TY - JOUR
T1 - Cardiac-restricted expression of VCP/TER94 RNAi or disease alleles perturbs drosophila heart structure and impairs function
AU - Viswanathan, Meera C.
AU - Blice-Baum, Anna C.
AU - Sang, Tzu Kang
AU - Cammarato, Anthony
N1 - Funding Information:
Acknowledgments: This work was funded by National Institutes of Health grants 1R56HL124091 (Anthony Cammarato), 1R01HL124091 (Anthony Cammarato), T-32 postdoctoral training grant-5T32HL007227-38 (Anna C. Blice-Baum) and the American Federation for Aging Research (AFAR) (Anthony Cammarato).
Publisher Copyright:
© 2016 by the authors; licensee MDPI, Basel, Switzerland.
PY - 2016/6
Y1 - 2016/6
N2 - Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP’s role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology.
AB - Valosin-containing protein (VCP) is a highly conserved mechanoenzyme that helps maintain protein homeostasis in all cells and serves specialized functions in distinct cell types. In skeletal muscle, it is critical for myofibrillogenesis and atrophy. However, little is known about VCP’s role(s) in the heart. Its functional diversity is determined by differential binding of distinct cofactors/adapters, which is likely disrupted during disease. VCP mutations cause multisystem proteinopathy (MSP), a pleiotropic degenerative disorder that involves inclusion body myopathy. MSP patients display progressive muscle weakness. They also exhibit cardiomyopathy and die from cardiac and respiratory failure, which are consistent with critical myocardial roles for the enzyme. Nonetheless, efficient models to interrogate VCP in cardiac muscle remain underdeveloped and poorly studied. Here, we investigated the significance of VCP and mutant VCP in the Drosophila heart. Cardiac-restricted RNAi-mediated knockdown of TER94, the Drosophila VCP homolog, severely perturbed myofibrillar organization and heart function in adult flies. Furthermore, expression of MSP disease-causing alleles engendered cardiomyopathy in adults and structural defects in embryonic hearts. Drosophila may therefore serve as a valuable model for examining role(s) of VCP in cardiogenesis and for identifying novel heart-specific VCP interactions, which when disrupted via mutation, contribute to or elicit cardiac pathology.
KW - Cdc48
KW - IBMPFD
KW - Multisystem proteinopathy
KW - Myopathy
KW - P97
KW - TER94
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U2 - 10.3390/jcdd3020019
DO - 10.3390/jcdd3020019
M3 - Article
AN - SCOPUS:85009171862
SN - 2308-3425
VL - 3
JO - Journal of Cardiovascular Development and Disease
JF - Journal of Cardiovascular Development and Disease
IS - 2
M1 - 19
ER -