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Updated: Jun 12, 2026
Mechanistic Insight into the Development of TNBS-Mediated Intestinal Fibrosis and Evaluating the Inhibitory Effects of Rapamycin
Published on: September 12, 2019
Skeletal muscle catabolism in trinitrobenzene sulfonic acid-induced murine colitis
Frances Puleo1, Katia Meirelles, Maithili Navaratnarajah
1Department of Surgery, Penn State College of Medicine, Hershey, PA 17033, USA.
Abstract:
The present study determined whether the muscle atrophy produced by colitis is associated with altered rates of muscle protein synthesis or degradation, as well as the potential role of the local (eg, muscle) insulin-like growth factor (IGF) system and muscle-specific ubiquitin E3 ligases atrogin-1 and MuRF1 in mediating altered muscle protein balance. Colitis was induced in C57BL/6 mice by intrarectal administration of trinitrobenzene sulfonic acid (TNBS), and blood and tissues were collected on day 10. Mice with inflammatory bowel disease demonstrated reduced skeletal muscle mass and protein content, whereas colonic segment weight and gross damage score were both increased in mice with colitis, compared with time-matched control values. There was no change in muscle protein synthesis in mice with inflammatory bowel disease; but there was an increased protein breakdown (45%), proteasome activity (85%), and messenger RNA (mRNA) expression for atrogin-1 and MuRF1 (200%-300%) in muscle. These changes were associated with a reduction in liver (but not muscle) IGF-I mRNA as well as a reduction in both total and free IGF-I in the blood. Colitis decreased the hepatic content of IGF binding protein (IGFBP)-3 mRNA by 40% and increased IGFBP-1 mRNA by 100%. In contrast, colitis did alter IGFBP mRNAs in muscle. The tumor necrosis factor-α, interleukin-6, and nitric oxide synthase 2 mRNA content of both liver and skeletal muscle was increased in TNBS-treated mice; and plasma tumor necrosis factor-α and interleukin-6 concentrations were also elevated. These data suggest that TNBS-induced colitis is independent of a change in muscle protein synthesis but dependent on stimulation of protein degradation via increased expression of muscle-specific atrogenes, which may be mediated in part by the reduction in circulating concentration of IGF-I and the concomitant increase in inflammatory mediators observed in the blood and muscle per se.
Insights
Colitis causes muscle atrophy by increasing protein breakdown, not decreasing synthesis. This involves elevated atrogin-1 and MuRF1 expression, potentially linked to lower insulin-like growth factor-I and increased inflammatory factors.
Area of Science:
- Muscle physiology
- Inflammatory bowel disease research
- Molecular biology
Background:
- Muscle atrophy is a common complication of inflammatory conditions like colitis.
- The molecular mechanisms underlying colitis-induced muscle wasting are not fully understood.
- Key regulators of muscle protein balance include the insulin-like growth factor (IGF) system and ubiquitin ligases like atrogin-1 and MuRF1.
Purpose of the Study:
- To investigate whether muscle atrophy in colitis is due to altered muscle protein synthesis or degradation.
- To examine the role of the local IGF system and muscle-specific E3 ligases (atrogin-1, MuRF1) in mediating muscle protein imbalance during colitis.
- To assess the impact of colitis on inflammatory markers in muscle and blood.
Main Methods:
- Colitis was induced in C57BL/6 mice using trinitrobenzene sulfonic acid (TNBS).
- Muscle and liver tissues, along with blood, were collected on day 10 post-induction.
- Muscle protein synthesis/degradation rates, proteasome activity, and mRNA expression of key genes (IGF-I, IGFBPs, atrogin-1, MuRF1, inflammatory cytokines) were analyzed.
Main Results:
- TNBS-induced colitis resulted in reduced skeletal muscle mass and protein content.
- Muscle protein synthesis remained unchanged, but protein breakdown increased by 45% and proteasome activity by 85%.
- Expression of atrogin-1 and MuRF1 mRNA significantly increased (200%-300%), alongside elevated inflammatory markers (TNF-α, IL-6, NOS2) in muscle and liver. Circulating IGF-I levels decreased.
Conclusions:
- Colitis-induced muscle atrophy is primarily driven by increased protein degradation, specifically through the upregulation of atrogin-1 and MuRF1.
- The observed muscle wasting is independent of changes in muscle protein synthesis.
- Reduced circulating IGF-I levels and elevated inflammatory mediators likely contribute to the enhanced protein breakdown in muscle during colitis.
