Eicosapentaenoic acid decreases TNF-α and protects dystrophic muscles of mdx mice from degeneration

Machado, Rafael Ventura; Maurício, Adriana Fogagnolo; Taniguti, Ana Paula Tiemi; Ferretti, Renato; Neto, Humberto Santo; Marques, Maria Júlia

doi:10.1016/j.jneuroim.2010.10.032

Cited by 39 publications

(38 citation statements)

References 44 publications

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“…These studies using other vector systems suggest an explanation for our observation of lower levels of mRNA transcripts despite equal amounts of vector DNA content in the mdx mice treated with AAV9 minidystrophin gene transfer alone. Taken together, these results plus the previously demonstrated increase in TNFα in muscles of mdx mice (16,36) suggest that mdx mice treated with AAV9 minidystrophin gene transfer and NBD peptide therapy likely had lower levels of circulating and muscle tissue TNFα that thus promoted higher levels of transgene expression from the CMV promoter.…”

Section: Discussionsupporting

confidence: 52%

Effect of Nuclear Factor κB Inhibition on Serotype 9 Adeno-Associated Viral (AAV9) Minidystrophin Gene Transfer to the mdx Mouse

Reay

Niizawa

Watchko

et al. 2012

Mol Med

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Gene therapy studies for Duchenne muscular dystrophy (DMD) have focused on viral vector-mediated gene transfer to provide therapeutic protein expression or treatment with drugs to limit dystrophic changes in muscle. The pathological activation of the nuclear factor (NF)-κB signaling pathway has emerged as an important cause of dystrophic muscle changes in muscular dystrophy. Furthermore, activation of NF-κB may inhibit gene transfer by promoting inflammation in response to the transgene or vector. Therefore, we hypothesized that inhibition of pathological NF-κB activation in muscle would complement the therapeutic benefits of dystrophin gene transfer in the mdx mouse model of DMD. Systemic gene transfer using serotype 9 adeno-associated viral (AAV9) vectors is promising for treatment of preclinical models of DMD because of vector tropism to cardiac and skeletal muscle. In quadriceps of C57BL/10ScSn-Dmd mdx /J (mdx) mice, the addition of octalysine (8K)-NF-κB essential modulator (NEMO)-binding domain (8K-NBD) peptide treatment to AAV9 minidystrophin gene delivery resulted in increased levels of recombinant dystrophin expression suggesting that 8K-NBD treatment promoted an environment in muscle tissue conducive to higher levels of expression. Indices of necrosis and regeneration were diminished with AAV9 gene delivery alone and to a greater degree with the addition of 8K-NBD treatment. In diaphragm muscle, high-level transgene expression was achieved with AAV9 minidystoophin gene delivery alone; therefore, improvements in histological and physiological indices were comparable in the two treatment groups. The data support benefit from 8K-NBD treatment to complement gene transfer therapy for DMD in muscle tissue that receives incomplete levels of transduction by gene transfer, which may be highly significant for clinical applications of muscle gene delivery.

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Section: Discussionsupporting

confidence: 52%

Effect of Nuclear Factor κB Inhibition on Serotype 9 Adeno-Associated Viral (AAV9) Minidystrophin Gene Transfer to the mdx Mouse

Reay

Niizawa

Watchko

et al. 2012

Mol Med

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“…The absence of effect of EPA on body weight gain can be due to the fact that EPA does not modify food intake in arthritic rats (Volker et al 2000, Castillero et al 2009b. A lack of effect of EPA on body weight together with a protective effect on muscle has also been reported in dystrophic muscle degeneration (Machado et al 2011). All these data suggest that the protective effect of EPA on IGF1 is not related to modifications in food intake.…”

