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The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease.

ABSTRACT: TNF-like weak inducer of apoptosis (TWEAK), a TNF superfamily ligand, and its bona fide receptor, the TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14), represent a pivotal axis for shaping both physiological and pathological tissue responses to acute or chronic injury and disease. In recent years significant advances have been made in delineating the prominent role of TWEAK-Fn14 dyad in regulating skeletal muscle mass and metabolism. Also emerging from the broad study of tissue injury in skeletal muscle and other organs is the role of the TWEAK-Fn14 pathway in promoting fibrosis. This review article highlights recent advancements toward understanding how the TWEAK-Fn14 pathway regulates the response to various skeletal muscle insults and, more broadly, engages multiple mechanisms to drive tissue fibrosis.

SUBMITTER: Tajrishi MM

PROVIDER: S-EPMC3999262 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease.

Tajrishi Marjan M MM Zheng Timothy S TS Burkly Linda C LC Kumar Ashok A

Cytokine & growth factor reviews 20131224 2

TNF-like weak inducer of apoptosis (TWEAK), a TNF superfamily ligand, and its bona fide receptor, the TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14), represent a pivotal axis for shaping both physiological and pathological tissue responses to acute or chronic injury and disease. In recent years significant advances have been made in delineating the prominent role of TWEAK-Fn14 dyad in regulating skeletal muscle mass and metabolism. Also emerging from the broad study ...[more]

PMID: 24444596

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Project description:BackgroundSpinal muscular atrophy (SMA) is a childhood neuromuscular disorder caused by depletion of the survival motor neuron (SMN) protein. SMA is characterized by the selective death of spinal cord motor neurons, leading to progressive muscle wasting. Loss of skeletal muscle in SMA is a combination of denervation-induced muscle atrophy and intrinsic muscle pathologies. Elucidation of the pathways involved is essential to identify the key molecules that contribute to and sustain muscle pathology. The tumor necrosis factor-like weak inducer of apoptosis (TWEAK)/TNF receptor superfamily member fibroblast growth factor-inducible 14 (Fn14) pathway has been shown to play a critical role in the regulation of denervation-induced muscle atrophy as well as muscle proliferation, differentiation, and metabolism in adults. However, it is not clear whether this pathway would be important in highly dynamic and developing muscle.MethodsWe thus investigated the potential role of the TWEAK/Fn14 pathway in SMA muscle pathology, using the severe Taiwanese Smn-/-; SMN2 and the less severe Smn2B/- SMA mice, which undergo a progressive neuromuscular decline in the first three post-natal weeks. We also used experimental models of denervation and muscle injury in pre-weaned wild-type (WT) animals and siRNA-mediated knockdown in C2C12 muscle cells to conduct additional mechanistic investigations.ResultsHere, we report significantly dysregulated expression of Tweak, Fn14, and previously proposed downstream effectors during disease progression in skeletal muscle of the two SMA mouse models. In addition, siRNA-mediated Smn knockdown in C2C12 myoblasts suggests a genetic interaction between Smn and the TWEAK/Fn14 pathway. Further analyses of SMA, Tweak-/-, and Fn14-/- mice revealed dysregulated myopathy, myogenesis, and glucose metabolism pathways as a common skeletal muscle feature, providing further evidence in support of a relationship between the TWEAK/Fn14 pathway and Smn. Finally, administration of the TWEAK/Fn14 agonist Fc-TWEAK improved disease phenotypes in the two SMA mouse models.ConclusionsOur study provides mechanistic insights into potential molecular players that contribute to muscle pathology in SMA and into likely differential responses of the TWEAK/Fn14 pathway in developing muscle.

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The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease.

Publications

The TWEAK-Fn14 pathway: a potent regulator of skeletal muscle biology in health and disease.

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