Histological assessment of SJL/J mice treated with the antioxidants coenzyme Q10 and resveratrol

Potgieter, Marnie; Pretorius, Etheresia; Merwe, C.F. van der; Beukes, Mervyn; Vieira, Warren Antonio; Auer, Roland; Auer, Manfred; Meyer, Sandra De

doi:10.1016/j.micron.2010.10.001

Cited by 19 publications

(12 citation statements)

References 38 publications

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“…In 2011, Potgieter and coworkers showed that high doses of coenzyme Q10 as well as combination resveratrol/ coenzyme Q10 markedly reduced the inflammatory insult characteristic of dysferlinopathy in the prominently affected quadriceps muscle (Potgieter et al 2011). The results of the present study show the same to be evident in less affected muscle groups.…”

Section: Discussionsupporting

confidence: 70%

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The Qualitative Effects of Resveratrol and Coenzyme Q10 Administration on the Gluteus Complex Muscle Morphology of SJL/J Mice with Dysferlinopathy

Spuy¹,

Pretorius²

2011

Int. J. Morphol.

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VAN DER SPUY, W. J. & PRETORIUS, E.The qualitative effects of resveratrol and coenzyme Q10 administration on the gluteus complex muscle morphology of SJL/J mice with dysferlinopathy. Int. J. Morphol., 29(3):876-884, 2011. SUMMARY:Dysferlinopathy is a form of muscular dystrophy affecting muscles of the shoulder and pelvic girdles, resulting from inheritance of a mutated dysferlin gene. The encoded dysferlin protein is proposed to be involved in sarcolemmal vesicle fusion with a disrupted plasma membrane; however, with defective protein function these vesicles accumulate beneath the disruption site but are unable to fuse with it and reseal the membrane, thus rendering the membrane repair mechanism defective. The SJL/J mouse model presents with characteristics much like the commonest human condition. Immune modulators have long been under study in the maintenance of muscle health in muscular dystrophies. Such supplementary treatment would ideally suppress inflammation, preventing the immune response toward degenerating muscle from causing additional muscle fiber death, and thus provide a mechanism by which to prolong the life of muscle fibers with inherently defective healing apparatus. For this purpose the anti-inflammatory supplement resveratrol and the membrane-protective supplement coenzyme Q10 were administered separately and in combination to experimental animals to determine their effectiveness in possible therapy of dysferlinopathy. The findings of this study report that low doses of resveratrol and coenzyme Q10 supplementation in exclusivity were unable to afford much protection to muscle fibers at the tissue level. High doses of coenzyme Q10 proved more effective in reducing attenuating inflammation; and combination treatment with resveratrol and coenzyme Q10 provided not only the membrane-protective effects of coenzyme Q10, but also the anti-inflammatory effects of resveratrol which failed to materialize at sufficient levels in exclusive administration.

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Section: Discussionsupporting

confidence: 70%

“…quadriceps) of dysferlinopathy (Potgieter et al, 2011). The question thus arose whether changes in morphology are visible in less affected muscle groups (i.e.…”

Section: Introductionmentioning

confidence: 99%

The Qualitative Effects of Resveratrol and Coenzyme Q10 Administration on the Gluteus Complex Muscle Morphology of SJL/J Mice with Dysferlinopathy

Spuy¹,

Pretorius²

2011

Int. J. Morphol.

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“…However, lipid peroxidation in the muscle from patients increased with the age of the patients and the duration of the disease. Treatment of the mouse model of Dysfy with antioxidants decreased the dystrophic markers and enhanced tissue integrity [48].…”

Section: Discussionmentioning

confidence: 98%

Oxidative Damage in Muscular Dystrophy Correlates with the Severity of the Pathology: Role of Glutathione Metabolism

