Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice

Messina, Sonia; Bitto, Alessandra; Aguennouz, M.; Minutoli, Letteria; Monici, Maria C.; Altavilla, Domenica; Squadrito, Francesco; Vita, Giuseppe

doi:10.1016/j.expneurol.2005.11.021

Cited by 138 publications

(147 citation statements)

References 47 publications

Supporting

Mentioning

125

Contrasting

Unclassified

Order By: Relevance

“…In addition, NFkB pathway is activated in Duchenne muscular dystrophy, and is involved in muscle degeneration and regeneration in dystrophin-deficient fibers. [31][32][33] NFkB forms a dimer with the inhibitory protein IkB, which maintains it in the cytoplasm in an inactive form. 34,35 Under a variety of signals, IkB becomes phosphorylated and is targeted to degradation by the proteasome.…”

Section: Discussionmentioning

confidence: 99%

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

et al. 2007

View full text Add to dashboard Cite

Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/abstract.php?id=4182 KEy wordS ABStrACtDuchenne Muscular Dystrophy (DMD) is an incurable inherited disease of childhood, characterized by progressive muscle degeneration and weakness. Our previous findings supported the idea that dystrophin and associated proteins, absent or greatly reduced in DMD, are degraded in dystrophin-deficient muscle by the proteasomal-dependent pathway. Indeed, treatment with the proteasome inhibitor MG-132 of skeletal muscles from mdx mice -a spontaneous mouse model of DMD-as well as from DMD patients, effectively rescued the expression and correct cellular localization of dystrophin and associated proteins. These promising results led us to further explore the use of proteasome inhibitors as a therapy for DMD. Therefore, we directed our attention towards two new dipeptide boronic acid inhibitors blocking the proteasomal-dependent degradation pathway: Velcade (bortezomib or PS-341) and MLN273 (PS-273). The exciting aspect of this development is that these drugs have already progressed to preclinical and clinical trials, in different fields than muscular dystrophy. Indeed, Velcade has been already FDA-approved for treatment of multiple myeloma and its side effects had been already explored and managed. Promisingly, MLN273 is currently in the preclinical trial phase. Here, we test the effectiveness of Velcade and MLN273 by local injection into the gastrocnemius muscle of mdx mice. We show the rescue of expression and membrane localization of a-dystroglycan, b-dystroglycan, a-sarcoglycan, and dystrophin after Velcade and MLN273 localized treatment, versus untreated (PBS only) mdx mice. Intriguingly, we also show that localized treatment with Velcade and MLN273 reduces the activation of Nuclear Factor-kappaB (NFkB). Because the NFkB pathway has been shown to be involved in inflammation responses in myopathies and DMD, our current results may have important clinical implications. Clearly, more investigations are needed, but our results emphasize the effectiveness of the pharmacological approach as a potential treatment for Duchenne muscular dystrophy.

show abstract

Section: Discussionmentioning

confidence: 99%

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

et al. 2007

View full text Add to dashboard Cite

show abstract

“…10,11 Pyrrolidine dithiocarbamate (PDTC), a synthetic antioxidant, inhibits NF-kB by preventing IkB degradation and the translocation of the active form to the nucleus. 12 Various studies have shown that PDTC can prevent hypertension in spontaneous hypertensive rats and ameliorate Ang II-induced inflammation damage in rats. 13,14 In this study, we duplicated the hypertensive rat model induced by prenatal exposure to LPS to explore the role of RAS and NF-kB in the development of hypertension.…”

Section: Introductionmentioning

confidence: 99%

Prenatal exposure to lipopolysaccharide alters the intrarenal renin–angiotensin system and renal damage in offspring rats