Section: Discussionmentioning

confidence: 93%

Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1

Castillero

López-Menduiña²,

Martín³

et al. 2011

Journal of Endocrinology

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Adjuvant-induced arthritis is a chronic inflammatory illness that induces muscle wasting and decreases circulating IGF1. Eicosapentaenoic acid (EPA) and fenofibrate, a peroxisome proliferator-activated receptors a agonist, have anti-inflammatory actions and ameliorate muscle wasting in arthritic rats. The aim of this work was to elucidate whether EPA and fenofibrate administration are able to prevent the effect of arthritis on the IGF1-IGFBP system. On day 4 after adjuvant injection control, arthritic rats were gavaged with EPA (1 g/kg) or fenofibrate (300 mg/kg) until day 15 when all rats were killed. Arthritis decreased body weight gain, serum IGF1, and liver Igf1 mRNA, whereas it increased gastrocnemius Igfbp3 mRNA. EPA, but not fenofibrate, administration prevented arthritis-induced decrease in serum IGF1 and liver Igf1 mRNA. In the rats treated with EPA arthritis increased Igfbp5 mRNA in the gastrocnemius. Fenofibrate treatment decreased IGF1 and Igf1 mRNA in the liver and gastrocnemius. In arthritic rats, fenofibrate increased body weight gain and decreased gastrocnemius Igfbp3 and Igfbp5 mRNA. These data suggest that the mechanisms through which EPA and fenofibrate act on the IGF1 system and ameliorate muscle wasting in arthritic rats are different. EPA administration increased circulating levels of IGF1, whereas fenofibrate decreased the Igfbp3 and Igfbp5 in the gastrocnemius muscle.

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“…This effect is amplified in humans in which muscle is often denervated for a longer period of time. -3 PUFAs, such as eicosapentaenoic acid, have been implicated previously in muscle protection in other models, such as muscle dystrophy (Machado et al, 2011).…”

Section: Discussionmentioning

confidence: 97%

Improved Outcome after Peripheral Nerve Injury in Mice with Increased Levels of Endogenous Omega-3 Polyunsaturated Fatty Acids

Gladman¹,

Huang²,

Lim³

et al. 2012

J. Neurosci.

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Functional recovery after a peripheral nerve injury (PNI) is often poor. There is a need for therapies that protect neurons against injury and enhance regeneration. Omega-3 polyunsaturated fatty acids (PUFAs) have been shown to have therapeutic potential in a variety of neurological disorders, including acute traumatic injury. The objective of this study was to assess the neuroprotective and proregenerative potential of -3 PUFAs in PNI. We investigated this in mice that express the fat-1 gene encoding for -3 fatty acid desaturase, which leads to an increase in endogenous -3 PUFAs and a concomitant decrease in -6 PUFAs. Dorsal root ganglion (DRG) neurons from wild-type or fat-1 mice were subjected to a mechanical strain or hypoxic injury, and cell death was assessed using ethidium homodimer-1 labeling. The fat-1 background appears to confer robust neuroprotection against both injuries. We then examined the early functional and morphological changes in wild-type and fat-1 mice after a sciatic nerve crush. An accelerated functional recovery 7 d after injury was seen in fat-1 mice when assessed using von Frey filaments and the sciatic nerve functional index. These observations were also mapped to changes in injury-related markers. The injury-induced expression of ATF-3 was decreased in the DRG of fat-1 mice, whereas the axons detected 6 mm distal to the crush were increased. Fat-1 animals also had some protection against muscle atrophy after injury. In conclusion, both in vitro and in vivo experiments support the idea that a higher endogenous -3 PUFA could lead to beneficial effects after a PNI.

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Eicosapentaenoic acid decreases TNF-α and protects dystrophic muscles of mdx mice from degeneration

Cited by 39 publications

References 44 publications

Effect of Nuclear Factor κB Inhibition on Serotype 9 Adeno-Associated Viral (AAV9) Minidystrophin Gene Transfer to the mdx Mouse

Effect of Nuclear Factor κB Inhibition on Serotype 9 Adeno-Associated Viral (AAV9) Minidystrophin Gene Transfer to the mdx Mouse

Comparison of the effects of the n-3 polyunsaturated fatty acid eicosapentaenoic and fenofibrate on the inhibitory effect of arthritis on IGF1

Improved Outcome after Peripheral Nerve Injury in Mice with Increased Levels of Endogenous Omega-3 Polyunsaturated Fatty Acids

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