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.

Redox Pathogenesis in Rheumatic Diseases

“… 158 PSS skin has an accelerated aging phenotype, with hallmarks of telomere attrition, genomic instability, epigenetic alterations, deregulated nutrient sensing, stem cell exhaustion, and mitochondrial dysfunction. 159 …”

“…Thus, CD38 expression might promote cellular senescence or senescent cells might induce CD38, connecting NAD metabolism and PSS. 159 Myofibroblasts are precursors of proliferating fibroblasts in PSS skin, which depend on mTOR activation 160 , 161 and availability of TGFβ 162 (Figure 5 ). NAD may also directly stimulate TGFβ production via CD38.…”

Cell Senescence-Independent Changes of Human Skin Fibroblasts with Age

“…There have been various mechanisms and implications proposed for the effect of senescent cells in human skin [23] and for ageing in general [21,[24][25][26], although the evidence is not conclusive [27]. Inflammatory signals are thought to activate myofibroblasts, which can be inhibited by activation of anti-ageing molecules such as AMPK [17,28].…”