et al. 2012

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Muscular dystrophies (MDs) such as Duchenne muscular dystrophy (DMD), sarcoglycanopathy (Sgpy) and dysferlinopathy (Dysfy) are recessive genetic neuromuscular diseases that display muscle degeneration. Although these MDs have comparable endpoints of muscle pathology, the onset, severity and the course of these diseases are diverse. Different mechanisms downstream of genetic mutations might underlie the disparity in these pathologies. We surmised that oxidative damage and altered antioxidant function might contribute to these differences. The oxidant and antioxidant markers in the muscle biopsies from patients with DMD (n = 15), Sgpy (n = 15) and Dysfy (n = 15) were compared to controls (n = 10). Protein oxidation and lipid peroxidation was evident in all MDs and correlated with the severity of pathology, with DMD, the most severe dystrophic condition showing maximum damage, followed by Sgpy and Dysfy. Oxidative damage in DMD and Sgpy was attributed to the depletion of glutathione (GSH) and lowered antioxidant activities while loss of GSH peroxidase and GSH-S-transferase activities was observed in Dysfy. Lower GSH level in DMD was due to lowered activity of gamma-glutamyl cysteine ligase, the rate limiting enzyme in GSH synthesis. Similar analysis in cardiotoxin (CTX) mouse model of MD showed that the dystrophic muscle pathology correlated with GSH depletion and lipid peroxidation. Depletion of GSH prior to CTX exposure in C2C12 myoblasts exacerbated oxidative damage and myotoxicity. We deduce that the pro and anti-oxidant mechanisms could be correlated to the severity of MD and might influence the dystrophic pathology to a different extent in various MDs. On a therapeutic note, this could help in evolving novel therapies that offer myoprotection in MD.

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“…Interestingly, the silencing of Nrf2 in the A/J resulted in an increase in X-ROS proteins (α-, β-tubulin and gp91 phox ), which may suggest a more complex interplay of redox homeostasis and the transcriptional regulation of these X-ROS-related proteins. Presently, pharmacological approaches that target single redox or ROS pathways (N-acetylcysteine, EGCG, Tocopherol) have shown mixed results in reducing the pathogenic progression of the muscular dystrophies (Scheuerbrandt, 2008), though combinatorial approaches may have better outcomes (Potgieter et al, 2011). In other diseases, genetic or pharmacological activation of Nrf2 has been shown to reduce oxidative and nitrosative stress and provide significant functional benefit (Thimmulappa et al, 2007; Sussan et al, 2009; Blake et al, 2010).…”

Section: Discussionmentioning

confidence: 99%

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

et al. 2014

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Oxidative stress is a critical disease modifier in the muscular dystrophies. Recently, we discovered a pathway by which mechanical stretch activates NADPH Oxidase 2 (Nox2) dependent ROS generation (X-ROS). Our work in dystrophic skeletal muscle revealed that X-ROS is excessive in dystrophin-deficient (mdx) skeletal muscle and contributes to muscle injury susceptibility, a hallmark of the dystrophic process. We also observed widespread alterations in the expression of genes associated with the X-ROS pathway and redox homeostasis in muscles from both Duchenne muscular dystrophy patients and mdx mice. As nuclear factor erythroid 2-related factor 2 (Nrf2) plays an essential role in the transcriptional regulation of genes involved in redox homeostasis, we hypothesized that Nrf2 deficiency may contribute to enhanced X-ROS signaling by reducing redox buffering. To directly test the effect of diminished Nrf2 activity, Nrf2 was genetically silenced in the A/J model of dysferlinopathy—a model with a mild histopathologic and functional phenotype. Nrf2-deficient A/J mice exhibited significant muscle-specific functional deficits, histopathologic abnormalities, and dramatically enhanced X-ROS compared to control A/J and WT mice, both with functional Nrf2. Having identified that reduced Nrf2 activity is a negative disease modifier, we propose that strategies targeting Nrf2 activation may address the generalized reduction in redox homeostasis to halt or slow dystrophic progression.

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Histological assessment of SJL/J mice treated with the antioxidants coenzyme Q10 and resveratrol

Cited by 19 publications

References 38 publications

The Qualitative Effects of Resveratrol and Coenzyme Q10 Administration on the Gluteus Complex Muscle Morphology of SJL/J Mice with Dysferlinopathy

The Qualitative Effects of Resveratrol and Coenzyme Q10 Administration on the Gluteus Complex Muscle Morphology of SJL/J Mice with Dysferlinopathy

Oxidative Damage in Muscular Dystrophy Correlates with the Severity of the Pathology: Role of Glutathione Metabolism

Genetic silencing of Nrf2 enhances X-ROS in dysferlin-deficient muscle

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