title: The TWEAK-Fn14 dyad is involved in age-associated pathological changes in skeletal muscle.
abstract: Progressive loss of skeletal muscle mass and strength (sarcopenia) is a major clinical problem in the elderly. Recently, proinflammatory cytokine TWEAK and its receptor Fn14 were identified as key mediators of muscle wasting in various catabolic states. However, the role of the TWEAK-Fn14 pathway in pathological changes in skeletal muscle during aging remains unknown. In this study, we demonstrate that the levels of Fn14 are increased in skeletal muscle of 18-month old (aged) mice compared with adult mice. Genetic ablation of Fn14 significantly increased the levels of specific muscle proteins and blunted the age-associated fiber atrophy in mice. While gene expression of two prominent muscle-specific E3 ubiquitin ligases MAFBx and MuRF1 remained comparable, levels of ubiquitinated proteins and the expression of autophagy-related molecule Atg12 were significantly reduced in Fn14-knockout (KO) mice compared with wild-type mice during aging. Ablation of Fn14 significantly diminished the DNA-binding activity of transcription factor nuclear factor-kappa B (NF-κB), gene expression of various inflammatory molecules, and interstitial fibrosis in skeletal muscle of aged mice. Collectively, our study suggests that the TWEAK-Fn14 signaling axis contributes to age-associated muscle atrophy and fibrosis potentially through its local activation of proteolytic systems and inflammatory pathways.
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Marjan M
authors.initials: MM
authors.lastname: Tajrishi
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Shuichi
authors.initials: S
authors.lastname: Sato
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Jonghyun
authors.initials: J
authors.lastname: Shin
authors.affiliation: Department of Immunology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142.
authors.forename: Timothy S
authors.initials: TS
authors.lastname: Zheng
authors.affiliation: Department of Immunology, Biogen Idec, 14 Cambridge Center, Cambridge, MA 02142.
authors.forename: Linda C
authors.initials: LC
authors.lastname: Burkly
authors.affiliation: Department of Anatomical Sciences and Neurobiology, University of Louisville School of Medicine, Louisville, KY 40202.
authors.forename: Ashok
authors.initials: A
authors.lastname: Kumar
mesh_terms: D000375:Aging; D000818:Animals; D003094:Collagen / Q000032:analysis / Q000378:metabolism; D005355:Fibrosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D017353:Gene Deletion; D051379:Mice; D018345:Mice, Knockout; D018482:Muscle, Skeletal / Q000378:metabolism / Q000473:pathology*; D009133:Muscular Atrophy / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D016328:NF-kappa B / Q000378:metabolism; D059748:Proteolysis; D018124:Receptors, Tumor Necrosis Factor / Q000235:genetics* / Q000378:metabolism*; D015398:Signal Transduction; D000074050:TWEAK Receptor
chemical_list: D016328:NF-kappa B; D018124:Receptors, Tumor Necrosis Factor; D000074050:TWEAK Receptor; C000613299:Tnfrsf12a protein, mouse; D003094:Collagen
keywords: Autophagy; Cytokines; NF-κB; Sarcopenia; Ubiquitin–proteasome system