T.P.4.11 Effect of calpain and proteasome inhibition on calcium-dependent proteolysis and muscle histopathology in the mdx mouse

Briguet, Alexandre; Erb, Michael; Courdier-Früh, Isabelle; Barzaghi, Patrizia; Santos, Guilherme Ide Marques dos; Herzner, Holger; Lescop, Cyrille; Siendt, H.; Henneboehle, Marco; Weyermann, Philipp; Dubach-Powell, Judith; Metz, Günther; Meier, Thomas; Magyar, Josef P.

doi:10.1016/j.nmd.2008.06.312

Cited by 6 publications

(9 citation statements)

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“…However, more substantial evidence was demonstrated by the use of leupeptin (LPTN), a nonspecific pharmacological calpain inhibitor, which increased fiber diameter and improved muscle histology (3). Another endogenous modulator of calpain is calpastatin, but there have been mixed results of using increased calpastatin to combat dystrophic pathology, where muscle-specific transgenic expression was shown to either provide histological benefit (32) or not (6), depending on which promoter was utilized. Thus, it remains an open question as to whether or not calpain inhibition is a good therapeutic target for DMD.…”

mentioning

confidence: 99%

Leupeptin-based inhibitors do not improve the mdx phenotype

Selsby¹,

Pendrak²,

Zadel

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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Calpain activation has been implicated in the disease pathology of Duchenne muscular dystrophy. Inhibition of calpain has been proposed as a promising therapeutic target, which could lessen the protein degradation and prevent progressive fibrosis. At the same time, there are conflicting reports as to whether elevation of calpastatin, an endogenous calpain inhibitor, alters pathology. We compared the effects of pharmacological calpain inhibition in the mdx mouse using leupeptin and a proprietary compound (C101) that linked the inhibitory portion of leupeptin to carnitine (to increase uptake into muscle). Administration of C101 for 4 wk did not improve muscle histology, function, or serum creatine kinase levels in mdx mice. Mdx mice injected daily with leupeptin (36 mg/kg) for 6 mo also failed to show improved muscle function, histology, or creatine kinase levels. Biochemical analysis revealed that leupeptin administration caused an increase in m-calpain autolysis and proteasome activity, yet calpastatin levels were similar between treated and untreated mdx mice. These data demonstrate that pharmacological inhibition of calpain is not a promising intervention for the treatment of Duchenne muscular dystrophy due to the ability of skeletal muscle to counter calpain inhibitors by increasing multiple degradative pathways.

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mentioning

confidence: 99%

Leupeptin-based inhibitors do not improve the mdx phenotype

Selsby¹,

Pendrak²,

Zadel

et al. 2010

American Journal of Physiology-Regulatory, Integrative and Comp

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“…Inhibition of TGF-is postulated to be the main mechanism through which the serine protease inhibitor BBIC exerts its therapeutic benefits (see section 3.4). The effectiveness of calpain inhibition in DMD therapy was then questioned following further reports that overexpression of calpastatin, under the control of a muscle CK promoter [521] and pharmacological inhibition using C101, another leupeptin-carnitine conjugate [522], did not in fact improve mdx pathology. A new study has confirmed lack of beneficial effect of C101 in GRMD [523].…”

Section: Protein Degradation Inhibitorsmentioning

confidence: 99%

“…A new study has confirmed lack of beneficial effect of C101 in GRMD [523]. Further investigations by these groups concluded that pharmacological inhibition of calpain is not a promising therapeutic intervention for DMD due to the ability of SM to counter calpain inhibitors by increasing m-calpain autolysis and proteasome activity, and that proteasome inhibition is required for improved histology [521,522]. It is hard to determine whether the discrepancies in the data can be attributed to varying levels of pharmacological or genetic calpain inhibition.…”

