One of the major goals of PAS-03-122, Frailty in Old Age: Pathophysiology and Interventions, is to enhance the development and evaluation of unique interventions that target processes that appear to play an important role in the mechanism(s) of the development and progression of frailty. Frailty has been defined as consisting of low muscle strength, slow walking speed, weight loss, and low physical activity. Clearly, sarcopenia, or the age related loss of muscle mass and muscle strength contributes substantially to the muscle strength and walking speed decrements of frailty. Beta-two adrenergic agonists (B2A) significantly increase muscle mass in the elderly; however, the mechanism(s) for this increase in muscle mass in humans is/are not known. We will examine: 1) the effects of 2.5 and 8.5 days of albuterol administration (16 mg/24h) on skeletal muscle protein synthesis (MPS) and the mRNAs for insulin like growth factor II, and Ca2+ dependent proteolysis using Real Time PCR as well as the phosphorylation status of P70 S6 Kinase using the Western Blot technique in elderly (age 60-85) men and women who have body mass indices that correspond to the presence of sarcopenia. Animal data suggest that B2A stimulate MPS for 2-3 days with inhibition of protein degradation occurring at later time points. The 8.5 day measurement will be to determine whether MPS remains elevated later in humans. Elucidating, the way in which B2A affect muscle protein metabolism may possibly lead to other therapeutic strategies to target specific components of protein synthetic and/or protein degradative pathways that are activated or deactivated by B2A. Additionally, if we determine the primary site of action of B2A we will able to hypothesize whether B2A will likely work in different aging related muscle wasting conditions. Because of the exploratory nature of this study the R21 granting mechanism is appropriate. Muscle mass loss as a result of aging is a major problem. Some strategies for attenuating muscle mass loss such as testosterone replacement may have unwanted side effects. Albuterol, an FDA approved drug, has been shown to increase muscle mass in the elderly with minimal side effects. Because this is the case, it is important to know the mechanism by which albuterol increases muscle mass in humans so that similar strategies may be developed. By finding the precise target(s) of albuterol action alternative strategies can be developed to attenuate the incidence of sarcopenia. ? ? ?
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