Extrajunctional resting Ca2+ influx is not increased in a severely dystrophic expiratory muscle (triangularis sterni) of the mdx mouse

Carlson, C. George; Gueorguiev, Anton; Roshek, Diana M.; Ashmore, Rebecca; Chu, Jacquelyne S; Anderson, Judy E.

doi:10.1016/s0969-9961(03)00128-1

Cited by 14 publications

(20 citation statements)

References 41 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Mdx (C57Bl10-mdx) and nondystrophic (C57Bl10SnJ) mice were euthanized in accordance with established procedures (Institutional Animal Care and Use Committee; IACUC) and individual muscles were freshly isolated in HEPES Ringer (147.5 mM NaCl, 5 mM KCl, 2 mM CaCl 2 , 11 mM glucose, 5 mM HEPES, pH 7.35) using standard techniques [10]. The individual muscles were immediately flash-frozen and stored at −78° C until used in the hydroxyproline determinations.…”

Section: Methodsmentioning

confidence: 99%

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

Graham

Singh

Millman

et al. 2010

Journal of the Neurological Sciences

View full text Add to dashboard Cite

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-κB 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-β1) and fibrolytic (MMP-9) mediators is 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-β1 with no corresponding increases in MMP-9 expression. Treatment with PDTC or UDCA did not influence collagen deposition or TGF-β1 expression in the mdx respiratory musculature. These results indicate that dystrophic increases in collagen are the result of NF-κB-independent signaling abnormalities, and that efforts to reduce excessive collagen accumulation will require treatments to more specifically reduce TGF-β1 signaling or enhance the expression and/or activity of matrix metalloproteases.

show abstract

Section: Methodsmentioning

confidence: 99%

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

Graham

Singh

Millman

et al. 2010

Journal of the Neurological Sciences

View full text Add to dashboard Cite

show abstract

“…However, several independent lines of evidence argue against this possibility. First, fluorometric studies of Mn 2+ quench rate indicated that resting Ca 2+ influx is not increased in adult dystrophic fibers [11,12]. Additional support for this conclusion was obtained from studies showing that concentrations of Gd 3+ sufficient to block resting Ca 2+ influx through nonselective cation channels and Ca 2+ leakage channels had no effect on the resting potential of either nondystrophic or mdx muscle fibers [6].…”

Section: Introductionmentioning

confidence: 99%

Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF-κB-dependent negative modulation of ouabain sensitive Na+–K+ pump activity

Miles

Cottey

et al. 2011

Journal of the Neurological Sciences

View full text Add to dashboard Cite

To examine potential mechanisms for the reduced resting membrane potentials (RP) of mature dystrophic (mdx) muscle fibers, the Na+ - K+ pump inhibitor ouabain was added to freshly isolated nondystrophic and mdx fibers. Ouabain produced a 71% smaller depolarization in mdx fibers than in nondystrophic fibers, increased the [Na+]i in nondystrophic fibers by 40%, but had no significant effect on the [Na+]i of mdx fibers, which was approximately double that observed in untreated nondystrophic fibers. Western blots indicated no difference in total and phosphorylated Na+ - K+ ATPase catalytic α1 subunit between nondystrophic and mdx muscle Examination of the effects of the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC) indicated that direct application of the drug slowly hyperpolarized mdx fibers (7 mV in 90 minutes) but had no effect on nondystrophic fibers. Pretreatment with ouabain abolished this hyperpolarization, and pretreatment with PDTC restored ouabain-induced depolarization and reduced [Na+]i Administration of an NF-κB inhibitor that utilizes a different mechanism for reducing nuclear NF-κB activation, ursodeoxycholic acid (UDCA), also hyperpolarized mdx fibers. These results suggest that in situ Na+ - K+ pump activity is depressed in mature dystrophic fibers by NF-κB dependent modulators, and that this reduced pump activity contributes to the weakness characteristic of dystrophic muscle.

show abstract

“…Initial results obtained in this laboratory indicated that long term in vivo treatment with the inhibitor of cytosolic IκB-α ubiquitination, pyrrolidine dithiocarbamate (PDTC; [27]), increased the number of clearly striated fibers and improved resting potentials in the triangularis sterni (TS), an expiratory muscle that is severely dystrophic in the mdx mouse model for Duchenne muscular dystrophy [28,29]. Additional studies in this laboratory indicated that PDTC and ursodeoxycholic acid (UDCA), an agent which inhibits nuclear NF-κB transactivation after binding to the glucocorticoid receptor [30], increases mdx limb muscle strength [31].…”

Section: Introductionmentioning

confidence: 99%

Increases in nuclear p65 activation in dystrophic skeletal muscle are secondary to increases in the cellular expression of p65 and are not solely produced by increases in IκB-α kinase activity

Singh

Millman

Turin

et al. 2009

Journal of the Neurological Sciences

View full text Add to dashboard Cite

Extrajunctional resting Ca2+ influx is not increased in a severely dystrophic expiratory muscle (triangularis sterni) of the mdx mouse

Cited by 14 publications

References 41 publications

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

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

Reduced resting potentials in dystrophic (mdx) muscle fibers are secondary to NF-κB-dependent negative modulation of ouabain sensitive Na+–K+ pump activity

Increases in nuclear p65 activation in dystrophic skeletal muscle are secondary to increases in the cellular expression of p65 and are not solely produced by increases in IκB-α kinase activity

Contact Info

Product

Resources

About