Age-related skeletal muscle atrophy, also known as sarcopenia, diminishes the health and quality of life of many Veteran patients. However, the molecular mechanisms of age-related muscle atrophy are poorly understood, and a pharmacologic therapy does not exist. As a result, many elderly Veterans suffer the consequences of muscle atrophy, including weakness, impaired activity, falls, prolonged hospitalization, delayed rehabilitation, loss of independent living, and increased mortality. This places enormous burdens on elderly Veterans, their families, and society in general. Importantly, despite its prevalence and severity, skeletal muscle atrophy lacks a specific and effective pharmacologic therapy and thus represents an enormous unmet medical need. Development of pharmacologic interventions for muscle atrophy has been hindered by the fact that the molecular basis of muscle atrophy is highly complex, poorly understood, and still largely unexplored. The research proposed here would help to address this issue by investigating a newly identified signaling pathway in skeletal muscle fibers that appears to be critically important for skeletal muscle aging. We originally discovered this pathway through unbiased systems-based strategies, which have, to date, identified several critical pathway components, including the transcriptional regulator ATF4 (the first and only known example of a skeletal muscle protein that is required for the loss of strength, muscle quality, muscle mass and endurance exercise capacity during aging), the p21 gene (a key ATF4 target gene in elderly skeletal muscle), and the p21 protein (a novel mediator of muscle fiber atrophy). Our proposed studies will build upon these important initial findings to more deeply investigate and understand the mechanisms by which ATF4 activates the p21 gene (Aim 1), the pathophysiological consequences of p21 expression in skeletal muscle fibers (Aim 2), and the downstream mechanism(s) by which p21 promotes muscle atrophy (Aim 3). Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic targets for age-related muscle atrophy, a disabling condition that affects many Veteran patients.
Muscle wasting, also known as skeletal muscle atrophy, is a very common problem in elderly Veteran patients, and leads to other problems such as weakness, reduced activity, falls, fractures, loss of independent living, and reduced quality of life. Although age-related muscle wasting is very common and serious, its causes are poorly understood and we do not have a medicine for it. In the research that we are proposing, we will study the causes of age-related muscle wasting. These studies are a very important step towards our long-term goal of finding a therapy for muscle wasting in elderly Veteran patients.
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