PGC-1α regulates autophagy to promote fibroblast activation and tissue fibrosis

Abstract

ObjectivesCoactivators are a heterogeneous family of transcriptional regulators that are essential for modulation of transcriptional outcomes and fine-tune numerous cellular processes. The aim of the present study was to evaluate the role of the coactivator peroxisome proliferator-activated receptor gamma coactivator-1α (PGC-1α) in the pathogenesis of systemic sclerosis (SSc).MethodsExpression of PGC-1α was analysed by real-time PCR, western blot and immunofluorescence. Modulation of autophagy was analysed by reporter studies by expression of autophagy-related genes. The effects of PGC-1α knockdown on collagen production and myofibroblast differentiation were analysed in cultured human fibroblasts and in two mouse models with fibroblast-specific knockout of PGC-1α.ResultsThe expression of PGC-1α was induced in dermal fibroblasts of patients with SSc and experimental murine fibrosis. Transforming growth factor beta (TGFβ), hypoxia and epigenetic mechanisms regulate the expression of PGC-1α in fibroblasts. Knockdown of PGC-1α prevented the activation of autophagy by TGFβ and this translated into reduced fibroblast-to-myofibroblast differentiation and collagen release. Knockout of PGC-1α in fibroblasts prevented skin fibrosis induced by bleomycin and by overexpression of a constitutively active TGFβ receptor type I. Moreover, pharmacological inhibition of PGC-1α by SR18292 induced regression of pre-established, bleomycin-induced skin fibrosis.ConclusionPGC-1α is upregulated in SSc and promotes autophagy to foster TGFβ-induced fibroblast activation. Targeting of PGC-1α prevents aberrant autophagy, inhibits fibroblast activation and tissue fibrosis and may over therapeutic potential.

The AP-1 Transcription Factor Fosl-2 Regulates Autophagy in Cardiac Fibroblasts during Myocardial Fibrogenesis

“…We observed that fibroblast-specific deletion of the autophagic gene Atg5 effectively reduced cardiac fibrosis in a mouse model of cardiac hypertrophy. In line with our data, knock-out of autophagy activator peroxisome proliferator-activated receptor gamma coactivator-1α in fibroblasts prevented development of skin fibrosis in a mouse model of systemic sclerosis [25]. The profibrotic role of autophagy in fibroblasts was further supported by in vitro data.…”

“…Here, we demonstrated a novel mechanism, by which the TGF-β-Fosl-2 axis regulated profibrotic changes in cardiac fibroblasts by activating autophagocytosis. Previous studies have already shown the significance of autophagy in promoting fibrotic processes in multiple organs including skin [25], lung [26], liver [27], kidney [28] and heart [9][10][11]. It should be noted that in the heart, autophagocytosis might also be involved in antifibrotic and cardioprotective processes [8,12,13].…”

“…Our in vitro data indicated that interplay between Fosl-2 and autophagy plays a crucial role in profibrotic changes in cardiac fibroblasts. To address whether these mechanisms are relevant during fibrogenesis in vivo, we analyzed fibrotic changes, using a model of experimental cardiac hypertrophy, in mice lacking either Fosl-2 or Atg5 in stromal cells using Ccl19 Cre Fosl2 flox/flox and Ccl19 Cre Atg5 flox/flox strains (Ccl19 is expressed in stromal cells 25 ), induced by continuous infusion of the vasoconstrictor angiotensin II delivered by osmotic minipumps. Continuous infusion of exogenous angiotensin II led to increased heart weight, collagen deposition and induced expression of Fosl-2 and Atg5 in mouse hearts ( Figure S3A-D).…”

Eight Weeks of High-Intensity Interval Static Strength Training Improves Skeletal Muscle Atrophy and Motor Function in Aged Rats via the PGC-1α/FNDC5/UCP1 Pathway

“… 19 PGC-1α promotes autophagy to foster TGF β-induced fibroblast activation. 20 So the fibroblast between muscles is less in siPGC-1α rat than in the wild type rat in the muscle images. The overexpression of PGC-lα and PGC-lβ may inhibit the expression of skeletal muscle-specific ubiquitin ligase, resisting denervated muscle shrinkage.…”

“… 25 , 26 So we find that the downregulation of PGC-1α level has more severe muscle atrophy in siPGC-1αgroup and primary molecular mechanism contributes to enhanced transcription of atrophy-related Atrogin-1 FoxO3 or NF-κB activation, and protein loss. 19 , 20 However, both long-term and acute exercise increases PGC-1α expression. 22 , 27 , 28 It enhances mitochondrial synthesis, and oxidative phosphorylation stimulates peroxisome proliferator-activated receptor (PPAR) to enable farnesoid X receptor (FXR) gene transcription, which promotes fat metabolism and prevents the incidence of sarcopenia.…”