Induction of MuRF1 Is Essential for TNF-α-Induced Loss of Muscle Function in Mice

Background: Humoral circulating inflammatory cytokines such as tumor necrosis factor alpha (TNF-alpha) can impair skeletal muscle contractility. Furthermore, TNF-alpha expression correlates with elevated levels of atrogin-like muscle-specific ubiquitin E3 ligases, which are presumed to mediate muscle protein breakdown and atrophy. However, the casual relationships between MuRF1 and TNF-alpha and their relative contributions to muscle function impairment are not known. Methods: TNF-alpha or saline was injected into either C57Bl6 or MuRF1(-/-) mice. After 16-24 h, the expression of MuRF1 in skeletal muscle was quantified by quantitative reverse transcription-PCR and Western blot analysis. Muscle function was measured in an organ bath. To obtain a broader overview On potential alterations, two-dimensional gel electrophoresis was performed. Results: Wild-type animals injected with TNF-alpha had higher MURF1 mRNA expression (saline versus TNF-alpha: 56.6 +/- 12.1 versits 133.6 +/- 30.3 arbitrary units; p < 0.05) and protein expression (saline versus TNF-alpha: 0.38 +/- 0.11 versils 1.07 +/- 0.25 arbitrary units; p < 0.05) as compared to saline-injected littermates. Furthermore, TNF-alpha reduced force development at 150 Hz by 25% in C57Bl6 animals (saline versus TNF-alpha: 2412 +/- 120 versus 1799 +/- 114 g/cm(2); p < 0.05), but not in MURF1(-/-) mice (saline versits TNF-alpha: 2424 +/- 198 versils 2431 +/- 180 g/cm(2); p = NS). Proteome analysis revealed a significant down-regulation of fast skeletal muscle troponin T in wild-type animals treated with TNF-alpha as compared to MuRF1(-/-) mice that received TNF-alpha. Conclusion: The results Of this Study demonstrate for the first time that TNF-alpha-induced reduction in skeletal muscle force development depends on the induction of the atrophy-related E3 ubiquitin ligase MuRF1. A link for the reduction in muscle force may be the TNF-alpha/MuRF1-mediated down-regulation of fast skeletal muscle troponin T. (c) 2008 Elsevier Ltd. All rights reserved.