Extracellular Matrix Stiffness: New Areas Affecting Cell Metabolism

Abstract

In recent years, in-depth studies have shown that extracellular matrix stiffness plays an important role in cell growth, proliferation, migration, immunity, malignant transformation, and apoptosis. Most of these processes entail metabolic reprogramming of cells. However, the exact mechanism through which extracellular matrix stiffness leads to metabolic reprogramming remains unclear. Insights regarding the relationship between extracellular matrix stiffness and metabolism could help unravel novel therapeutic targets and guide development of clinical approaches against a myriad of diseases. This review provides an overview of different pathways of extracellular matrix stiffness involved in regulating glucose, lipid and amino acid metabolism.

Keywords: amino acid metabolism; extracellular matrix stiffness; glucose metabolism; lipid metabolism; metabolic reprogramming.

Figure 1

Profiles of pathways through which extracellular matrix stiffness affects glucose metabolism. Extracellular matrix stiffness affects glucose metabolism in the following seven pathways: (i) YAP/TAZ pathway; (ii) TXNIP pathway; (iii) Rho/Rock-actin cytoskeleton pathway; (iv) Rho/Rock-PTEN pathway; (v) integrin-FAK-PI3K-Akt pathway; (vi) GSK3 pathway; and (vii) AMPK pathway. The effects of extracellular matrix stiffness on cellular glucose metabolism can ultimately be summarized as follows: (i) Changes in the number of glucose transport proteins in the cell membrane; (ii) Alteration of glycolytic enzyme activity; (iii) Alteration of glycogen synthase activity; (iv) Expression of gluconeogenic genes; (v) Enhancement of the pentose phosphate pathway; and (vi) Endocytosis of cells.

Figure 2

Profiles of pathways through which extracellular matrix stiffness affects lipid metabolism. Extracellular matrix stiffness affects lipid metabolism in the following five pathways: (i) integrin-FAK-PI3K-Akt pathway; (ii) YAP/TAZ pathway; (iii) AMPK pathway; (iv) Rho/Rock-actin cytoskeleton pathway; and (v) TXNIP pathway. The effects of extracellular matrix stiffness on cellular lipid metabolism can be described as upregulation of SREBP, LDLR, LPL and CD36.

Figure 3

Profiles of pathways through which extracellular matrix stiffness affects amino acid metabolism. Extracellular matrix stiffness affects amino acid metabolism in the following three pathways: (i) YAP/TAZ pathway; (ii) kindlin-2 pathway; and (iii) integrin-FAK-PI3K-Akt pathway. The effects of extracellular matrix stiffness on cellular amino acid metabolism can ultimately be summarized as follows: (i) regulating the number of amino acid transport proteins in the cell membrane; (ii) regulating the quantity and activity of enzymes involved in the amino acid synthesis; (iii) regulation of glutamine catabolism; (iv) regulation of the synthesis of glutamine.