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Muscle wasting in hTNFtg mice, an animal model for rheumatoid arthritis, due to increased cathepsin L expression
  1. Silvia Hayer,
  2. Martin Willburger,
  3. Birgit Niederreiter,
  4. Aurica Jelinek,
  5. Tetyana Shvets,
  6. Josef Smolen,
  7. Kurt Redlich
  1. Medical University of Vienna, Internal Medicine III, Rheumatology, Vienna, Austria

Abstract

Objective To investigate skeletal myopathy in a chronic inflammatory, erosive animal model for rheumatoid arthritis, the human tumour necrosis factor transgenic (hTNFtg) mice.

Methods To evaluate whether hTNFtg mice are suffering from skeletal muscle atrophy, the authors isolated Triceps surae muscles from hTNFtg animals from various time-points of age starting 4 weeks until 16 weeks after birth. Muscle weight and body weight were assessed from these animals. Muscle tissue, muscle weight and bodyweight from age and sex-matched wildtype animals served as controls. To investigate whether tumour necrosis factor (TNF) blockade protects hTNFtg animals from muscle atrophy, 5 female hTNFtg animals were treated with anti-TNF ab (Infliximab, 10mg/kg, 3x per week, ip). Untreated hTNFtg animals served as controls. To identify proteolysis pathways and pro-inflammatory cytokine expression involved in muscle atrophy, the authors performed quantitative real-time PCR for Cathepsin L, B, S, H, D, MMP-9 and Interleukin (IL)-1 and IL-6 from mRNA isolated from muscle tissues of hTNFtg and wildtype animals. To further investigate infiltration of inflammatory cells, muscle tissue sections are stained for macrophages, neutrophils, T cells and B cells and convential hematoxylin/eosin.

Results The authors demonstrate that hTNFtg mice show significantly less triceps surae muscle weight compared to sex- and age matched wildtype animals. Reductions in muscle weight became already manifest at the early age of 4 weeks and were continuously reduced until week 16. Due to decreased muscle weight, bodyweight was also significantly decreased in hTNFtg animals compared to their wildtype littermates. The authors found a significantly increased mRNA expression levels of Cathepsin L, a lysosomal endopeptidase responsible for muscle protein degradation, in muscles from hTNFtg compared to their wildtype littermates. In contrast, other proteases such as cathepsin B, S, H, D did not reach significantly increased expression levels between these 2 genotypes. Moreover, proinflammatory cytokines such as IL1 and IL6 are also significantly upregulated in muscles from hTNFtg mice.

Conclusion Despite spontaneous development of chronic inflamed, erosive arthritis, chronic overexpression of TNF leads to skeletal muscle atrophy due to increased tissue-degrading cathepsin L in hTNFtg animals.

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