2006 AFAR Research Grant: Targeted Rescue of Protein Translation and Synthesis in Aged Skeletal Muscle

Please give a brief summary of your AFAR research project.
The activity of the enzyme 5'-AMP-activated protein kinase (AMPK; which suppresses the synthesis of the new muscle proteins) is elevated in aged skeletal muscle. Because the synthesis of new proteins is important for muscle growth and the maintenance of muscle size, the aim of this investigation is to determine if elevated AMPK activity is responsible for the age-related decline in capacity for growth in muscles of old animals. This experiment will administer a chemical called Compound C, which blocks AMPK activity, to rats while their muscles are being stimulated to grow by an overload model (a rat model similar to strength training). Typically, the growth of muscle in aged animals using this model is very low compared to young animals. It is hypothesized that suppression of AMPK activity via Compound C will rescue protein synthesis and growth in the overloaded muscles of old rats to levels seen in young rats. To determine how AMPK is acting, we will also measure a large number of enzyme molecules that regulate the synthesis of new muscle proteins, and which may be controlled by AMPK. The long-term objectives of this investigation are to elucidate mechanism(s) underlying impaired growth (and potentially long-term wasting) of aging muscle, and to identify potential interventional targets for the rescue of protein synthesis, mass, and growth in aging muscle.

What problems are you addressing and what specific questions will your research seek to answer?
With age, the gradual but significant loss (atrophy) of skeletal muscle mass (sarcopenia) and strength is a major component of age-related decline in overall quality of life and ability to accomplish basic activities of daily living. The resultant impact on functional independence, institutionalization, and health care costs in our rapidly expanding older population is enormous; sarcopenia-related disabilities have been estimated to cost $300 billion per year in the U.S. The ability of aged skeletal muscle to get larger in response to interventions such as strength training is also diminished with age. Thus, the long-term objective of my research is to elucidate and potentially prevent mechanisms underlying the atrophy and impaired growth of aging skeletal muscles. My laboratory has recently published findings that the enzyme 5'-AMP- activated protein kinase (AMPK) appears to inhibit skeletal muscle growth in aged muscle because it blocks the synthesis of new proteins in the muscle. The proposed experiments will attempt to block activity of this enzyme and establish it as a potential target to rescue muscle mass and growth in aged rats.

What aspects of your project are most interesting from a scientific point of view?
A major factor in maintaining or increasing skeletal muscle mass is the ability of the muscle cells to synthesize new protein; however, resting skeletal muscle protein synthesis rate markedly declines with age. The enzyme AMPK has been called a "fuel-gauge" because it regulates the metabolism of fat and carbohydrate as well as the synthesis of new proteins. Thus, it is a key enzyme that almost acts as a "master switch". There have been many potential mechanisms identified in aged muscle that may result in its wasting.

However, it is rare to find a molecule that appears to play such a central role. Furthermore, even when mechanisms of muscle wasting are identified, it has also been rare to be able to correct the problem by targeting the defect. If successful, this research will identify such an exciting prospect. There are great benefits of enlarging muscle mass as a medical strategy in conditions other than sarcopenia, such as spinal cord injury, limb immobilization, AIDS, and other states of severe muscle wasting. Determination of the mechanisms underlying muscle atrophy and overload-induced hypertrophy would provide a scientific basis for devising dietary supplements, drugs, gene medicine, strategies, cell therapies, or other methods to produce muscle enlargement in those individuals for whom exercise is perhaps impossible.

What are the implications of your research for age-related diseases and disorders?
The proposed experiments will attempt to block the activity of AMPK and establish it as a potential target to rescue muscle mass and growth in aged rats. If successful, the application of such a targeted intervention could eventually be widespread in humans, and may have advantages over hormonal replacement therapy, a relatively ineffective pharmaceutical strategy to increase muscle mass in the elderly (with many potential systemic adverse effects). Possible future implications also potentially include various types of gene therapy or other pharmaceutical interventions to block AMPK in older individuals and therefore potentially increase their muscle mass and strength.

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