The broad, long range objective is to understand molecular mechanisms that regulate initiation of skeletal muscle (skm) atrophy. The objective of this application is to explore the role of Merg1a in initiation of skm atrophy. The central hypothesis is that Merg1a activates the ubiquitin proteasome pathway (UPP), known to be active in atrophying tissue, and participates in the onset of skm atrophy by modulating sarcolemmal Ca++ channel activity. The hypothesis is based on data which show that Merg1a is present in atrophying muscle and that its function can induce UPP activity and atrophy. Addtionally, data show that E3 ligase (part of the UPP) mRNAs are transcribed in response to Merg1a expression. Two pathways are known to induce E3 ligase synthesis: IKK-2/I:B-1/NF-:B and PI3K/Akt/FOXO. Therefore, our first two specific aims are to determine if: 1) Merg1a expression initiates UPP activity by activating the IKK-2/I:B-1/NF-:B pathway;and 2) Merg1a expression initiates UPP activity by the PI3K/Akt/FOXO pathway. Data also show that a connection exists between Ca++ levels and Merg1a expression. Thus, our third aim is to determine the effect of Merg1a expression on Ca++ current density and intracellular Ca++ concentration and if changes in Ca++ modulation are necessary for increased UPP activity. The first two aims will measure the effect(s) of in vivo ectopic co- expression of Merg1a and either constitutively active or dominant negative forms of proteins known to participate in the pathways leading to E3 ligase production.
The third aim will involve use of a C2C12 clonal cell line which conditionally expresses Merg1a to determine the effect(s) of Merg1a expression on Ca++ current density, Ca++ channel subunit expression, intracellular calcium levels, and calpain activity. Finally, various pharmacological modulators of Ca++ handling will be used to determine if Ca++ is involved in Merg1a signaling to the UPP. Relevance. Skeletal muscle atrophy occurs with many pathological conditions (e.g., AIDS, diabetes, cancer cachexia, etc.) and is related to increased disability, morbidity and mortality. This research is significant because it will explore a novel initiator of skm atrophy and produce information that will allow for development of more effective therapies and, thereby, reduce the number of cases of this debilitating condition.
Skeletal muscle atrophy occurs with many pathological conditions (e.g., AIDS, diabetes, cancer cachexia, etc.) and is related to increased disability, morbidity and mortality. The Merg1a potassium channel has been shown to be involved in the atrophic process. Investigation of the link between Merg1a and skeletal muscle atrophy will produce information that will allow for development of more effective therapies and, thereby, reduce the number of cases of this debilitating condition.
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