TNF-α impairs regulation of muscle oxidative phenotype: implications for cachexia?

Remels, Alexander; Gosker, Harry R.; Schrauwen, Patrick; Hommelberg, Pascal P. H.; Sliwiński, P; Polkey, Michael I.; Gáldiz, Juan B.; Wouters, Emiel F.M.; Langen, Ramon; Schols, A.M.W.J.

doi:10.1096/fj.09-150714

Cited by 103 publications

(58 citation statements)

References 55 publications

(11 reference statements)

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“…The fold change analysis was followed by a protein network analysis which revealed three distinct functional modules affected by cachexia: Fo complex, electron transport chain, and contractile fibre. Reduced levels of electron transport chain proteins were also reported for skeletal muscles of chronic obstructive pulmonary disease patients 36. Dysregulation of mitochondrial electron transport chain and focal adhesion was also observed by Dahlman and co‐workers in cca patients 32.…”

Section: Discussionsupporting

confidence: 52%

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Ebhardt

Degen

Tadini

et al. 2017

J cachexia sarcopenia muscle

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BackgroundCancer cachexia (cancer‐induced muscle wasting) is found in a subgroup of cancer patients leaving the patients with a poor prognosis for survival due to a lower tolerance of the chemotherapeutic drug. The cause of the muscle wasting in these patients is not fully understood, and no predictive biomarker exists to identify these patients early on. Skeletal muscle loss is an inevitable consequence of advancing age. As cancer frequently occurs in old age, identifying and differentiating the molecular mechanisms mediating muscle wasting in cancer cachexia vs. age‐related sarcopenia are a challenge. However, the ability to distinguish between them is critical for early intervention, and simple measures of body weight may not be sufficiently sensitive to detect cachexia early.MethodsWe used a range of omics approaches: (i) undepleted proteome was quantified using advanced high mass accuracy mass spectrometers in SWATH‐MS acquisition mode; (ii) phospho epitopes were quantified using protein arrays; and (iii) morphology was assessed using fluorescent microscopy.ResultsWe quantified the soluble proteome of muscle biopsies from cancer cachexia patients and compared them with cohorts of cancer patients and healthy individuals with and without age‐related muscle loss (aka age‐related sarcopenia). Comparing the proteomes of these cohorts, we quantified changes in muscle contractile myosins and energy metabolism allowing for a clear identification of cachexia patients. In an in vitro time lapse experiment, we mimicked cancer cachexia and identified signal transduction pathways governing cell fusion to play a pivotal role in preventing muscle regeneration.ConclusionsThe work presented here lays the foundation for further understanding of muscle wasting diseases and holds the promise of overcoming ambiguous weight loss as a measure for defining cachexia to be replaced by a precise protein signature.

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Section: Discussionsupporting

confidence: 52%

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Ebhardt

Degen

Tadini

et al. 2017

J cachexia sarcopenia muscle

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“…COPD patients also exhibit high TNF levels in skeletal muscle alongside decreased PGC-1 expression [291]. This repression can be replicated in vitro by chronically treating the C2C12 muscle cell line with TNF The subsequent inhibition of oxidative phosphorylation is dependent on NF-B [291,292].…”

Section: Mutual Influence Of Inflammatory Factors and Pgc-1smentioning

confidence: 98%

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Eisele

Handschin

2013

Semin Immunopathol

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(150 -250 words) [165] Skeletal muscle is an organ involved in whole body movement and energy metabolism with the ability to dynamically adapt to different states of (dis-)use. At a molecular level, the peroxisome proliferatoractivated receptor  coactivators 1 (PGC-1) are important mediators of oxidative metabolism in skeletal muscle and in other organs. Musculoskeletal disorders as well as obesity and its sequelae are associated with PGC-1 dysregulation in muscle with a concomitant local or systemic inflammatory reaction. In this review, we outline the function of PGC-1 coactivators in physiological and pathological conditions as well as the complex interplay of metabolic dysregulation and inflammation in obesity with special focus on skeletal muscle. We further put forward the hypothesis that in this tissue, oxidative metabolism and inflammatory processes mutually antagonize each other. The nuclear factor κB (NF-B) pathway thereby plays a key role in linking metabolic and inflammatory programs in muscle cells. We conclude this review with a perspective about the consequences of such a negative crosstalk on the immune system and the possibilities this opens for clinical applications.

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“…TNF-a, a downstream target of C/EBP b, has been reported to be associated with neuropathological effects underlying several neurodegenerative disorders (15,16). A substantial amount of evidence has revealed that TNF-a can elicit a wide variety of cellular responses, including profound alterations in transcriptional programs, perturbation of mitochondrial function, production of ROS, enhancement of inflammatory response and apoptosis in a number of cell types (15,(17)(18)(19)(20). In addition, several studies have demonstrated that the suppression of TNF-a production reduces KA-mediated excitotoxicity (21,22); however, it is not yet clear how the C/EBP b-TNF-a signaling axis medi-ates excitotoxic brain damage.…”

mentioning

confidence: 99%

Troxerutin Counteracts Domoic Acid–Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein β–Mediated Inflammatory Response and Oxidative Stress

Lü

Zheng

et al. 2013

The Journal of Immunology

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The C/EBP β is a basic leucine zipper transcription factor that regulates a variety of biological processes, including metabolism, cell proliferation and differentiation, and immune response. Recent findings show that C/EBP β–induced inflammatory responses mediate kainic acid–triggered excitotoxic brain injury. In this article, we show that protein kinase C ζ enhances K-ras expression and subsequently activates the Raf/MEK/ERK1/2 pathway in the hippocampus of domoic acid (DA)–treated mice, which promotes C/EBP β expression and induces inflammatory responses. Elevated production of TNF-α impairs mitochondrial function and increases the levels of reactive oxygen species by IκB kinase β/NF-κB signaling. The aforementioned inflammation and oxidative stress lead to memory deficits in DA-treated mice. However, troxerutin inhibits cyclin-dependent kinase 1 expression, enhances type 1 protein phosphatase α dephosphorylation, and abolishes MEK/ERK1/2/C/EBP β activation, which subsequently reverses the memory impairment observed in the DA-treated mice. Thus, troxerutin is recommended as a potential candidate for the prevention and therapeutic treatment of cognitive deficits resulting from excitotoxic brain damage and other brain disorders.

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TNF-α impairs regulation of muscle oxidative phenotype: implications for cachexia?

Cited by 103 publications

References 55 publications

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Comprehensive proteome analysis of human skeletal muscle in cachexia and sarcopenia: a pilot study

Functional crosstalk of PGC-1 coactivators and inflammation in skeletal muscle pathophysiology

Troxerutin Counteracts Domoic Acid–Induced Memory Deficits in Mice by Inhibiting CCAAT/Enhancer Binding Protein β–Mediated Inflammatory Response and Oxidative Stress

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