In skeletal muscle, modest disruptions in myofiber electrical activity, resulting from immobilization, aging or prolonged bed-rest, or severe disruptions, caused by trauma to the nervous system, inevitably lead to muscle atrophy. Atrophic myofibers, due to their smaller cross-sectional area, have a reduced capacity to generate force, but they neither degenerate nor undergo apoptosis. Indeed, atrophic myofibers retain most of the structural features that are characteristic of normal muscle. After short periods of inactivity, muscle atrophy is reversible;even after prolonged periods of disuse, myofiber degeneration remains uncommon, and atrophy can be partially reversed. In contrast, in a variety of congenital myopathies, muscle wasting is far more dramatic. Taken together, these results raise the possibility that muscle disuse induces compensatory mechanisms to maintain skeletal myofibers and limit atrophy when myofiber electrical activity is reduced. We found that expression of the transcription factor Runxi is substantially induced in muscle following denervation as well as in other models of muscle disuse. Importantly, in the absence of Runxi induction, myofibers undergo severe structural changes, autophagy and a dramatic reduction in cell size. These findings indicate that a reduction in myofiber electrical activity places demands on muscle that are met, in part, by induction of Runxi. In the absence of Runxi, myofibers cannot meet these demands and undergo severe wasting. To begin to understand how Runxi regulates muscle structure and wasting, we screened microarrays and identified twenty-nine genes that are regulated by Runxi in skeletal muscle. These findings indicate that miss-expression of a small number of Runxi-dependent genes is responsible for the structural defects and severe muscle wasting. Experiments described in this proposal are designed to reveal how the Runxi compensatory program is activated and how this Runxi program prevents muscle wasting. Experiments described in the first aim are designed to provide insight into how runxl expression is regulated by electrical activity, and these findings will provide a basis for future studies designed to learn whether defects in Runxi may be responsible for certain congenital myopathies or critical illness myopathy. Experiments described in the second aim are designed to understand how Runxi regulates muscle structure and prevents muscle wasting by studying the roles of the twenty-nine Runxi-dependent genes in muscle wasting. Experiments described in the third aim are designed to understand the role that autophagy, a major pathway for protein degradation, plays in muscle atrophy and in the severe muscle wasting found in denervated, runxl mutant muscle.
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