SIRT1: A Novel Target for the Treatment of Muscular Dystrophies

Kuno, Atsushi; Horio, Yoshiyuki

doi:10.1155/2016/6714686

Cited by 26 publications

(23 citation statements)

References 112 publications

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“…We found a strong upregulation of gp91phox (NOX2), the main source of ROS production [ 14 , 15 ], in the diaphragm of 2-week-old mdx mice compared to wild-type littermates ( Figure 1(a) ), suggesting the presence of pro-oxidant conditions during the early disease stages. This was supported by a significant reduction in SIRT1 and Nrf2 expressions (Figures 1(b) and 1(c) ), which are important mediators that promote the antioxidant response by activating several antioxidant enzymes [ 16 – 20 ].…”

Section: Resultsmentioning

confidence: 99%

Increased Circulating Levels of Interleukin‐6 Induce Perturbation in Redox‐Regulated Signaling Cascades in Muscle of Dystrophic Mice

Pelosi

Forcina

Nicoletti

et al. 2017

Oxidative Medicine and Cellular Longevity

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Duchenne muscular dystrophy (DMD) is an X-linked genetic disease in which dystrophin gene is mutated, resulting in dysfunctional or absent dystrophin protein. The pathology of dystrophic muscle includes degeneration, necrosis with inflammatory cell invasion, regeneration, and fibrous and fatty changes. Nevertheless, the mechanisms by which the absence of dystrophin leads to muscle degeneration remain to be fully elucidated. An imbalance between oxidant and antioxidant systems has been proposed as a secondary effect of DMD. However, the significance and precise extent of the perturbation in redox signaling cascades is poorly understood. We report that mdx dystrophic mice are able to activate a compensatory antioxidant response at the presymptomatic stage of the disease. In contrast, increased circulating levels of IL-6 perturb the redox signaling cascade, even prior to the necrotic stage, leading to severe features and progressive nature of muscular dystrophy.

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Section: Resultsmentioning

confidence: 99%

Increased Circulating Levels of Interleukin‐6 Induce Perturbation in Redox‐Regulated Signaling Cascades in Muscle of Dystrophic Mice

Pelosi

Forcina

Nicoletti

et al. 2017

Oxidative Medicine and Cellular Longevity

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“…Resveratrol, among others, is an antioxidant drug that has a positive role on DMD [ 36 ]; interestingly, it is a potent activator of sirtuin1 (SIRT1). Moreover, SIRT1 overexpression in muscle reverses the phenotype of mdx mice [ 37 ].…”

Section: Discussionmentioning

confidence: 99%

Role of miR‐200c in Myogenic Differentiation Impairment via p66Shc: Implication in Skeletal Muscle Regeneration of Dystrophic mdx Mice

D'agostino

Torcinaro

Madaro

et al. 2018

Oxidative Medicine and Cellular Longevity

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Duchenne muscular dystrophy (DMD) is a genetic disease associated with mutations of Dystrophin gene that regulate myofiber integrity and muscle degeneration, characterized by oxidative stress increase. We previously published that reactive oxygen species (ROS) induce miR-200c that is responsible for apoptosis and senescence. Moreover, we demonstrated that miR-200c increases ROS production and phosphorylates p66Shc in Ser-36. p66Shc plays an important role in muscle differentiation; we previously showed that p66Shc−/− muscle satellite cells display lower oxidative stress levels and higher proliferation rate and differentiated faster than wild-type (wt) cells. Moreover, myogenic conversion, induced by MyoD overexpression, is more efficient in p66Shc−/− fibroblasts compared to wt cells. Herein, we report that miR-200c overexpression in cultured myoblasts impairs skeletal muscle differentiation. Further, its overexpression in differentiated myotubes decreases differentiation indexes. Moreover, anti-miR-200c treatment ameliorates myogenic differentiation. In keeping, we found that miR-200c and p66Shc Ser-36 phosphorylation increase in mdx muscles. In conclusion, miR-200c inhibits muscle differentiation, whereas its inhibition ameliorates differentiation and its expression levels are increased in mdx mice and in differentiated human myoblasts of DMD. Therefore, miR-200c might be responsible for muscle wasting and myotube loss, most probably via a p66Shc-dependent mechanism in a pathological disease such as DMD.

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“…Furthermore, the observed upregulation of both SIRT1 and mGPAT may represent compensatory responses to combat MV‐induced oxidative stress. SIRT1, a metabolic sensor that acts as a NAD(+)‐dependent deacetylase for histone and non‐histone proteins has the ability to reduce mitochondria‐derived oxidative stress by inducing the expression of anti‐oxidant proteins, and was previously reported to decrease inflammation in mdx muscles . Increased mGPAT expression has the potential to limit mitochondrial oxidative stress through effects on fatty acid oxidation …”

Section: Discussionmentioning

confidence: 99%

“…SIRT1, a metabolic sensor that acts as a NAD(1)-dependent deacetylase for histone and non-histone proteins has the ability to reduce mitochondria-derived oxidative stress by inducing the expression of anti-oxidant proteins, [23][24][25][26] and was previously reported to decrease inflammation in mdx muscles. 27 Increased mGPAT expression has the potential to limit mitochondrial oxidative stress through effects on fatty acid oxidation. 28 Both human 4 and animal model 13 studies have previously established that upregulation of the autophagy proteolysis pathway occurs in nondystrophic diaphragms during MV.…”

Section: Discussionmentioning

confidence: 99%