Section: Protein Degradation Inhibitorsmentioning

confidence: 99%

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Fairclough

Perkins²,

Davies³

2012

CGT

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DMD is a devastatingly progressive muscle wasting disorder of childhood that significantly shortens life expectancy. Despite efforts to develop an effective therapy that dates back over a century, clinical interventions are still restricted to management of symptoms rather than a cure. The rationale to develop effective therapies changed in 1986 with the discovery of the dystrophin gene. Since then extensive research into both the molecular basis and pathophysiology of DMD has paved the way not only for development of strategies which aim to correct the primary defect, but also towards the identification of countless therapeutic targets with the potential to alleviate the downstream pathology. In addition to gene and cell-based therapies, which aim to deliver the missing gene and/or protein, an exciting spectrum of pharmacological approaches aimed at modulating therapeutic targets within DMD muscle cells through the use of small drugs are also being developed. This review presents promising pharmacological approaches aimed at targeting the primary defect, including suppression of nonsense mutations and functional compensation by upregulation of the dystrophin homologue, utrophin. Downstream of the primary membrane fragility, inflammation and fibrosis are reduced by blocking NF-κB, TGF-α and TGF-β, and free radical damage has been targeted using antioxidants and dietary/nutritional supplements. There are new hopes that ACE and PDE5 inhibitors can protect against skeletal as well as cardiac pathology, and modulating Ca2+ influx, NO, BMP, protein degradation and the mitochondrial permeability pore hold further promise in tackling the complex pathogenesis of this multifaceted disorder.

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“…234 Alleviating mdx muscle degeneration and necrosis by targetting calpain overactivity has been successful, using natural (calpastatin) or pharmacological means, including leupeptin, prodrug BN82270, dystrypsin (camostat mesylate) and enhanced-uptake cell-penetrating alpha-keto-amide calpain inhibitors (reviewed in Fairclough et al). 162 However, despite links between calpain inhibition and TGF-β downregulation, 235 calpastatin overexpression 236 or administration of leupeptin-carnitine conjugate C101 was ineffective in mdx 236 and GRMD 237 models. Further, calpain inhibitors are also endogenously countered via elevated proteasome activity, 164,236 which may preclude their pharmacological use.…”

Section: Protein-degradation Inhibitorsmentioning

confidence: 99%

“…162 However, despite links between calpain inhibition and TGF-β downregulation, 235 calpastatin overexpression 236 or administration of leupeptin-carnitine conjugate C101 was ineffective in mdx 236 and GRMD 237 models. Further, calpain inhibitors are also endogenously countered via elevated proteasome activity, 164,236 which may preclude their pharmacological use. Alternatively, proteasomal targeting by systemic administration of nonspecific (MG-132) and specific (bortezomib) ubiquitin ligase inhibitors effectively reduces NF-κB-mediated inflammation and restores DAPC components to the sarcolemma in mdx [238][239][240] and DMD explants.…”

Section: Protein-degradation Inhibitorsmentioning

confidence: 99%

Recent advances in Duchenne muscular dystrophy

Perkins

Davies

2012

DNND

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Duchenne muscular dystrophy (DMD), an allelic X-linked progressive musclewasting disease, is one of the most common single-gene disorders in the developed world. Despite knowledge of the underlying genetic causation and resultant pathophysiology from lack of dystrophin protein at the muscle sarcolemma, clinical intervention is currently restricted to symptom management. In recent years, however, unprecedented advances in strategies devised to correct the primary defect through gene-and cell-based therapeutics hold particular promise for treating dystrophic muscle. Conventional gene replacement and endogenous modification strategies have greatly benefited from continued improvements in encapsidation capacity, transduction efficiency, and systemic delivery. In particular, RNA-based modifying approaches such as exon skipping enable expression of a shorter but functional dystrophin protein and rapid progress toward clinical application. Emerging combined gene-and cell-therapy strategies also illustrate particular promise in enabling ex vivo genetic correction and autologous transplantation to circumvent a number of immune challenges. These approaches are complemented by a vast array of pharmacological approaches, in particular the successful identification of molecules that enable functional replacement or ameliorate secondary DMD pathology. Animal models have been instrumental in providing proof of principle for many of these strategies, leading to several recent trials that have investigated their efficacy in DMD patients. Although none has reached the point of clinical use, rapid improvements in experimental technology and design draw this goal ever closer. Here, we review therapeutic approaches to DMD, with particular emphasis on recent progress in strategic development, preclinical evaluation and establishment of clinical efficacy. Further, we discuss the numerous challenges faced and synergistic approaches being devised to combat dystrophic pathology effectively.

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T.P.4.11 Effect of calpain and proteasome inhibition on calcium-dependent proteolysis and muscle histopathology in the mdx mouse

Cited by 6 publications

References 0 publications

Leupeptin-based inhibitors do not improve the mdx phenotype

Leupeptin-based inhibitors do not improve the mdx phenotype

Pharmacologically Targeting the Primary Defect and Downstream Pathology in Duchenne Muscular Dystrophy

Recent advances in Duchenne muscular dystrophy

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