et al. 2009

View full text Add to dashboard Cite

Prenatal exposure to inflammation produces offspring that are hypertensive in adulthood. This study explored alterations of the renin-angiotensin system (RAS) during the development of hypertension induced by prenatal exposure to lipopolysaccharide (LPS). In addition, the effects of an inhibitor of the nuclear transcription factor (NF)-jB (pyrrolidine dithiocarbamate, PDTC) on this process were assessed. Pregnant rats were randomly divided into four groups (n¼8): a control group, an LPS group, a PDTC group and an LPS+PDTC group. The rats in these groups were intraperitoneally administered vehicle, 0.79 mg kg À1 LPS, 100 mg kg À1 PDTC or LPS plus PDTC, respectively. LPS was given on the 8th, 10th and 12th days, whereas PDTC was given from the 8th to the 14th day during gestation. At various ages from day 1 to 25 weeks, plasma renin activity, plasma angiotensin II (Ang II) levels, renal function, glomerular number, mRNA expression levels of renal cortex renin and angiotensin-converting enzyme (ACE), the number of Ang II-positive cells and NF-jB activation were determined. The results showed that prenatal exposure to LPS resulted in significantly lower glomerular numbers and creatinine clearance rates and higher urinary protein and renal cortex ACE mRNA expression in adult offspring. Prenatal LPS also decreased the renal cortex renin mRNA expression and the number of Ang II-positive cells in offspring at 1 day of age, but these increased at 7, 16 and 25 weeks, whereas the plasma renin activity and Ang II concentration remained unchanged. Simultaneously, PDTC treatment markedly reversed the action of LPS. In conclusion, prenatal exposure to LPS resulted in alteration of the intrarenal RAS and renal damage in adult offspring rats. INTRODUCTIONThe effects of hypertension on the cardiovascular and renal systems are of major concern due to its morbidity and mortality. Though many efforts have been made to understand the pathophysiology of hypertension, it is still unclear because of its complexity. 1 A growing body of evidence indicates that hypertension is an inflammatory state wherein proinflammatory cytokines, such as tumor necrosis factor-a and interleukin-6, contribute to the hypertensive effect. 2-5 Angiotensin II (Ang II), the major biologically active component of the reninangiotensin system (RAS), not only induces vasoconstriction, aldosterone release and sodium reabsorption by the nephron, but is also intricately interrelated with inflammation. Furthermore, the association of Ang II and inflammation induces an amplification process that involves oxidative stress and proinflammatory transcription factors, leading to progressive vascular injury 6 and having an important role in the development of hypertension and target organ damage. 2 It has been shown in our laboratory that maternal exposure to lipopolysaccharide (LPS) results in hypertension in offspring rats. 7

show abstract

“…NF-kB is a ubiquitously expressed transcription factor in mammals that has a key role in muscular dystrophy by promoting the inflammatory response. 10,11 Numerous studies have demonstrated the chronic inflammation in DMD dystrophic muscles, which has been evidenced to be regulated by the classical pathway of NF-kB activation 12 and results in secondary pathologies such as muscle necrosis and wasting. Recently, blocking IKKb has been considered as a potential approach for anti-chronic inflammation in dystrophic muscles by targeting the upstream activator of the classical NF-kB pathway.…”

Section: Discussionmentioning

confidence: 99%

“…9 Previous studies demonstrate that in muscular dystrophies, chronic inflammation is promoted by an upregulated NF-kB signaling pathway. 10,11 Elevated levels of NF-kB activation have been detected in more than one type of muscular dystrophy, including DMD 12 and limb girdle muscular dystrophy. 13 Chronic activation of the classic NF-kB signaling pathway is required for DMD pathology by acting on both immune cells and damaged skeletal muscles to promote inflammation and to inhibit myogenic differentiation of muscle precursors in mdx mice.…”

Section: Introductionmentioning

confidence: 99%

AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice

et al. 2012

View full text Add to dashboard Cite

Chronic inflammation, promoted by an upregulated NF-kappa B (NF-kB) pathway, has a key role in Duchenne muscular dystrophy (DMD) patients' pathogenesis. Blocking the NF-kB pathway has been shown to be a viable approach to diminish chronic inflammation and necrosis in the dystrophin-defective mdx mouse, a murine DMD model. In this study, we used the recombinant adeno-associated virus serotype 9 (AAV9) carrying an short hairpin RNA (shRNA) specifically targeting the messenger RNA of NF-kB/p65 (p65-shRNA), the major subunit of NF-kB associated with chronic inflammation in mdx mice. We examined whether i.m. AAV9-mediated delivery of p65-shRNA could decrease NF-kB activation, allowing for amelioration of muscle pathologies in 1-and 4-month-old mdx mice. At 1 month after treatment, NF-kB/p65 levels were significantly decreased by AAV gene transfer of p65-shRNA in the two ages of treatment groups, with necrosis significantly decreased compared with controls. Quantitative analysis revealed that central nucleation (CN) of the myofibers of p65-shRNA-treated 1-month-old mdx muscles was reduced from 67 to 34%, but the level of CN was not significantly decreased in treated 4-month-old mdx mice. Moreover, delivery of the p65-shRNA enhanced the capacity of myofiber regeneration in old mdx mice treated at 4 months of age when the dystrophic myofibers were most exhausted; however, such p65 silencing diminished the myofiber regeneration in young mdx mice treated at 1 month of age. Taken together, these findings demonstrate that the AAV-mediated delivery of p65-shRNA has the capacity to ameliorate muscle pathologies in mdx mice by selectively reducing NF-kB/p65 activity.

show abstract

Nuclear factor kappa-B blockade reduces skeletal muscle degeneration and enhances muscle function in Mdx mice

Cited by 138 publications

References 47 publications

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

Localized Treatment with a Novel FDA-Approved Proteasome Inhibitor Blocks the Degradation of Dystrophin and Dystrophin-Associated Proteins in mdx Mice

Prenatal exposure to lipopolysaccharide alters the intrarenal renin–angiotensin system and renal damage in offspring rats

AAV-based shRNA silencing of NF-κB ameliorates muscle pathologies in mdx mice

Contact Info

Product

Resources

About