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Updated: Oct 10, 2026
Isometric and Eccentric Force Generation Assessment of Skeletal Muscles Isolated from Murine Models of Muscular Dystrophies
Published on: January 31, 2013
Altered pathological progression of diaphragm and quadriceps muscle in TNF-deficient, dystrophin-deficient mice
M J Spencer1, M W Marino, W M Winckler
1Department of Pediatrics, University of California, Los Angeles, 90095-1606, USA. mspencer@mednet.ucla.edu
Abstract:
We have previously demonstrated a role for T cells in Duchenne muscular dystrophy (DMD) using the mdx mouse and have shown that T cell killing of dystrophic muscle can occur through perforin-dependent and perforin-independent mechanisms. In this investigation, we explore the possibility that one perforin-independent mechanism utilized by the T cells is cytokine-based killing, specifically by tumor necrosis factor (TNF). We tested this hypothesis by generating mice that are TNF-deficient and dystrophin-deficient (TNF-/mdx). Body mass and muscle mass of the TNF-/mdx mice were significantly less than TNF+/mdx mice at 8 weeks of age. Creatine kinase levels and overall muscle strength were unchanged. Histopathology measurements showed different results in the diaphragm and quadriceps muscles. These data suggest that removal of TNF in vivo in dystrophic mice has differential effects on diaphragm and quadriceps suggesting that TNF is an unfavorable target for immunotherapy for DMD.
Insights
Tumor necrosis factor (TNF) plays a complex role in Duchenne muscular dystrophy (DMD). Removing TNF in dystrophic mice had varied effects on muscle groups, suggesting it may not be an ideal target for DMD immunotherapy.
Area of Science:
- Immunology
- Muscle Biology
- Genetics
Background:
- T cells are implicated in Duchenne muscular dystrophy (DMD) pathogenesis.
- Muscle damage in DMD can occur via perforin-dependent and independent T cell mechanisms.
Purpose of the Study:
- To investigate if tumor necrosis factor (TNF) mediates a perforin-independent T cell killing mechanism in DMD.
- To assess the impact of TNF deficiency on dystrophic muscle in vivo.
Main Methods:
- Generated double-mutant mice deficient in both dystrophin and TNF (TNF-/mdx).
- Compared physiological and histopathological parameters between TNF-/mdx and control mdx mice.
Main Results:
- TNF-/mdx mice exhibited reduced body and muscle mass compared to controls.
- Creatine kinase levels and muscle strength remained unchanged.
- Histopathology revealed differential effects of TNF deficiency on diaphragm and quadriceps muscles.
Conclusions:
- TNF deficiency has distinct impacts on different muscle groups in the context of DMD.
- These findings suggest TNF is not a universally favorable target for Duchenne muscular dystrophy immunotherapy.
