AMPK signaling inhibits the differentiation of myofibroblasts: impact on age-related tissue fibrosis and degeneration

Abstract

Disruption of the extracellular matrix (ECM) and an accumulation of fibrotic lesions within tissues are two of the distinctive hallmarks of the aging process. Tissue fibroblasts are mesenchymal cells which display an impressive plasticity in the regulation of ECM integrity and thus on tissue homeostasis. Single-cell transcriptome studies have revealed that tissue fibroblasts exhibit a remarkable heterogeneity with aging and in age-related diseases. Excessive stress and inflammatory insults induce the differentiation of fibroblasts into myofibroblasts which are fusiform contractile cells and abundantly secrete the components of the ECM and proteolytic enzymes as well as many inflammatory mediators. Detrimental stresses can also induce the transdifferentiation of certain mesenchymal and myeloid cells into myofibroblasts. Interestingly, many age-related stresses, such as oxidative and endoplasmic reticulum stresses, ECM stiffness, inflammatory mediators, telomere shortening, and several alarmins from damaged cells are potent inducers of myofibroblast differentiation. Intriguingly, there is convincing evidence that the signaling pathways stimulated by the AMP-activated protein kinase (AMPK) are potent inhibitors of myofibroblast differentiation and accordingly AMPK signaling reduces fibrotic lesions within tissues, e.g., in age-related cardiac and pulmonary fibrosis. AMPK signaling is not only an important regulator of energy metabolism but it is also able to control cell fate determination and many functions of the immune system. It is known that AMPK signaling can delay the aging process via an integrated signaling network. AMPK signaling inhibits myofibroblast differentiation, e.g., by suppressing signaling through the TGF-β, NF-κB, STAT3, and YAP/TAZ pathways. It seems that AMPK signaling can alleviate age-related tissue fibrosis and degeneration by inhibiting the differentiation of myofibroblasts.