Molecular pathogenesis of skeletal muscle atrophy

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PROJECT SUMMARY / ABSTRACT Age-related skeletal muscle weakness and atrophy diminish the health and quality of life of many elderly people. However, the molecular mechanisms that cause muscle weakness and atrophy during aging are poorly understood, and highly effective therapeutic approaches do not exist. As a result, many elderly individuals suffer the consequences of muscle atrophy, including weakness, fatigue, restricted activity, falls, debilitation, and loss of independence. These issues place enormous burdens on patients, their families, and society in general. Our research program is focused on molecular mechanisms of skeletal muscle atrophy and the discovery and development of small molecules that could potentially be used to prevent or treat this condition. In preliminary studies, performed in mouse models, we identified the first example of a protein that is required for the loss of skeletal muscle mass, quality, strength, and endurance exercise capacity during aging: the transcription factor ATF4. We found that conditional knockout mice lacking ATF4 expression in skeletal muscle fibers from birth develop normally and exhibit normal muscle mass and function into middle age; however, they are resistant to age-induced declines in muscle mass, strength, quality, and endurance exercise capacity. Conversely, forced expression of ATF4 in young adult skeletal muscle fibers is sufficient to induce atrophy. Furthermore, we discovered two structurally dissimilar small molecules that significantly reduce age-related muscle weakness and atrophy, and interestingly, both of these small molecules blunt ATF4 activity in aged skeletal muscle. Collectively, these results strongly suggest a key role for the ATF4 pathway in age-related muscle weakness and atrophy. Moreover, these data elucidate several important areas for further investigation. For example, we do not yet know if a specific reduction of ATF4 activity, acutely applied to aged skeletal muscle, is sufficient to treat age-related muscle weakness and atrophy. Moreover, the downstream mechanisms by which ATF4 promotes muscle weakness and atrophy during aging are not understood. To begin to resolve these important issues, we propose three specific aims, all using mouse models. In Aim 1, we will test the hypothesis that an acute, targeted reduction of ATF4 expression in skeletal muscle fibers of old mice will reverse age-related changes in muscle mass and function. In Aim 2, we will identify ATF4-dependent mRNAs that are required for age-related skeletal muscle atrophy, testing the hypothesis that ATF4 promotes muscle loss by activating certain skeletal muscle genes whose protein products are necessary for muscle fiber atrophy during aging. In Aim 3, we will determine the role of ATF4 in protein metabolism in aged skeletal muscle, testing the hypothesis that ATF4 is at least partly responsible for age-related derangements in protein metabolism that are central to muscle weakness and atrophy. Through these studies, we hope to elucidate fundamental molecular mechanisms and new therapeutic approaches for age-related muscle weakness and atrophy, a disabling condition that affects millions of elderly people in the US alone.