New insight into the role of MMP14 in metabolic balance

PeerJ

article

Hidetoshi Mori¹  Ramray Bhat²  Alexandre Bruni-Cardoso²  Emily I. Chen⁵  Danielle M. Jorgens⁶  Kester Coutinho⁶  Katherine Louie⁷  Benjamin Ben Bowen⁷  Jamie L. Inman²  Victoria Tecca²  Sarah J. Lee²  Sabine Becker-Weimann²  Trent Northen⁷  Motoharu Seiki⁸  Alexander D. Borowsky¹  Manfred Auer⁶  Mina J. Bissell² 

[1] Department of Pathology, Center for Comparative Medicine, University of California;Biological Systems and Engineering Division, Lawrence Berkeley National Laboratory;Calcutta Medical College, University of Calcutta;Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo;Department of Pharmacology, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center;Molecular Biophysics and Integrated Bioimaging Division, Lawrence Berkeley National Laboratory;Environmental Genomics and Systems Biology, Lawrence Berkeley National Laboratory;Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University

关键词: Autophagy;    Homeostasis;    Mammary gland;    Glycogen;    Mmp14KO mouse;    Triglycerides;    Lipids;    Energy metabolism;    Glucose;    Matrix metalloproteinase 14;   

DOI  :  10.7717/peerj.2142

学科分类：社会科学、人文和艺术（综合）

来源: Inra

【 摘 要 】

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.

【 授权许可】

CC BY