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Title: New insight into the role of MMP14 in metabolic balance

Abstract

Membrane-anchored matrix metalloproteinase 14 (MMP14) is involved broadly in organ development through both its proteolytic and signal-transducing functions. Knockout of Mmp14 (KO) in mice results in a dramatic reduction of body size and wasting followed by premature death, the mechanism of which is poorly understood. Since the mammary gland develops after birth and is thus dependent for its functional progression on systemic and local cues, we chose it as an organ model for understanding why KO mice fail to thrive. A global analysis of the mammary glands’ proteome in the wild type (WT) and KO mice provided insight into an unexpected role of MMP14 in maintaining metabolism and homeostasis. We performed mass spectrometry and quantitative proteomics to determine the protein signatures of mammary glands from 7 to 11 days old WT and KO mice and found that KO rudiments had a significantly higher level of rate-limiting enzymes involved in catabolic pathways. Glycogen and lipid levels in KO rudiments were reduced, and the circulating levels of triglycerides and glucose were lower. Analysis of the ultrastructure of mammary glands imaged by electron microscopy revealed a significant increase in autophagy signatures in KO mice. Finally, Mmp14 silenced mammary epithelial cells displayed enhanced autophagy.more » Applied to a systemic level, these findings indicate that MMP14 is a crucial regulator of tissue homeostasis. If operative on a systemic level, these findings could explain how Mmp14KO litter fail to thrive due to disorder in metabolism.« less

Authors:
 [1];  [2];  [3];  [4];  [5];  [5];  [5];  [5];  [5];  [5];  [5];  [5];  [5];  [6];  [7];  [5];  [5]
  1. Univ. of California, Davis, CA (United States); Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  2. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. of Calcutta, Calcutta (India)
  3. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States); Univ. de Sao Paulo, Sao Paulo (Brazil)
  4. Columbia Univ. Medical Center, New York, NY (United States)
  5. Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
  6. Kanazawa Univ., Kanazawa (Japan)
  7. Univ. of California, Davis, CA (United States)
Publication Date:
Research Org.:
Lawrence Berkeley National Lab. (LBNL), Berkeley, CA (United States)
Sponsoring Org.:
USDOE Office of Science (SC), Biological and Environmental Research (BER) (SC-23)
OSTI Identifier:
1378994
Grant/Contract Number:
AC02-05CH11231
Resource Type:
Journal Article: Accepted Manuscript
Journal Name:
PeerJ
Additional Journal Information:
Journal Volume: 4; Journal Issue: 7; Journal ID: ISSN 2167-8359
Publisher:
PeerJ Inc.
Country of Publication:
United States
Language:
English
Subject:
59 BASIC BIOLOGICAL SCIENCES

Citation Formats

Mori, Hidetoshi, Bhat, Ramray, Bruni-Cardoso, Alexandre, Chen, Emily I., Jorgens, Danielle M., Coutinho, Kester, Louie, Katherine, Bowen, Benjamin Ben, Inman, Jamie L., Tecca, Victoria, Lee, Sarah J., Becker-Weimann, Sabine, Northen, Trent, Seiki, Motoharu, Borowsky, Alexander D., Auer, Manfred, and Bissell, Mina J.. New insight into the role of MMP14 in metabolic balance. United States: N. p., 2016. Web. doi:10.7717/peerj.2142.
Mori, Hidetoshi, Bhat, Ramray, Bruni-Cardoso, Alexandre, Chen, Emily I., Jorgens, Danielle M., Coutinho, Kester, Louie, Katherine, Bowen, Benjamin Ben, Inman, Jamie L., Tecca, Victoria, Lee, Sarah J., Becker-Weimann, Sabine, Northen, Trent, Seiki, Motoharu, Borowsky, Alexander D., Auer, Manfred, & Bissell, Mina J.. New insight into the role of MMP14 in metabolic balance. United States. doi:10.7717/peerj.2142.
Mori, Hidetoshi, Bhat, Ramray, Bruni-Cardoso, Alexandre, Chen, Emily I., Jorgens, Danielle M., Coutinho, Kester, Louie, Katherine, Bowen, Benjamin Ben, Inman, Jamie L., Tecca, Victoria, Lee, Sarah J., Becker-Weimann, Sabine, Northen, Trent, Seiki, Motoharu, Borowsky, Alexander D., Auer, Manfred, and Bissell, Mina J.. 2016. "New insight into the role of MMP14 in metabolic balance". United States. doi:10.7717/peerj.2142. https://www.osti.gov/servlets/purl/1378994.
@article{osti_1378994,
title = {New insight into the role of MMP14 in metabolic balance},
author = {Mori, Hidetoshi and Bhat, Ramray and Bruni-Cardoso, Alexandre and Chen, Emily I. and Jorgens, Danielle M. and Coutinho, Kester and Louie, Katherine and Bowen, Benjamin Ben and Inman, Jamie L. and Tecca, Victoria and Lee, Sarah J. and Becker-Weimann, Sabine and Northen, Trent and Seiki, Motoharu and Borowsky, Alexander D. and Auer, Manfred and Bissell, Mina J.},
abstractNote = {Membrane-anchored matrix metalloproteinase 14 (MMP14) is involved broadly in organ development through both its proteolytic and signal-transducing functions. Knockout of Mmp14 (KO) in mice results in a dramatic reduction of body size and wasting followed by premature death, the mechanism of which is poorly understood. Since the mammary gland develops after birth and is thus dependent for its functional progression on systemic and local cues, we chose it as an organ model for understanding why KO mice fail to thrive. A global analysis of the mammary glands’ proteome in the wild type (WT) and KO mice provided insight into an unexpected role of MMP14 in maintaining metabolism and homeostasis. We performed mass spectrometry and quantitative proteomics to determine the protein signatures of mammary glands from 7 to 11 days old WT and KO mice and found that KO rudiments had a significantly higher level of rate-limiting enzymes involved in catabolic pathways. Glycogen and lipid levels in KO rudiments were reduced, and the circulating levels of triglycerides and glucose were lower. Analysis of the ultrastructure of mammary glands imaged by electron microscopy revealed a significant increase in autophagy signatures in KO mice. Finally, Mmp14 silenced mammary epithelial cells displayed enhanced autophagy. Applied to a systemic level, these findings indicate that MMP14 is a crucial regulator of tissue homeostasis. If operative on a systemic level, these findings could explain how Mmp14KO litter fail to thrive due to disorder in metabolism.},
doi = {10.7717/peerj.2142},
journal = {PeerJ},
number = 7,
volume = 4,
place = {United States},
year = 2016,
month = 7
}

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