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PGC1? repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state.

ABSTRACT: Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (PPARGC1A, encoding PGC1?), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expression and function of PGC1?. In vitro PGC1? manipulation was performed by small interfering RNA knockdown or overexpression. Fibroblast activation was assessed by quantitative PCR, Western blotting, matrix deposition, secreted cytokine array, immunofluorescence and traction force microscopy. Mitochondrial function was assessed by Seahorse analyzer and mitochondria mass and number by flow cytometry, mitochondrial DNA quantification and transmission electron microscopy (TEM). We found that PGC1? levels are stably repressed in IPF fibroblasts. After bleomycin injury in young mice, PGC1? expression drops transiently but then increases prior to fibrosis resolution. In contrast, PGC1? expression fails to recover in aged mice with persistent fibrosis. PGC1? knockdown alone in normal human lung fibroblasts reduces mitochondrial mass and function while enhancing contractile and matrix synthetic fibroblast activation, senescence-related gene expression and soluble profibrotic and prosenescence signalling. Re-expression of PGC1? in IPF fibroblasts ameliorates all of these pathological cellular functions. Pharmacological treatment of IPF fibroblasts with rosiglitazone, but not thyroid hormone, elevated PGC1? expression and attenuated fibroblast activation. The sustained repression of PGC1? and beneficial effects of its rescue in IPF fibroblasts identifies PGC1? as an important regulator of the fibroblast's pathological state in IPF.

SUBMITTER: Caporarello N

PROVIDER: S-EPMC6703129 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state.

Caporarello Nunzia N Meridew Jeffrey A JA Jones Dakota L DL Tan Qi Q Haak Andrew J AJ Choi Kyoung M KM Manlove Logan J LJ Prakash Y S YS Tschumperlin Daniel J DJ Ligresti Giovanni G

Thorax 20190610 8

Idiopathic pulmonary fibrosis (IPF) is a fatal ageing-related disease linked to mitochondrial dysfunction. The present study aimed to determine whether peroxisome proliferator activated receptor gamma co-activator 1-alpha (<i>PPARGC1A</i>, encoding PGC1α), a master regulator of mitochondrial biogenesis, is diminished in IPF and controls pathologic fibroblast activation. Primary human IPF, control lung fibroblasts and fibroblasts sorted from bleomycin-injured mice were used to evaluate the expres ...[more]

PMID: 31182654

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Project description:Facioscapulohumeral muscular dystrophy (FSHD) is a prevalent, incurable myopathy, linked to epigenetic derepression of D4Z4 repeats on chromosome 4q, leading to ectopic DUX4 expression. FSHD patient myoblasts have defective myogenic differentiation, forming smaller myotubes with reduced myosin content. However, molecular mechanisms driving such disrupted myogenesis in FSHD are poorly understood. We performed high-throughput morphological analysis describing FSHD and control myogenesis, revealing altered myogenic differentiation results in hypotrophic myotubes. Employing polynomial models and an empirical Bayes approach, we established eight critical time points during which human healthy and FSHD myogenesis differ. RNA-sequencing at these eight nodal time points in triplicate, provided temporal depth for a multivariate regression analysis, allowing assessment of interaction between progression of differentiation and FSHD disease status. Importantly, the unique size and structure of our data permitted identification of many novel FSHD pathomechanisms undetectable by previous approaches. For further analysis here, we selected pathways that control mitochondria: of interest considering known alterations in mitochondrial structure and function in FSHD muscle, and sensitivity of FSHD cells to oxidative stress. Notably, we identified suppression of mitochondrial biogenesis, in particular via peroxisome proliferator-activated receptor gamma coactivator 1-? (PGC1?), the cofactor and activator of oestrogen-related receptor ? (ERR?). PGC1? knock-down caused hypotrophic myotubes to form from control myoblasts. Known ERR? agonists and safe food supplements biochanin A, daidzein or genistein, each rescued the hypotrophic FSHD myotube phenotype. Together our work describes transcriptomic changes in high resolution that occur during myogenesis in FSHD ex vivo, identifying suppression of the PGC1?-ERR? axis leading to perturbed myogenic differentiation, which can effectively be rescued by readily available food supplements.

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PGC1? repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state.

Publications

PGC1α repression in IPF fibroblasts drives a pathologic metabolic, secretory and fibrogenic state.

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