substantial contribution in several ways:

• Robert Rizza, M.D. , His enormous expertise in glucose metabolism in diabetes and his critical analysis have been a great support in Dr. Nair's research program.
• Michael Jensen, M.D., an expert on obesity and fat metabolism who collaborates on measuring body composition in aging people.
• James Levine, M.D., who lends his expertise in understanding the role that activity level plays in the aging process.
• Michael Joyner, M.D., collaborates to understand how exercise program can prevent and alter the aging process.
• Sundeep Khosla, M.D., works closely to understand how hormonal changes affect both muscle and bone.
• Sreekumar Raghavakaimal, M.D., is an expert on gene array analysis and closely works with Dr. Nair in understanding the gene and protein expression changes that occur in aging and diabetes.
• Michael Charlton, M.D., from the Division of Gastroenterology and Hepatology collaborated with Dr. Nair to study the changes in gut protein metabolism.
• Michael Brennan, M.D., collaborates to understand the role of thyroid hormones in muscle functions.
• Gary Sieck, Ph.D., collaborates in the study of muscle fiber dynamics and morphology.
• Kevin Short, Ph.D., is a close collaborator on muscle mitochondrial studies and exercise effects.

The work done in Dr. Nair's lab helps further the Mayo Clinic mission by training graduate students and doctors who, upon completion of their degrees, go to other laboratories and take the Mayo Clinic research ethic with them. It is an ethic marked by commitment to the ideal that biomedical science's first responsibility is to serve patients. Over the last 10 years, Dr. Nair has mentored 26 trainees: three in Sweden, one in Denmark, one in France, one in Italy, one in the UK, and several at leading medical centers in the United States, including Mayo.