Skeletal muscle atrophy is a common, debilitating consequence of aging and a variety of medical conditions, including diabetes, stroke, and heart failure. In addition to having poorer clinical outcomes, patients with muscle atrophy experience more frequent falls and fractures, prolonged rehabilitation, and loss of independent living. Despite its prevalence and severity, the molecular pathogenesis of muscle atrophy remains poorly understood and no effective medical therapies exist. Based on our preliminary data, we hypothesize that induction of Gadd45a (growth arrest and DNA damage-inducible 45a) and its downstream target Cdkn1a (cyclin-dependent kinase inhibitor 1a) are critical events in the molecular pathogenesis of skeletal muscle atrophy. We and others have shown that Gadd45a and Cdkn1a mRNA levels are increased by various atrophy-promoting stresses, including aging, immobilization, fasting, and muscle denervation. Furthermore, using overexpression and RNA interference-mediated knockdown of Gadd45a and Cdkn1a in mouse skeletal muscle, we have shown that both Gadd45a and Cdkn1a are necessary and sufficient to cause muscle atrophy. Taken together, these data show that many muscle stresses induce skeletal muscle expression of Gadd45a and Cdkn1a, which then promote skeletal muscle atrophy. If this understanding is correct, then Gadd45a, Cdkn1a, and their upstream and downstream mediators comprise a critical pathway leading to skeletal muscle atrophy in ill and aged human patients. We propose two aims to test this model.
In Aim 1, we will determine the mechanism by which the lysine deacetylase HDAC4 increases Gadd45a mRNA levels.
In Aim 2, we will study the mechanism by which Cdkn1a reduces expression of the anti-atrophy transcriptional co-activator PGC-1? and causes muscle atrophy. Through these studies, we hope to identify a central pathway that drives skeletal muscle atrophy and, in doing so, identify new therapeutic targets to treat this devastating condition, which affects millions of Americans annually.
Skeletal muscle atrophy has tremendous personal and social costs for patients and their families, leading to weakness, debilitation, and reduced quality of life. The proposed research will study an essential molecular pathway mediating muscle atrophy and identify novel therapeutic targets for this devastating, currently untreatable condition affecting millions of Americans annually.
