Skeletal muscle undergoes adaptation in response to a sustained increase of contractile activity through activation of multiple signaling pathways. Accumulating evidence suggests that exercise induced-expression of peroxisome proliferator-activated receptor * co-activator-U (PGC-U) plays a pivotal role in the adaptation. Hence, gaining insights into the PGC-U gene regulation will improve our understanding of the molecular mechanism underlying skeletal muscle adaptation. We have previously developed a novel imaging analysis for promoter activity in skeletal muscles in living mice and have shown that contractile activity-induced PGC-U gene transcription in skeletal muscle depends on both the myocyte enhancer factor 2 (MEF2) binding sites and the cyclic AMP response element (CRE) on the PGC-U promoter. To date, several findings with gain-of-function genetic approaches have shown that PGC-U protein expression can be enhanced by muscle-specific overexpression of active forms of potential upstream regulatory factors; however, there has been no studies delineating the direct interactions between the upstream regulatory factor and the PGC-U promoter using loss-of-function approaches in whole animal models. We hypothesize that transcription factors that directly interact with the MEF2 and CRE binding sites and the signaling molecules that modulate the activities of these transcription factors regulate PGC-U transcription in response to increased contractile activity in skeletal muscle in vivo.
The specific aims are to: 1. To define the functional role of the MEF2 and CRE sequence elements in contractile activity-induced PGC-U promoter activity in living mice. 2. Determine the transcription factor-promoter interaction that is required for contractile activity-induced PGC-U promoter activity. The experimental plan includes a novel in vivo approach that was developed in our laboratory. We anticipate important new information to emerge. Findings from this research will likely foster innovative approaches to improve skeletal muscle function and treat diseases related to skeletal muscle disorder.
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