title: 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.affiliation: Dept. of Physiology, Kirksville College of Osteopathic Medicine, AT Still University, 800 W. Jefferson St. Kirksville, MO 63501-1497, USA.
authors.forename: K M
authors.initials: KM
authors.lastname: Graham
authors.forename: R
authors.initials: R
authors.lastname: Singh
authors.forename: G
authors.initials: G
authors.lastname: Millman
authors.forename: G
authors.initials: G
authors.lastname: Malnassy
authors.forename: F
authors.initials: F
authors.lastname: Gatti
authors.forename: K
authors.initials: K
authors.lastname: Bruemmer
authors.forename: C
authors.initials: C
authors.lastname: Stefanski
authors.forename: H
authors.initials: H
authors.lastname: Curtis
authors.forename: J
authors.initials: J
authors.lastname: Sesti
authors.forename: C G
authors.initials: CG
authors.lastname: Carlson
mesh_terms: D000818:Animals; D003094:Collagen / Q000378:metabolism*; D003964:Diaphragm / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism; D005260:Female; D005355:Fibrosis / Q000188:drug therapy / Q000378:metabolism; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018101:Mice, Inbred mdx; D018482:Muscle, Skeletal / Q000254:growth & development / Q000378:metabolism; D009136:Muscular Dystrophies / Q000188:drug therapy / Q000378:metabolism*; D016328:NF-kappa B / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011759:Pyrrolidines / Q000494:pharmacology; D012132:Respiratory Muscles / Q000187:drug effects / Q000254:growth & development / Q000378:metabolism*; D019141:Respiratory System Agents / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects; D013859:Thiocarbamates / Q000494:pharmacology; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D014580:Ursodeoxycholic Acid / Q000494:pharmacology
chemical_list: D016328:NF-kappa B; D011759:Pyrrolidines; D019141:Respiratory System Agents; D013859:Thiocarbamates; D053773:Transforming Growth Factor beta1; C020972:pyrrolidine dithiocarbamic acid; D014580:Ursodeoxycholic Acid; D003094:Collagen; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse
references.citation: Muscle Nerve. 2001 Mar;24(3):428-32
references.pmid: 11353432
references.citation: J Neurol Sci. 1982 Apr;54(1):79-87
references.pmid: 7077357
references.citation: Methods Mol Med. 2005;117:69-80
references.pmid: 16118446
references.citation: FASEB J. 2003 Mar;17(3):386-96
references.pmid: 12631578
references.citation: J Neurol Sci. 1987 Dec;82(1-3):271-80
references.pmid: 3440869
references.citation: J Biol Chem. 2001 Dec 14;276(50):47371-8
references.pmid: 11577102
references.citation: Neurobiol Dis. 2005 Dec;20(3):719-30
references.pmid: 15955706
references.citation: J Clin Invest. 1995 Aug;96(2):1137-44
references.pmid: 7635950
references.citation: Am J Pathol. 2004 Mar;164(3):1007-19
references.pmid: 14982854
references.citation: Muscle Nerve. 2004 Nov;30(5):645-53
references.pmid: 15389721
references.citation: Neuromuscul Disord. 2009 Feb;19(2):131-9
references.pmid: 19054675
references.citation: Anal Biochem. 1971 Feb;39(2):487-91
references.pmid: 4324532
references.citation: Br J Pharmacol. 2002 Jan;135(2):496-510
references.pmid: 11815386
references.citation: Genes Dev. 2004 Sep 15;18(18):2195-224
references.pmid: 15371334
references.citation: J Neurol Sci. 1994 Mar;122(1):44-56
references.pmid: 8195802
references.citation: Anal Biochem. 1960 Nov;1:228-39
references.pmid: 13738134
references.citation: J Neurol Sci. 2009 Oct 15;285(1-2):159-71
references.pmid: 19631348
references.citation: Neurobiol Dis. 2003 Nov;14(2):229-39
references.pmid: 14572445
references.citation: EMBO J. 2003 Jul 1;22(13):3356-66
references.pmid: 12839997
references.citation: J Neuroimmunol. 2006 Jun;175(1-2):77-86
references.pmid: 16647144
references.citation: Nature. 1991 Aug 8;352(6335):536-9
references.pmid: 1865908