Role of co-chaperone, BAG3, in muscle degeneration under physiological stress

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DESCRIPTION (provided by applicant): Project Summary. BAG3 is a member of co-chaperones that binds to and regulates Hsp70-family molecular chaperones. BAG3 is expressed in muscle and has been reported to possess anti-apoptotic. Mice with homozygous disruption of their bagS genes have been generated, revealing a striking post-natal phenotype whereby animals stop growing after 2 weeks of age, and uniformly die by 4 weeks. These bag3-deficient animals develop myofibrillar degeneration with apoptotic feature. The muscle degeneration is especially severe in the diaphragm and soleus muscles, suggesting that physiological use predisposes to muscle degeneration in the absence of BAG3. In bag3 deficient muscle, accumulation of ubiquitinated protein, upregulation of proteasome subunit and degradation of troponin T has been observed. Ring finger type ubiquitin ligase, Siah family protein directly interact to BAG3 protein. Additionally, several lines of evidence indicate that bagS inhibits the ubiquitin proteasome system. Gene knockdown of bag3 in C2C12 myoblast indicates increased apoptosis and accumulation of ubiquitinated proteins. Taken together, BAG3 appears to be critical for protection of muscle through inhibition of apoptosis and ubiquitin proteasome proteolysis. Experiments are proposed to explore the molecular mechanism of inhibition of apoptosis and ubiquitin proteasome including: (1) Studying the molecular mechanisms of apoptosis caused by bagS-deficiency; (2) To determine the function of BAG3 in regulation of ubiquitin proteasome and interacting protein in skeletal muscle and (3) Generation and Analyzing the effects of bag3 depletion in skeletal muscle by Cre-lox system or skeletal muscle specific over-expression of bag3 in vivo using pathophysiological model and cross mating experiments. Relevance: These studies will provide insights about the roles of BAG3 in muscle cell survival under physiological stress, and may provide us clues for understanding molecular mechanisms of myofibrillar degeneration and for investigating the new target for therapy of muscular degenerative human diseases