Treatment with inhibitors of the NF-κB pathway improves whole body tension development in the mdx mouse

Siegel, Ashley L.; Bledsoe, Cathy; Lavin, Jesse; Gatti, Francesca; Berge, Jonas; Millman, Gregory; Turin, Eric; Winders, W. Tyler; Rutter, John; Palmeiri, Beniamino; Carlson, C. George

doi:10.1016/j.nmd.2008.10.006

Cited by 39 publications

(71 citation statements)

References 27 publications

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“…(B1)-(B3) show the corresponding inter-trial correlations and indicates that the highest R value (0.62; p < 0.001) was obtained for the mean holding impulse, which exhibited a slope of 1.04 and a y-intercept of 0.725 N s (B3). significant deficit in WBT persisted in the mdx population up to 18 months of age (Siegel et al, 2009). In contrast, the present study shows that a deficit in the ability to produce sustained limb tension to oppose gravity (four limb wire screen holding test) is not present in mdx mice aged between 6 and 10 months.…”

Section: Discussioncontrasting

confidence: 87%

“…Determinations of WBT from wild type (C57Bl10SnJ) and mdx (C57Bl10-mdx) mice were obtained using conventional techniques (Carlson and Makiejus, 1990;Siegel et al, 2009). Briefly, a 0.5-in.…”

Section: Wbt Measurementsmentioning

confidence: 99%

“…Sessions in which less than 15 FPTs were elicited over a 5 min interval were not included in the analyses. The body weight of each mouse was measured, and the WBT5 and WBT10 were obtained by dividing the average of the top 5 or top 10 FPTs, respectively, by the body weight (Carlson and Makiejus, 1990;Siegel et al, 2009). This normalization procedure controls for developmental increases in body mass (Carlson and Makiejus, 1990).…”

Section: Wbt Measurementsmentioning

confidence: 99%

“…These measures include the whole body tension (WBT) or escape test (Carlson and Makiejus, 1990;Makiejus et al, 1991;Hudecki et al, 1993;Deconinck et al, 1997;Gillis, 2002;Fougerousse et al, 2003;Raymackers et al, 2003;Siegel et al, 2009), the forelimb grip strength test (Connolly et al, 2001;De Luca et al, 2003;Keeling et al, 2007); and various types of hang time measurements (Gomez et al, 1997;Rafael et al, 2000;Hosaka et al, 2002). However, each of these tests involves behavioral components that are difficult to control.…”

Section: Introductionmentioning

confidence: 99%

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A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength

Carlson

Rutter

Bledsoe

et al. 2010

Journal of Neuroscience Methods

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Section: Discussioncontrasting

confidence: 87%

Section: Wbt Measurementsmentioning

confidence: 99%

Section: Wbt Measurementsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength

Carlson

Rutter

Bledsoe

et al. 2010

Journal of Neuroscience Methods

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“…In addition to NBD, other anti-NF-κB pharmacological and biological agents (5,(15)(16)(17)(18)(19)(20)(21) have been shown to be efficacious in rescuing mdx pathology to varying degrees. However, unknown at this point is whether any of these agents are suitable for development into clinically useable drugs.…”

Section: Peptide-based Inhibition Of Nf-κb Rescues Diaphragm Muscle Cmentioning

confidence: 99%

Peptide-Based Inhibition of NF-κB Rescues Diaphragm Muscle Contractile Dysfunction in a Murine Model of Duchenne Muscular Dystrophy

Peterson

Kline

Canan

et al. 2011

Mol Med

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Deterioration of diaphragm function is one of the prominent factors that contributes to the susceptibility of serious respiratory infections and development of respiratory failure in patients with Duchenne Muscular Dystrophy (DMD). The NF-κB signaling pathway has been implicated as a contributing factor of dystrophic pathology, making it a potential therapeutic target. Previously, we demonstrated that pharmacological inhibition of NF-κB via a small NEMO Binding Domain (NBD) peptide was beneficial for reducing pathological features of mdx mice. Now, we stringently test the effectiveness and clinical potential of NBD by treating mdx mice with various formulations of NBD and use diaphragm function as our primary outcome criteria. We found that administering DMSO-soluble NBD rescued 78% of the contractile deficit between mdx and wild-type (WT) diaphragm. Interestingly, synthesis of a GLP NBD peptide as an acetate salt permitted its solubility in water, but as a negative consequence, also greatly attenuated functional efficacy. However, replacing the acetic acid counterion of the NBD peptide with trifluoroacetic acid retained the peptide's water solubility and significantly restored mdx diaphragm contractile function and improved histopathological indices of disease in both diaphragm and limb muscle. Together, these results support the feasibility of using a mass-produced, water-soluble NBD peptide for clinical use.

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The Influence of Passive Stretch and NF‐κB Inhibitors on the Morphology of Dystrophic Muscle Fibers

Siegel

Henley

Zimmerman

et al. 2010

The Anatomical Record

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The triangularis sterni (TS) is an expiratory muscle that is passively stretched during inspiration. The magnitude of passive stretch depends upon the location of individual fibers within the TS muscle, with fibers located more caudally being stretched $ 5% to 10% more than fibers in the cephalad region. In the mdx mouse model for muscular dystrophy, the TS exhibits severe pathological alterations that are ameliorated by treatment with inhibitors of the NF-jB pathway. The purpose of this study was to assess the influence of passive stretch in vivo on fiber morphology in nondystrophic and mdx TS muscles, and the morphological benefits of treating mdx mice with two distinct NF-jB inhibitors, pyrrolidine dithiocarbamate (PDTC), and ursodeoxycholic acid (UDCA). Transmission electron microscopy revealed Z-line streaming, hypercontraction, and disassociation of the plasma membrane from the basal lamina in mdx fibers. In both nondystrophic and mdx TS muscles, fiber density was larger in more caudal regions. In comparison with nondystrophic TS, fibers in the mdx TS exhibited substantial reductions in diameter throughout all regions. In vivo treatment with either PDTC or UDCA tended to increase fiber diameter in the middle and decrease fiber diameter in the caudal TS, while reducing centronucleation in the middle region. These results suggest that passive stretch induces hypercontraction and plasma membrane abnormalities in dystrophic muscle, and that differences in the magnitude of passive stretch may influence fiber morphology and the actions of NF-jB inhibitors on dystrophic morphology. Anat Rec, 294:132-144, 2011. V V C 2010 Wiley-Liss, Inc.

show abstract

Treatment with inhibitors of the NF-κB pathway improves whole body tension development in the mdx mouse

Cited by 39 publications

References 27 publications

A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength

A simple protocol for assessing inter-trial and inter-examiner reliability for two noninvasive measures of limb muscle strength

Peptide-Based Inhibition of NF-κB Rescues Diaphragm Muscle Contractile Dysfunction in a Murine Model of Duchenne Muscular Dystrophy

The Influence of Passive Stretch and NF‐κB Inhibitors on the Morphology of Dystrophic Muscle Fibers

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