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

Abstract

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.

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

“…The mean RP of untreated fibers in the caudal region of the severely dystrophic mdx TS muscle [20] at 7 to 9 months of age (−54.8 ± 0.9 mV, N = 208 fibers, 19 muscles) was 4.2 mV less negative (p<0.01, Mann-Whitney Rank Sum Test) than that observed in nondystrophic TS muscles (−59.0 ± 0.7 mV, N= 128 fibers, 12 muscles). Fibers from a cohort of nondystrophic mice (7 to 9 month) were depolarized by 14.7 mV (from −61.1 to −46.4 mV; N= 80 fibers, 8 muscles) following a 30 minute exposure to 1 mM ouabain (Fig.…”

“…The left TS muscle was removed as previously described [6, 12, 20] and placed in a muscle chamber containing mouse Ringer solution (in mM: 125 NaCl, 5 KCl, 2 CaCl 2 , 24 NaHCO 3 , 1 NaH 2 PO 4 , 11 glucose, pH 7.35; room temperature). The solution was continually re-circulated and bubbled with 95% O 2 /5% CO 2 .…”

“…Since PDTC is an NF-κB inhibitor [13] that increased cytosolic IκB-α in the mdx costal diaphragm, these results initially suggested that long term inhibition of the NF-κB pathway had beneficial effects on dystrophic (mdx) muscle [6]. Several studies from this and other laboratories now provide substantial evidence that inhibition of the NF-κB pathway has both morphological and functional benefits for dystrophic muscle [6, 14–20]. …”

Ursodeoxycholic acid and 4-phenylbutyrate prevent endoplasmic reticulum stress-induced podocyte apoptosis in diabetic nephropathy

“…4-PBA-treated diabetic group (n = 12), treated with 100 mg/kg/d 4-PBA (Santa Cruz Biotechnology, CA, USA) in vehicle. 23,24 All mice were treated for 12 weeks.…”

In vivo treatment with the NF‐κB inhibitor ursodeoxycholic acid (UDCA) improves tension development in the isolated mdx costal diaphragm

“…Several studies have indicated that dystrophic human and murine ( mdx ) muscle exhibits substantial increases in NF‐κB signaling and that inhibition of the NF‐κB pathway in vivo improves muscle structure and function in the mdx model for Duchenne muscular dystrophy . Ursodeoxycholic acid (UDCA) is composed of a substituted 17 carbon steroid backbone and is used clinically to treat hepatobiliary disorders .…”