Excessive collagen accumulation in dystrophic (mdx) respiratory musculature is independent of enhanced activation of the NF-kappaB pathway.

Abstract

Skeletal muscle fibrosis is present in the diaphragm of the mdx mouse, a model for Duchenne dystrophy. In both the mouse and human, dystrophic muscle exhibits pronounced increases in NF-kappa B signaling. Various inhibitors of this pathway, such as pyrrolidine dithiocarbamate (PDTC) and ursodeoxycholic acid (UDCA), have been shown to have beneficial effects on dystrophic (mdx) muscle. The present study characterizes the development of fibrosis in the mdx musculature, and determines the fibrolytic efficacy of PDTC and UDCA. The results indicate that collagen accumulation and the expression of fibrogenic (TGF-beta1) and fibrolytic (MMP-9) mediators are dependent on muscle origin in both nondystrophic and mdx mice. Excessive collagen accumulation is observed in the mdx respiratory musculature prior to substantial muscle degeneration and cellular infiltration, and is associated with dystrophic increases in the expression of TGF-beta1 with no corresponding increases in MMP-9 expression. Treatment with PDTC or UDCA did not influence collagen deposition or TGF-beta1 expression in the mdx respiratory musculature. These results indicate that dystrophic increases in collagen are the result of NF-kappaB-independent signaling abnormalities, and that efforts to reduce excessive collagen accumulation will require treatments to more specifically reduce TGF-beta1 signaling or enhance the expression and/or activity of matrix metalloproteases.

• Authors: K M Graham, R Singh, G Millman, G Malnassy, F Gatti, K Bruemmer, C Stefanski, H Curtis, J Sesti, C G Carlson
• Journal: Journal of the neurological sciences (J Neurol Sci) Vol. 294 Issue 1-2 Pg. 43-50 (Jul 15 2010) ISSN: 1878-5883 [Electronic] Netherlands
• PMID: 20471037 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: Copyright 2010 Elsevier B.V. All rights reserved.

Chemical References

• NF-kappa B
• Pyrrolidines
• Respiratory System Agents
• Thiocarbamates
• Transforming Growth Factor beta1
• pyrrolidine dithiocarbamic acid
• Ursodeoxycholic Acid
• Collagen
• Matrix Metalloproteinase 9
• Mmp9 protein, mouse

Topics

• Animals
• Collagen (metabolism)
• Diaphragm (drug effects, growth & development, metabolism)
• Female
• Fibrosis (drug therapy, metabolism)
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Inbred mdx
• Muscle, Skeletal (growth & development, metabolism)
• Muscular Dystrophies (drug therapy, metabolism)
• NF-kappa B (antagonists & inhibitors, metabolism)
• Pyrrolidines (pharmacology)
• Respiratory Muscles (drug effects, growth & development, metabolism)
• Respiratory System Agents (pharmacology)
• Signal Transduction (drug effects)
• Thiocarbamates (pharmacology)
• Transforming Growth Factor beta1 (metabolism)
• Ursodeoxycholic Acid (pharmacology)