PGC1α plays a critical role in TWEAK-induced cardiac dysfunction

Cardiac Muscle Research Laboratory, Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts, United States of America.
PLoS ONE (Impact Factor: 3.23). 01/2013; 8(1):e54054. DOI: 10.1371/journal.pone.0054054
Source: PubMed


Inflammatory cytokines play an important role in the pathogenesis of heart failure. We have recently found the cytokine TWEAK (tumor necrosis factor (TNF)-like weak inducer of apoptosis), a member of the TNF superfamily, to be increased in patients with cardiomyopathy and result in the development of heart failure when overexpressed in mice. The molecular mechanisms underlying TWEAK-induced cardiac pathology, however, remain unknown.

Methodology and Critical Finding
Using mouse models of elevated circulating TWEAK levels, established through intravenous injection of adenovirus expressing TWEAK or recombinant TWEAK protein, we find that TWEAK induces a progressive dilated cardiomyopathy with impaired contractile function in mice. Moreover, TWEAK treatment is associated with decreased expression of peroxisome proliferator-activated receptor gamma coactivator-1α (PGC1α) and genes required for mitochondrial oxidative phosphorylation, which precede the onset of cardiac dysfunction. TWEAK-induced downregulation of PGC1α requires expression of its cell surface receptor, fibroblast growth factor-inducible 14 (Fn14). We further find that TWEAK downregulates PGC1α gene expression via the TNF receptor-associated factor 2 (TRAF2) and NFκB signaling pathways. Maintaining PGC1α levels through adenoviral-mediated gene expression is sufficient to protect against TWEAK-induced cardiomyocyte dysfunction.

Collectively, our data suggest that TWEAK induces cardiac dysfunction via downregulation of PGC1α, through FN14-TRAF2-NFκB-dependent signaling. Selective targeting of the FN14-TRAF2-NFκB-dependent signaling pathway or augmenting PGC1α levels may serve as novel therapeutic strategies for cardiomyopathy and heart failure.

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Available from: Linda Burkly, May 09, 2014
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    • "TWEAK-induced proliferation and collagen synthesis of rat cardiac fibroblasts in vitro was mediated by the activation of NF-κB signaling (70). Moreover, DCM induced through elevated circulating TWEAK levels occurred via an FN14-TRAF2-NF-κB-dependent signaling pathway (99). In addition, cardiomyocyte-specific TRAF2 overexpressing mice provoked adverse cardiac remodeling associated with elevated NF-κB signaling (60). "
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    ABSTRACT: Tumor necrosis factor (TNF) has been firmly established as a pathogenic factor in heart failure, a significant socio-economic burden. In this review, we will explore the role of other members of the TNF/TNF receptor superfamily (TNFSF/TNFRSF) in cardiovascular diseases (CVDs) focusing on TWEAK and its receptor Fn14, new players in myocardial remodeling and heart failure. The TWEAK/Fn14 pathway controls a variety of cellular activities such as proliferation, differentiation, and apoptosis and has diverse biological functions in pathological mechanisms like inflammation and fibrosis that are associated with CVDs. Furthermore, it has recently been shown that the TWEAK/Fn14 axis is a positive regulator of cardiac hypertrophy and that deletion of Fn14 receptor protects from right heart fibrosis and dysfunction. We discuss the potential use of the TWEAK/Fn14 axis as biomarker for CVDs as well as therapeutic target for future treatment of human heart failure based on supporting data from animal models and in vitro studies. Collectively, existing data strongly suggest the TWEAK/Fn14 axis as a potential new therapeutic target for achieving cardiac protection in patients with CVDs.
    Frontiers in Immunology 02/2014; 5:50. DOI:10.3389/fimmu.2014.00050
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    • "TWEAK also reduced the expression of PGC-1α and several mitochondrial genes in cultured myotubes (81). Recent studies also suggest that TWEAK represses PGC-1α in cultured cardiomyocytes and myotubes through the activation of canonical NF-κB signaling pathway (67, 90). Collectively, these studies suggest that the repression of PGC-1α is an important mechanism by which TWEAK reduces mitochondrial content and oxidative phosphorylation capacity in skeletal muscle and in other cell types. "
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    ABSTRACT: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) through binding to its receptor fibroblast growth factor inducible 14 (Fn14) has been shown to regulate many cellular responses including proliferation, differentiation, apoptosis, inflammation, and fibrosis, under both physiological and pathological conditions. Emerging evidence suggests that TWEAK is also a major muscle wasting cytokine. TWEAK activates nuclear factor-κB signaling and proteolytic pathways such as ubiquitin-proteasome system, autophagy, and caspases to induce muscle proteolysis in cultured myotubes. Fn14 is dormant or expressed in minimal amounts in normal healthy muscle. However, specific atrophic conditions, such as denervation, immobilization, and starvation stimulate the expression of Fn14 leading to activation of TWEAK/Fn14 signaling and eventually skeletal muscle atrophy. TWEAK also causes slow- to fast-type fiber transition in skeletal muscle. Furthermore, recent studies suggest that TWEAK diminishes mitochondrial content and represses skeletal muscle oxidative phosphorylation capacity. TWEAK mediates these effects through affecting the expression of a number of genes and microRNAs. In this review article, we have discussed the recent advancements toward understanding the role and mechanisms of action of TWEAK/Fn14 signaling in skeletal muscle with particular reference to different models of atrophy and oxidative metabolism.
    Frontiers in Immunology 01/2014; 5:18. DOI:10.3389/fimmu.2014.00018
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    • "The goal of this study was to find an immunomodulatory therapy to improve cardiac repair and LV remodelling after MI. We tested the effects of exogenous administration of HSA-Flag-TWEAK, a recombinant variant of the naturally occurring soluble form of the multi-functional cytokine TWEAK which, together with its receptor Fn14, is robustly up-regulated after MI and can influence cardiac repair [32], ischemic tolerance [12], inflammatory processes, and apoptosis [9]. We hypothesized that this TWEAK variant would beneficially influence wound healing after MI; however, our experiments demonstrated that administration of the variant in a model of non-reperfused infarction resulted in high mortality and an increased incidence of rupture. "
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    ABSTRACT: Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) and its receptor fibroblast growth factor-inducible 14 (Fn14) are upregulated after myocardial infarction (MI) in both humans and mice. They modulate inflammation and the extracellular matrix, and could therefore be important for healing and remodeling after MI. However, the function of TWEAK after MI remains poorly defined. Following ligation of the left coronary artery, mice were injected twice per week with a recombinant human serum albumin conjugated variant of TWEAK (HSA-Flag-TWEAK), mimicking the activity of soluble TWEAK. Treatment with HSA-Flag-TWEAK resulted in significantly increased mortality in comparison to the placebo group due to myocardial rupture. Infarct size, extracellular matrix remodeling, and apoptosis rates were not different after MI. However, HSA-Flag-TWEAK treatment increased infiltration of proinflammatory cells into the myocardium. Accordingly, depletion of neutrophils prevented cardiac ruptures without modulating all-cause mortality. Treatment of mice with HSA-Flag-TWEAK induces myocardial healing defects after experimental MI. This is mediated by an exaggerated neutrophil infiltration into the myocardium.
    PLoS ONE 11/2013; 8(11):e78938. DOI:10.1371/journal.pone.0078938 · 3.23 Impact Factor
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